SunUp: Hangover antidote

Here’s the science behind our formula –

Introduction

Contrary to common belief, dehydration is a symptom and not a cause of hangovers.[1][2] These two phenomena are concurrent because of the diuretic effects of alcohol, but dehydration does not cause the actual hangover feeling. According to one study, “markers of dehydration (e.g., vasopressin) were not significantly related to hangover severity.”[3] Public misconceptions surrounding hangovers are not surprising since studies on hangovers remain few in number. One report notes, “Although numerous scientific papers cover the acute effects of alcohol consumption, researchers largely neglected the issue of alcohol hangover.”[4] Considering the widespread issues associated with alcohol hangover, including an estimated $249 billion in economic loss in the United States resulting from absenteeism and decreased productivity in the workplace,[5] 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 four main causes of a hangover, as far as research has shown to this point, and then explains how our product addresses each one.

 

Underlying causes of a hangover

Although scientists are still trying to fully understand hangovers, there are four main contributors that have been identified by scientific research: 1) acetaldehyde buildup, 2) glutamine rebound, 3) immunologic disturbances, and 4) vitamin and electrolyte loss.

 

  1. Acetaldehyde buildup

Acetaldehyde significantly contributes to hangovers.[6] As ethanol is broken down in the liver, this toxic molecule is created, wreaking havoc on the body. “Alcohol is metabolized in a multi-step process into various metabolites which have unique biochemical effects of their own. The first step in this process is the conversion of alcohol to acetaldehyde.”[7] This acetaldehyde is up to 30 times more toxic than ethanol.[8] It accounts for the “Asian glow,” which is a genetic deficiency in the acetaldehyde dehydrogenase enzyme in Asian populations. Acetaldehyde also interferes with functions of other molecules through a process called “cross-linking.”

The enzyme alcohol dehydrogenase breaks down alcohol into acetaldehyde, which is metabolized by aldehyde dehydrogenase into its harmless form, acetate. Acetaldehyde is reactive, and binds to biologically essential compounds.

  1. Glutamine rebound

Alcohol influences neurotransmitter systems in the brain, including glutamate receptors and the glutamate signaling pathway.[9] Glutamine (a precursor to glutamate) temporarily increases with drinking alcohol, leading to higher energy levels. After alcohol consumption is finished the glutamate receptors in the brain sense reduced glutamine signaling, leading to increased glutamine production, or so called “glutamine rebound.”[10] This frequently occurs during deep sleep, stimulating the brain and often causing drinkers to wake up earlier than their body would like. Disrupted sleep is a major cause of fatigue the next morning. Although further testing is needed, “severe glutamine rebound during a hangover may be responsible for tremors, restlessness, anxiety and increased blood pressure.”[11]

  1. Immunologic disturbances

Immunologic disturbances may occur from excess alcohol consumption as the body reacts to its toxic effects.[12] 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 (IL-10, IL-12, and IFN-gamma) is associated with the symptoms of hangovers.”[13]

Increased cytokines 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.”[14] Recent studies support a link between the immune system and central nervous system[15],[16] strengthening this conjecture. Studies have shown how the effects caused by cytokines are nearly identical to hangover symptoms, including “loss of appetite, sleepiness, withdrawal from normal social activities, fever, aching joints and fatigue.”[17] Cytokines have also been causally linked to memory impairment, in addition to mood changes.[18]

  1. Vitamin loss

Studies have shown that alcohol depletes essential vitamins[19],[20],[21] and electrolytes,[22] which play a major role in the body’s daily functions. Along with using up such nutrients in the metabolic processes required to digest alcohol, the diuretic nature of alcohol also contributes to vitamin and electrolyte loss through urination. After a night of drinking, the resulting lack of key B and C vitamins, as well as potassium, magnesium and zinc can have a devastating effect on the body. B vitamins help regulate the nervous system, form red blood cells, turn food into energy, as well as aiding in other important biological processes. Vitamin C is a key antioxidant with a variety of functions, including neuroprotective effects and regulation of blood flow. Electrolytes support vital functions in the body, such as nerve reaction, muscle function and blood pressure regulation, and a deficiency may cause fatigue, aching and other hangover-like symptoms. The loss of key antioxidants is further compounded by alcohol’s effect on free radicals: “Alcohol promotes the generation of ROS [reactive oxygen species] and/or interferes with the body’s normal defense mechanisms against these compounds through numerous processes, particularly in the liver.”[23]

