Alcohol hangover: The health impact with a historic and Chinese perspective

Introduction

A total of 2.3 billion people in the world regularly consume alcohol (WHO, 2018). Of these, 60% drink in a pattern known as heavy episodic drinking (more than 60 g (7.5 UK units) of alcohol in a single session) which means that they may experience a hangover once the effects of the alcohol intoxication has worn off.

Alcohol hangover has many definitions but all of them recognise it as a collection of negative symptoms; some of the most commonly reported are fatigue, thirst and reduced alertness and concentration problems (Penning et al., 2012). The most recent definition of alcohol hangover comes from the Alcohol Hangover Research Group ‘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 approaches zero’ (van Schrojenstein Lantman et al., 2016). This common, mostly self-afflicted phenomenon dates back over 3000 years with the earliest description being found in an Indian textbook on Vedic medicine in the Susruta Samhita (Verster, 2012). Herbs have been used to treat hangover in China for several centuries (Wang et al., 2016).

As described above, alcohol hangover is commonly experienced and therefore should be considered as a public health concern. Moreover, the long-term health impacts are largely unknown. Additionally, alcohol hangover has a societal and economic impact and was estimated to cost the US 4619 million dollars in 2010 in lost revenue due to absenteeism alone (Sacks et al., 2015). This figure is thought to be even higher when reduced productivity and poorer performance are considered. Increased likelihood of accidents is also a consequence of alcohol hangover, and recent research has demonstrated that cognitive performance is severely impacted when in a hungover state (Verster et al., 2014b).

Asians may experience more severe hangovers perhaps because of the common variations in the aldehyde dehydrogenase (ALDH2) gene that delay the clearance of this major metabolite of alcohol. See Wall et al. (2000) and below. Hangover symptoms in Asian Americans correlate to some extent with the presence of this genetic variant – see below. In this short review, we will examine the current theories underlying alcohol hangover and how hangovers may be an indication of damaged health; we also provide a comparison of these in Eastern as well as in Western populations.

Hangover in China

In the late Shang dynasty of China (1600 BC–1046 BC), heavy drinking among the nobility became popular, and that was considered a contributing factor to social disorder. Praepositus who overthrew the Shang Dynasty and established the Zhou Dynasty believed that the hangover would lead to a decline in morality and issued the earliest prohibition of alcohol in Chinese history. In traditional Chinese medicine ancient books and records, a lot of discussion on the generation and treatment of hangover can be found. For example, in the Health Care Collection, written by Zhang Zhan, who lived in the Eastern Jin Dynasty (317–420 AD), it has been recorded that excessive drinking could lead to physical weakness and mental malaise. In the Treatise on the Spleen and Stomach (written by Li Gao at 1249 AD), there is a chapter On Liquor Injury which recorded that liquor was full of heat and is poisonous if abused; hangover should be treated with medicines which promote sweating, and pueraria flower was recommended.

Current traditional Chinese medicine theories consider that hangover is caused by damp and heat in the liquor, which induces the production of turbid phlegm in the body; turbid phlegm enters into the brain and causes mental malaise, restlessness and even delirium. The treatment for this includes regulating with medicine to restore homeobalance; the recommended herbs for hangover includes pueraria flower, pueraria lobata, pseudo-ginseng, licorice, amomum cardamomum, turnjujube, etc. Researchers have been trying to screen these herbal remedies to reduce hangover, focusing on the ability to activate acetaldehyde dehydrogenase, but none of the remedies screened in vitro has the ability to alleviate hangover in vivo.

The liver is also considered to be the most important organ to dispel the effects of alcohol; some liver-protecting substances, such as tartary buckwheat flavones and oleanolic acid, are added into liquor to alleviate hangover.

How hangovers may be an indication of harm

Many people today consider hangover to be an indication of over-indulgence and a gentle (or not so gentle) reminder to drink more responsibly. Many believe that a hangover cure would encourage higher rates of intoxication leading to higher levels of alcohol dependence (Rohsenow et al., 2012). However, a recent research survey of 1837 drinking subjects reported that 71.6% who said they would purchase a potential hangover cure also said that this would not lead to an increase in their alcohol consumption (Mackus et al., 2017). Additional research has also suggested that alcohol-related negative experiences (including hangover) did not alter drinking behaviours in a cohort of 303 college students (Mallett et al., 2006). The argument of the morality of developing a hangover cure is still ongoing. However, more focus and research are needed to determine the potential health benefits of reducing the alcohol hangover.

