by Dr. Joris Verster, PhD
The alcohol hangover refers to the combination of negative mental and physical symptoms, which can be experienced after a single episode of alcohol consumption, starting when blood alcohol concentration (BAC) approaches zero [1,2]. Contrary to common belief, dehydration is an effect of alcohol consumption that may accompany the alcohol hangover state, but is nota cause of hangovers. According to one study, markers of dehydration (e.g., vasopressin) were not significantly related to hangover severity , and another more recent study revealed that the consumption of water had no impact on hangover severity of people completing an 18-km hike in Greece .
Public misconceptions surrounding hangovers are not surprising since studies on hangovers remain few in number. Although numerous scientific papers cover the acute effects of alcohol consumption, researchers largely neglected the issue of alcohol hangover. Considering the widespread issues associated with alcohol hangover, including an estimated $173 billion in economic loss in the United States resulting from absenteeism and decreased productivity in the workplace , this is both surprising and concerning. One problem with studying hangovers is that they are different for everyone and also depend on a myriad of factors such as sleep, diet, type of drink, and countless others. This paper lays out the three main causes of a hangover, as far as research has shown to this point, and then explains how Tomo®addresses each one.
Underlying causes of a hangover
Although scientists are still trying to fully understand hangovers, there are three main contributors that have been identified by scientific research : 1) oxidative stress, 2) depletion of antioxidants, and 3) immunologic disturbances due to alcohol consumption (See Figure 1). In the sections below we describe how.
Figure 1. Causes of the alcohol hangover.
Percentual changes between assessments made 12 hours after alcohol consumption relative to T0 (the assessment made before alcohol consumption) are shown. Abbreviations: CRP = C-reactive protein, IL-6 = interleukin-6, SOD = superoxide dismutase. SOURCE: Van de Loo et al. 2020, reference ).
Accelerating alcohol metabolism
Alcohol is metabolized primarily in the liver via a two-step reaction (See Figure 2).
Figure 2. Pathways involved in alcohol metabolism.
SOURCE: Verster et al. 2020, reference 
First, ethanol is oxidized into acetaldehyde, which is highly toxic. 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+and H+.
Van de Loo et al.  discussed multiple lines of evidence suggesting that the amount of ethanol present in the blood is an important determinant of hangover severity. Specifically, faster conversion of ethanol into acetaldehyde and other aldehydes is associated with having less severe hangovers . Compounds that are capable of accelerating the breakdown of ethanol are thought to contribute to experiencing less severe hangovers . Taking this into account, Tomo®contains several ingredients that support a quick breakdown of ethanol (niacin, zinc, and green tea leaf extract)and dihydromyricetin (DHM) to expedite the breakdown of acetaldehyde.
Oxidative stress and depletion of antioxidants
The conversion of ethanol into acetaldehyde involves the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS), which are both harmful for the body, and elicit an immune response . The free radicals are usually neutralized by antioxidants such as superoxide dismutase (SOD) or glutathione. The free radicals are highly reactive and combine into so-called adducts. The body recognizes these adducts as foreign substances, and as a result, an immune response is elicited [10-12], including increased secretion of cytokines and chemokines. Other important biomarkers of oxidative stress are isoprostanes. Van de Loo et al.  found significant correlations between the amount of biomarkers of oxidative stress in the blood and reported hangover severity. If ethanol metabolism was relatively slow, they found more acetaldehyde and oxidative stress the morning after drinking, which was associated with having more severe hangovers. This data supports the hypothesis behind Tomo®that administering ingredients with antioxidants properties (e.g., Vitamin C, L-cysteine) could diminish the alcohol hangover by reducing the oxidative stress reaction.
Immunologic disturbances may occur from excess alcohol consumption as the body reacts to its toxic effects . Alcohol triggers your immune system to produce an inflammatory reaction. One major sign of this process is the overproduction of cytokines, essentially the body’s immune system in overdrive, which causes physical and mental discomfort.According to one study, Concentrations of [cytokines] were significantly increased during the hangover state compared with the concentrations in normal conditions. These results support the suggestion that the dysregulated cytokine pathway (e.g., increased levels of IL-6, IL-10, and IFN-gamma in the blood) and elevated CRP are associated with the hangover severity [6, 13-14].
Scientific studies support a link between the immune system and the central nervous system,strengthening this conjecture. As a result, increased cytokine concentrations contribute not only to the discomfort of hangovers (aching and malaise), but also to the ‘cognitive’ alcohol hangover effects such as memory impairment and mood changes.Studies that have not investigated alcohol effects showed that elevation in cytokine levels has been associated to symptoms that are nearly identical to hangover symptoms, including “loss of appetite, sleepiness, withdrawal from normal social activities, fever, aching joints and fatigue [16-17].
Van de Loo et al.  demonstrated the direct link between oxidative stress and the inflammatory response to alcohol, in relation to the alcohol hangover. Several studies in humans have shown that reducing the inflammatory response is associated with experiencing less severe hangovers. Ingredients of Tomo®specifically aim to reduce the forthcoming inflammatory response (mung bean sprout powder, L-Alanyl-Glutamine, and green tea leaf extract).