 

Our shield

There has been insufficient scientific research directed at hangover prevention for two primary reasons: 1) it is hard to perform a blind test since considerable amounts of alcohol must be consumed, which cannot be concealed from the patient, and 2) it is difficult to control for all factors potentially influencing a hangover (such as meals eaten, type of alcohol, time period/ amount of consumption, weight, hereditary predisposition, sleep, etc). As a consequence, we and others have relied on studies in rodents to test effectiveness of various compounds. Of the few studies in humans, several tested hangover preventatives (including prickly pear, used by some of our competitors) demonstrated “no compelling evidence… to suggest that any conventional or complementary intervention is effective for preventing or treating alcohol hangover.”[24]

In contrast, tests of the ingredients in our dietary supplement, used in isolation or in combination, have shown some efficacy to prevent the four underlying causes of a hangover detailed above. We are the only hangover product (to our knowledge) that targets all four causes. For full disclosure, many of these studies were performed on rodents, not humans, and there is limited scientific evidence linking our ingredients directly to hangover prevention. However, our inferences on our product’s potential effectiveness are not baseless, rather making assumptions from the limited scientific research in this field.

Ingredients and use:

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Helping enzymes break down toxic acetaldehyde

A key part of our original formula stems from a study that we came across that provides evidence that sulforaphane (a compound found in cruciferous vegetables such as broccoli) helps eliminate acetaldehyde by inducing the enzyme aldehyde dehydrogenase (ALDH).[25]

Along with sulforaphane, other ingredients in our formula seek to help enzymes eliminate acetaldehyde by boosting glutathione, “the mother of all antioxidants,” 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 use glutathione precursors n-acetylcysteine (NAC),[26] vitamin C, and alanyl glutamine[27] to stimulate its production in the body.[28]

We also use NAC to combat acetaldehyde toxicity in the liver.[29],[30] “Cysteine and glutathione are active against acetaldehyde (and formaldehyde) because they contain a reduced (unoxidized) form of sulfur called a sulfhydryl group, which contains a sulfur atom bonded to a hydrogen atom.”[31] The sulfhydryl renders aldehydes unable to form cross links, which do damage to cells. Another study demonstrates how a combination of cysteine, thiamine (a sulfur-containing nutrient depleted by alcohol) and Vitamin C aid in acetaldehyde detoxification.[32]

Balancing glutamine levels

No other hangover-related product that we know of seeks to help with the glutamine rebound that disturbs sleep patterns. Glutamine stores can be increased by simply ingesting L-alanylglutamine, a dipeptide molecule of glutamine and alanine. Studies have shown that L-alanylglutamine is better absorbed in the body than L-glutamine.[33] Glutamine also acts to stabilize blood sugar levels by suppressing insulin to stop decline of sugar levels and stimulating glycogen release in order to increase blood sugar to more normal levels.[34]

Additionally, B vitamins, zinc, and magnesium are thought to deepen REM sleep,[35] which is the important part of sleep that is disrupted by glutamine rebound.

Preventing overproduction of cytokines

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.[36] The second ingredient, epigallocatechin gallate (ECGC), has shown similar results. As one study concludes: “These results indicate that ECGC suppresses LPS-induced inflammatory response and oxidant stress.”[37] For mung bean and ECGC, inflammatory cytokine reduction can likely be attributed to their anti-HMGB1[38] properties.[39][40]

Increasing electrolytes and vitamins

Our blend of vitamins and electrolytes aims to increase these essential nutrients in the body to prepare for the loss resulting from alcohol consumption. In addition to playing important roles in normal biological functions, these vitamins and electrolytes also help prevent a hangover in other ways. Zinc, Magnesium and B Vitamins, in addition to benefiting REM sleep, support the alcohol dehydrogenase enzyme that breaks down acetaldehyde.[41][42] Vitamin C, Magnesium and Zinc also serve as antioxidants, fighting the free radicals that become a problem with alcohol consumption.

