Introductory Note and Disclaimer: The following was written by Dr. Joris C. Verster, principal investigator at the Division of Pharmacology at Utrecht University and an expert in conducting clinical research in the area of food and pharma. Dr. Verster is the founder of the Alcohol Hangover Research Group, and also serves as a scientific advisor for Toast! Supplements. The views and opinions expressed in this article are those of Dr. Joris Verster and do not necessarily reflect the views or positions of Toast! Supplements. The following has not been edited or materially changed by Toast!.
The Alcohol Hangover
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 . The hangover can comprise a variety of symptoms including fatigue, headache, nausea, weakness, mood changes, and concentration problems. Although the presence and intensity of symptoms may differ from one drinking occasion to the other, the general feeling of malaise that characterizes the hangover state may have a significant negative impact on daily activities such as school, job performance, and driving a car. As people prefer both the pleasant experience of alcohol consumption, but at the same time like to have a normal and productive next-day, it is understandable that most drinkers advocate the development of an effective and safe hangover treatment .
Theories from the Past
The first written accounts of the alcohol hangover date back to over 3000 years ago from an Indian textbook on Vedic medicine, called the Suśruta Samhitā . And already more than a thousand years ago, the Kitab al-Tabikh, an Arab cook book, suggested to drink lemonade along with your alcohol in order to prevent hangovers . Throughout history there have been numerous accounts of proposed hangover treatments that would definitely ease or prevent the hangover state. However, those that advocated these treatments could not refer to scientific evidence to support the proposed efficacy, but instead relied on anecdotic evidence. It therefore remains unknown whether these treatments actually work or not.
It took until the 1970’s for science to investigate the pathology of alcohol hangovers in a more systematic manner, and in the 1980’s the first clinical trials investigating potential hangover treatments were conducted. For a long time it was thought that a hangover was caused by dehydration, and that consuming water would be an effective way to prevent hangovers [5,6]. In addition, supplementation of electrolytes and vitamins were thought to reduce next-day hangovers. However, today these theories are dismissed [5,6].
Current Theories on the Pathology of the Alcohol Hangover
In 2010, hangover researchers around the world united, and the Alcohol Hangover Research Group was established. This fueled research into the pathology and treatments of the alcohol hangover. It appeared that not dehydration, but alcohol metabolism and the inflammatory response associated with alcohol consumption play a critical role in the presence and severity of next day hangovers [7,8].
Alcohol consumption can elicit an inflammatory response, and research has shown that this reaction of the body is associated with the presence and severity of alcohol hangover . Recent research revealed significant relationships between the presence of substances of the immune system (cytokines) in blood and saliva and the severity of hangovers [7,9]. It is therefore likely that treatments that prevent or reduce this inflammatory response will also ease or prevent alcohol hangovers.
In addition, studies examining alcohol metabolism revealed that not the amount of acetaldehyde, a breakdown product of alcohol, but the amount of ethanol itself is critical in determining the presence and severity of hangovers . This observation is probably related to the fact that ethanol can cross the blood-brain barrier, whereas acetaldehyde does not. Drinkers that metabolize ethanol more quickly have less ethanol to enter the brain, which resulted in less severe hangovers . However, research is still investigating the role of acetaldehyde as it plays a role in oxidative stress processes in the liver that can elicit an inflammatory response [7,8].
The First Attempts to Develop an Effective Hangover Treatment
Despite the clear need for an effective hangover treatment , only a limited number of potential hangover treatments have been scientifically investigated [11-13]. These studies were often based on currently outdated theories on the pathology of the alcohol hangover. It is therefore not surprising that these studies showed that products comprised solely of electrolytes and vitamins were not effective in the treatment of hangovers.
A study on tolfenamic acid, an inhibitor of prostaglandins (lipid compounds that control processes such as inflammation), found significant reductions in headache, nausea, vomiting, and irritation . Other studies revealed that prickly pear (Opuntia ficus indica, nopal powder extract) reduces some of the hangover symptoms and prevented severe hangovers. Its effect is presumably caused by counteracting the inflammatory response produced by alcohol consumption. That is, the findings were supported by assessments of biomarkers of immune functioning in the blood (c-reactive protein), which was highly elevated in the hangover state, but remained unchanged after prickly pear was administered . These studies support the idea that the immune system is involved in the pathology of the alcohol hangover, and that products that modulate the inflammatory response to alcohol consumption may be effective hangover treatments.