There has been insufficient scientific research in humans directed at hangover prevention. As a consequence, we and others have relied primarily on studies in rodents to select various compounds, added with limited evidence from clinical trials in humans. The tests of the ingredients in our dietary supplement, used in isolation or in combination, have shown some efficacy to prevent the three underlying causes of a hangover detailed above.
Ingredients and use:
Accelerating alcohol metabolism
Two nutrients are known to play an important role in alcohol metabolism, namely nicotinic acid and zinc [18-19]. Dietary intake of these micronutrients is necessary, as the body is unable to synthesize them itself [20-21]. Since zinc is essential in the conversion of ethanol into acetaldehyde [18-19], drinkers who consume abundant amounts of dietary zinc may metabolize alcohol faster than those who consume relatively lower levels. Niacin and its equivalents, such as nicotinic acid, are the main dietary source of NAD+. For the MEOS alcohol metabolism pathway, NADP+is required. Nicotinic acid and its equivalents are the dietary sources of both NAD+and NADP+, which together catalyze alcohol metabolism. Verster et al.  found that higher dietary nicotinic acid and zinc intake was associated with experiencing less severe hangovers.
Other research in mice revealed that green tea extract speeds up alcohol metabolism. Green tea extract showed to significantly reduce blood ethanol levels 3h after alcohol consumption . In addition, green tea leaf extract non-significantly reduced acetaldehyde levels and significantly increased levels of acetate and acetone. Crude green tea extract also significantly reduced ethanol levels in liver cells.
Together it is believed that niacin, zinc, DHM, and green tea leaf extract will accelerate alcohol metabolism and thereby reduce hangover severity.
Reducing oxidative stress
In our formula, several ingredients with antioxidant properties are combined to reduce oxidative stress. Sulforaphane (a compound found in broccoli sprouts) is added as it helps to reduce oxidative stress by eliminating acetaldehyde by inducing the enzyme aldehyde dehydrogenase (ALDH) .
Mung bean sprout powder is also added for its antioxidant properties [24-26]. In addition, green tea leaf extract contains epigallocatechin gallate (EGCG), which has antioxidant properties. In rats, green tea extract showed to protect against alcohol-induced liver damage . The researchers observed that ethanol significantly increased the accumulation of protein adducts of 4-hydroxynonenal, a product of lipid peroxidation and an index of oxidative stress; green tea extract blocked this effect almost completely. An in vitro model of oxidative stress revealed that EGCG increased expression of glutathionine peroxidase 4 (GPX4) and tended to reduce the expression of SOD2 induced by ethanol .
Other ingredients in our formulaalso help enzymes eliminate acetaldehyde by boosting glutathione, an amino acid that protects cells from free radicals and helps neutralize acetaldehyde. However, because glutathione breaks down into amino acids in the stomach, we useglutathione precursors L-cysteine, vitamin C, and alanyl glutamine  to stimulate the production of antioxidants in the body .
We believe that our mix of ingredients comprises sufficient power to significantly reduce oxidative stress caused by alcohol consumption, and thereby reduce hangover severity.
Prevention of the anti-inflammatory response
Our hangover product formula also contains anti-inflammatory agents. We use two main ingredients to reduce the inflammatory cytokines that cause sickness-like symptoms. The first, mung bean powder, has been shown to decrease inflammation due to cytokines [25,31]. The second ingredient, epigallocatechin gallate (ECGC) from green tea leaf extract, has shown similar results. As one study concludes: “These results indicate that ECGC suppresses LPS-induced inflammatory response and oxidant stress” . For mung bean and ECGC, inflammatory cytokine reduction can likely be attributed to their anti-HMGB1 properties [33-34]. Finally, glutamine administration has shown to significantly reduce elevated C-reactive protein (CRP) levels after exhaustive exercise , suggesting that L-Alanyl-Glutamine could help reduce the inflammatory response caused by alcohol consumption.
Our product is designed to be taken before or during alcohol consumption to allow for complete uptake of supplements.
Although our product acts as a shield against the next-day effects of alcohol, it does not inhibit the feelings of intoxication.
Some people have suggested that a hangover cure might encourage more frequent consumption of alcohol. Based on studies, we argue that this is unlikely because hangovers do not seem to be a major factor in preventing students from drinking. Mackus et al.  examined this important issue among 1837 Dutch students and found that “Social drinkers second the need for an effective hangover treatment. However, according to the vast majority of them, the availability of an effective hangover treatment would not result in an increase of alcohol consumption”. It is therefore unlikely that our product will encourage people to drink more alcohol than they usually do.
Many of the body’s basic natural processes are overwhelmed by large quantities of alcohol, unable to carry on their usual functions, and key nutrients are depleted. Our dietary supplement helps restore balance and function to the body, allowing it to return to normal after a night of drinking by attacking the three underlying causes of hangover symptoms: oxidative stress, antioxidant depletion, and immunologic disturbances.
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