Timing

Our product is designed to be taken before alcohol consumption to allow for complete update of supplements. In addition, studies have shown that ingesting NAC after alcohol consumption could cause liver damage, while NAC taken before alcohol intake may reduce liver damage.[43]

Additional Notes

Although our product acts as a shield against alcohol, it does not inhibit the pleasant feelings of intoxication. Studies have shown that the pharmacological effects of alcohol operate separately from the toxic effects.[44] In other words, you can have your beer and drink it too.

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. One study asserts, “No evidence suggests that alleviation of hangover symptoms leads to further alcohol consumption, and the discomfort caused by such symptoms may do so.”[45] In terms of our product encouraging people to drink more, we would restate that hangover symptoms do not play a major role in limiting one’s consumption of drinks per night. Of course, if one drinks to access our product cannot possibly prevent the damaging consequences. In initial self-administered trials the product is effective at relieving hangover symptoms for alcohol consumption less than 112 grams of pure alcohol per night (roughly equivalent to 8 mixed drinks). The act of taking a hangover preventative could make people more aware of their drinking habits, causing more responsible consumption, although further study is needed regarding this conjecture.

In a final note, we will add that the by-product (or congener) content in alcoholic beverages has been shown to make hangovers more severe,[46],[47] and so drinking beverages with lower congener content is highly recommended. (see charts below)

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Verster, Joris C. “The alcohol hangover–a puzzling phenomenon.” Alcohol and alcoholism 43.2 (2008): 124-126.

Conclusion

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 four underlying causes of hangover symptoms: acetaldehyde buildup, glutamine rebound, immunologic disturbances, and vitamin and electrolyte loss.

[1] Fowkes, Steven. “Living with Alcohol.” CERI: Living with Alcohol. Cognitive Enhancement Research Institute, 13 Dec. 1996. Web. 12 Dec. 2016. <http://www.ceri.com/alcohol.htm&gt;.

[2] Verster, Joris C. “The alcohol hangover–a puzzling phenomenon.” Alcohol and alcoholism 43.2 (2008): 124-126.

[3] Penning, Renske, et al. “The pathology of alcohol hangover.” Current drug abuse reviews 3.2 (2010): 68-75.

[4] Verster, Joris C. “The alcohol hangover–a puzzling phenomenon.” Alcohol and alcoholism 43.2 (2008): 124-126.

[5] “Excessive Alcohol Use Continues to Be Drain on American Economy.” Centers for Disease Control and Prevention. Centers for Disease Control and Prevention, 15 Oct. 2015. Web. 12 Dec. 2016. <http://www.cdc.gov/media/releases/2015/p1015-excessive-alcohol.html&gt;.

[6] Eriksson, C. J. “The role of acetaldehyde in the actions of alcohol (update 2000).” Alcoholism: Clinical and Experimental Research 25.s1 (2001): 15S-32S.

[7] Fowkes, Steven. “Living with Alcohol.” CERI: Living with Alcohol. Cognitive Enhancement Research Institute, 13 Dec. 1996. Web. 12 Dec. 2016. <http://www.ceri.com/alcohol.htm&gt;.

[8] Sprince, Herbert, et al. “Protection against Acetaldehyde Toxicity in the rat byl-cysteine, thiamin andl-2-Methylthiazolidine-4-carboxylic acid.” Agents and actions 4.2 (1974): 125-130.

[9] Valenzuela, C. Fernando. “Alcohol and neurotransmitter interactions.” Alcohol Research and Health 21.2 (1997): 144.

[10] “What Causes Hangovers?” Dihydromyricetin Depot | What Causes Hangovers. N.p., n.d. Web. 12 Dec. 2016. <http://dhmdepot.com/pages/what-causes-hangovers&gt;.