The Lack of Efficacy of Currently Marketed Products
A search on Amazon evaluated hangover products that are marketed in the US . The most frequently included ingredients of these 82 products were vitamin B, vitamin C, milk thistle extract (silymarin), dihydromyricetin (DHM), and N-acetyl L-cysteine (NAC). A search of the scientific literature revealed that the efficacy of none of these products had been scientifically proven in double-blind clinical trials in human subjects. Notwithstanding the lack of (credible) scientific support, companies are marketing these products and also claim that their products are effective and safe.
Despite evidence that vitamins are ineffective, they remain among the most popular ingredients of currently marketed hangover treatments. Research also showed that DHM is not effective in reducing or preventing alcohol hangovers . Nevertheless, almost half (47.6%) of the marketed hangover products contain DHM. Another popular ingredient included in 45.1% of products is NAC. However, NAC is considered a medicine by FDA, and its inclusion in supplements is therefore prohibited in USA. Moreover, a recent study showed that NAC did not significantly reduce overall hangover severity. For most of the other ingredients of the marketed products, it remains to be determined whether these are effective in reducing or preventing hangovers.
A Note on Studies that have been Conducted
Surprisingly few double-blind studies in humans have been conducted to evaluate hangover products. Most studies that did investigate hangover products have significant methodological shortcomings [11-13]. Most notable are the improper assessment of hangover severity (assessing a random number of individual hangover symptoms rather than an overall hangover severity score) , small sample sizes, limited sample sizes (only male participants, or limited to an Asian population), or using the wrong statistics (for example testing one-sided instead of two-sided, thereby incorrectly increasing a favorable effect of the product). Therefore, the positive effects observed in some studies described below should be confirmed by additional research. Finally, some studies showed positive effects on some specific individual hangover symptoms (e.g., nausea or being tired), but did not assess overall hangover severity.
What Does Work?
Studies on hangover products found that polysaccharide-rich extract of Acanthopanax senticosus, red ginseng, Korean pear juice, KSS formula (a combination of Citrus tangerine Hort. Et Tanaka and Zingiber officinale), and After‐Effect were associated with a significant improvements of some of the hangover symptoms [11-13]. Improvement were seen for symptoms such as being tired, nausea and stomach pain. However, none of the treatments were effective in preventing all hangover symptoms. More recently, research showed that individuals with higher levels of dietary nutrient intake of niacin and zinc reported less severe hangovers . A recent pilot study also reported the efficacy of SJP-001 (a combination of naproxen and fexofenadine) . The efficacy to reduce or prevent hangovers of other popular ingredients such as milk thistle extract (silymarin) or green tea have not yet been investigated in humans.
Most hangover products comprise a combination of two or more ingredients. It is important to investigate the product as a whole, and not rely on data that evaluated the ingredients individually. On the one hand, there may be unknown interactions between ingredients that compromise safety. On the other hand, for ingredients that do not produce significant hangover relief when administered alone (such as l-cysteine  or thiamin), administering these ingredients together may release a sufficient combined effect that does significantly counteract the inflammatory response and then reduces or prevent the hangover.
Although there is increasing interest and research into the alcohol hangover, it is worrisome that most marketed hangover products have not been scientifically evaluated to demonstrate their efficacy and safety. At the same time, companies persist in promoting products based on ingredients that have shown to be ineffective in reducing of preventing hangovers such as vitamins [11-13], NAC  or DHM , or that have never been evaluated for this purpose in clinical trials in humans.
In the interest of alcohol consumers, future research should continue research on potential hangover treatments. It is important that high quality research is conducted to provide convincing and reliable scientific evidence. This means independent double-blind, placebo-controlled clinical trials with a sufficient sample size, two-sided statistical analysis, and assessment of overall hangover severity rather that a couple of individual symptoms. In the interest of the advancement of science, also the so-called ‘negative outcomes’ (that is, the product is no better than the placebo) should be published in peer-reviewed scientific journals. Recently such negative outcomes were reported for The Hangover Secret  and Rapid Recovery . These studies provide useful insight in the pathology of the alcohol hangover and can aid the development of future hangover treatments.
The current leading evidence-based theories on the pathology of the alcohol hangover suggest that the speed of alcohol metabolism and the inflammatory response to alcohol are the main causes of the presence and severity of the alcohol hangovers. Hangover products that aim to speed up ethanol breakdown and prevent the inflammatory response to alcohol are therefore most likely to be successful products to reduce or prevent hangovers. Until this has been sufficiently demonstrated for a hangover product, the best guarantee to prevent a hangover is to moderate alcohol consumption.
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