[11] “Hangovers – How to Lessen the Pain.” Liver Doctor. N.p., n.d. Web. 12 Dec. 2016. <https://www.liverdoctor.com/hangovers-lessen-pain/&gt;.

[12] Swift, Robert, and Dena Davidson. “Alcohol hangover.” Alcohol Health Res World 22 (1998): 54-60.

[13] Kim, Dai-Jin, et al. “Effects of alcohol hangover on cytokine production in healthy subjects.” Alcohol 31.3 (2003): 167-170.

[14] Verster, Joris C. “The alcohol hangover–a puzzling phenomenon.” Alcohol and alcoholism 43.2 (2008): 124-126.

[15] Maier, Steven F. “Bi-directional immune–brain communication: implications for understanding stress, pain, and cognition.” Brain, behavior, and immunity 17.2 (2003): 69-85.

[16] Maier, Steven F., and Linda R. Watkins. “Cytokines for psychologists: implications of bidirectional immune-to-brain communication for understanding behavior, mood, and cognition.” Psychological review 105.1 (1998): 83.

[17] Dantzer, Robert, and Keith W. Kelley. “Twenty years of research on cytokine-induced sickness behavior.” Brain, behavior, and immunity 21.2 (2007): 153-160.

[18] Reichenberg, Abraham, et al. “Cytokine-associated emotional and cognitive disturbances in humans.” Archives of general psychiatry 58.5 (2001): 445-452.

[19] Lieber, Charles S. “Relationships between nutrition, alcohol use, and liver disease.” Alcohol Research and Health 27 (2003): 220-231.

[20] Ke, Zun‐Ji, et al. “Ethanol Promotes Thiamine Deficiency‐Induced Neuronal Death: Involvement of Double‐Stranded RNA‐activated Protein Kinase.” Alcoholism: Clinical and Experimental Research 33.6 (2009): 1097-1103.

[21] Vech, R. L., Lawrence Lumeng, and Ting-Kai Li. “Vitamin B6 metabolism in chronic alcohol abuse The effect of ethanol oxidation on hepatic pyridoxal 5′-phosphate metabolism.” Journal of Clinical Investigation 55.5 (1975): 1026.

[22] Kaysen, George, and Robert H. Noth. “The effects of alcohol on blood pressure and electrolytes.” Medical Clinics of North America 68.1 (1984): 221-246.

[23] Wu, Defeng, and Arthur I. Cederbaum. “Alcohol, oxidative stress, and free radical damage.” Alcohol Research and Health 27 (2003): 277-284.

[24] Pittler, Max H., Joris C. Verster, and Edzard Ernst. “Interventions for preventing or treating alcohol hangover: systematic review of randomised controlled trials.” Bmj 331.7531 (2005): 1515-1518.

[25] Ushida, Yusuke, and Paul Talalay. “Sulforaphane accelerates acetaldehyde metabolism by inducing aldehyde dehydrogenases: relevance to ethanol intolerance.” Alcohol and alcoholism 48.5 (2013): 526-534.

[26] Frank Giorlando MBBS, BMedSc. “N-acetylcysteine in psychiatry: current therapeutic evidence and potential mechanisms of action.” Journal of psychiatry & neuroscience: JPN 36.2 (2011): 78.

[27] Yu, Jian-Chun, Zhu-Ming Jiang, and De-Min Li. “Glutamine: a precursor of glutathione and its effect on liver.” World journal of Gastroenterology 5 (1999): 143-146.

[28] http://www.huffingtonpost.com/dr-mark-hyman/glutathione-the-mother-of_b_530494.html

[29] Jaya, D. S., J. Augustine, and V. P. Menon. “Protective role of N-acetylcysteine against alcohol and paracetamol induced toxicity.” Indian Journal of Clinical Biochemistry 9.2 (1994): 64-71.

[30] Sprince H et al., Protectants against acetaldehyde toxicity: Sulfhydryl compounds and ascorbic acid. Fed Proc 33(3) (Part 1): March 1974. See also: Sprince H et al., Agents and Actions 5(2): 164-73, 1975 and Sprince H et al., Intl J Vit Nutr Res 47 (Supplement 1G): 185-212, 1977.

[31] Fowkes, Steven. “Living with Alcohol.” CERI: Living with Alcohol. Cognitive Enhancement Research Institute, 13 Dec. 1996. Web. 12 Dec. 2016. <http://www.ceri.com/alcohol.htm&gt;.

[32] Sprince H et al., Protectants against acetaldehyde toxicity: Sulfhydryl compounds and ascorbic acid. Fed Proc 33(3) (Part 1): March 1974. See also: Sprince H et al., Agents and Actions 5(2): 164-73, 1975 and Sprince H et al., Intl J Vit Nutr Res 47 (Supplement 1G): 185-212, 1977.

[33] Harris, Roger C., et al. “L-glutamine absorption is enhanced after ingestion of L-alanylglutamine compared with the free amino acid or wheat protein.” Nutrition Research 32.4 (2012): 272-277.

[34] Rotovnik Kozjek N, et al Oral glutamine supplementation during preoperative radiochemotherapy in patients with rectal cancer: a randomised double blinded, placebo controlled pilot study . Clin Nutr. (2011)

[35] Ebben, Matthew, Anthony Lequerica, and Arthur Spielman. “Effects of pyridoxine on dreaming: a preliminary study.” Perceptual and motor skills94.1 (2002): 135-140.

[36] Lee, Suk-Jun, et al. “Effect of mung bean ethanol extract on pro-inflammtory cytokines in LPS stimulated macrophages.” Food Science and Biotechnology20.2 (2011): 519-524.

[37] Liu, Qiaoli, et al. “EGCG attenuates pro-inflammatory cytokines and chemokines production in LPS-stimulated L02 hepatocyte.” Acta biochimica et biophysica Sinica 46.1 (2014): 31-39.

[38] Yang, Huan, et al. “The cytokine activity of HMGB1.” Journal of leukocyte biology 78.1 (2005): 1-8.

[39] Li, Wei, et al. “EGCG stimulates autophagy and reduces cytoplasmic HMGB1 levels in endotoxin-stimulated macrophages.” Biochemical pharmacology81.9 (2011): 1152-1163.

[40] Shu Zhu, Wei Li, Jianhua Li, Arvin Jundoria, Andrew E. Sama, and Haichao Wang, “It Is Not Just Folklore: The Aqueous Extract of Mung Bean Coat Is Protective against Sepsis,” Evidence-Based Complementary and Alternative Medicine, vol. 2012, Article ID 498467, 10 pages, 2012. doi:10.1155/2012/498467

[41] KLGI, JEREMIAS HR, and BERT L. VALLEE. “The role of zinc in alcohol dehydrogenase.” The Journal of biological chemistry 235.11 (1960).

[42] von Wartburg, Jean-Pierre, J. L. Bethune, and Bert L. Vallee. “Human Liver-Alcohol Dehydrogenase. Kinetic and Physicochemical Properties*.” Biochemistry 3.11 (1964): 1775-1782.

[43] Wang, An-Lian, et al. “A dual effect of N-acetylcysteine on acute ethanol-induced liver damage in mice.” Hepatology research 34.3 (2006): 199-206.

[44] Busnel RG and Lehman AG, Behavioral Brain Research 351-6, 1980.

[45] Wiese, Jeffrey G., Michael G. Shlipak, and Warren S. Browner. “The alcohol hangover.” Annals of internal medicine 132.11 (2000): 897-902.

[46] Damrau, Frederic, and Emma Liddy. “Hangovers and whisky congeners: comparison of whisky with vodka.” Journal of the National Medical Association 52.4 (1960): 262.

[47] Chapman, Loring F. “Experimental induction of hangover.” Quarterly Journal of Studies on Alcohol. Supplement (1970).