Research into alcohol hangovers has not yet conclusively identified the mechanism of how alcohol induces these symptoms up to 23 h after it has left the body (van Schrojenstein Lantman et al., 2018a). However, there are several studies which suggest that these unwanted symptoms are actually an indicator of damaged health (oxidative stress, inflammation and carcinogenesis) (Balbo and Brooks, 2015; Karadayian et al., 2016; Penning et al., 2010; Qin et al., 2008; Wu et al., 2006). Repeated damage of this nature may have lasting health impacts that still need to be properly investigated.

Hangover is caused by alcohol (ethanol) consumption; it is therefore logical that hangover could be caused either by alcohol itself or by the breakdown products of alcohol, as these may still be present in the body during hangover, after the ethanol has been eliminated. One suggested contributor of tissue damage caused by acute alcohol consumption is acetaldehyde which is the major breakdown product of alcohol. Acetaldehyde is a highly toxic substance in its own right, and animal research has shown that in mice the level of aldehyde dehydrogenase (the enzyme that clears acetaldehyde from the blood) affects the level of hangover. Moreover, inducing the enzyme with rosiglitazone to accelerate clearance of acetaldehyde reduced hangover in rats (Jung et al., 2006). In the Asian population that has genetically lower activity of this enzyme, hangovers are reported as being especially problematic if they consume as much alcohol as those without this metabolic variant (Yokoyama et al., 2005). The ALDH2-rs671 variant, which is common in East Asian populations, greatly slows acetaldehyde breakdown, and this may make them more vulnerable to hangover severity (Millwood et al., 2019).

One way which researchers have proposed acetaldehyde leads to the symptoms of hangovers is by impairing the actions of proteins (Bajaj and Singh, 2018). Moreover, acetaldehyde can also damage DNA and this is thought to contribute to some of the toxicity caused by alcohol consumption (Freeman et al., 2005). One study which measured acetaldehyde (taken from the blood of hungover volunteers) did not find any correlation with hangover severity (Ylikahri et al., 1974a). However, this research is complicated by the fact that acetaldehyde is difficult to measure in the blood during hangover (Ylikahri et al., 1974b), and can be produced at different rates in the body by the liver and in the brain (Quertemont et al., 2005). Further research is therefore required to determine the role of acetaldehyde in the negative symptoms of alcohol hangovers.

After alcohol is converted to acetaldehyde, this is further metabolised to acetate before finally being excreted in the urine. Research using a headache model in rats has suggested that acetate rather than acetaldehyde may in fact contribute to toxicities which induce the unpleasant symptoms of a hangover (Maxwell et al., 2010). Further research is required to accurately understand how the toxic breakdown products of alcohol contribute to hangover and how they cause harm.

Many researchers have also noted the similarity between the hangover condition and the common cold or other illnesses caused by infection (Dantzer, 2004). This has led to the theory that hangover might be caused by an inflammatory reaction in the tissues as a response to high levels of alcohol consumption. It is well known that heavy alcohol consumption, like that experienced by alcoholics, can cause inflammation in the brain and can influence the immune system (Alfonso-Loeches and Guerri, 2011). Initial research which demonstrated an increase in proinflammatory systemic cytokines during hangover suggests that the immune system does play a role in hangover (Kim et al., 2003), but it remains unclear if the extent and type of immune response during hangover is similar (but on a smaller scale) to that experienced by alcoholics or whether it is different.

Alcohol hangover research is fraught with complications, establishing that a representative hangover model in animals has several limitations, for example, measuring the severity of hangover in animals is much more difficult than in humans, as most human research uses subjective hangover rating scales. Clinical investigations of hangovers are also complicated, as volunteers tend to be younger and therefore do not accurately represent all the populations which experience hangovers. The nature of alcohol consumption causing participants to act irresponsibly and be forgetful also complicates hangover research, as many participants who experience the most severe hangovers and therefore may provide the most valuable data are less likely to complete a study. Despite these limitations, alcohol hangover research is a growing field and research is underway to further understand this phenomenon.

As discussed above, there is some debate about the difference between alcohol hangover and alcohol withdrawal syndrome which occurs after the cessation of chronic alcohol consumption of an individual who is physically dependant on alcohol (De Witte et al., 2003). Many of the symptoms of withdrawal occur because of neuroadaptations which develop over the course of chronic alcohol abuse.

Alcohol withdrawal symptoms include: sleeping disturbance, tremor, restlessness, nausea, sweating, tachycardia, seizure and delirium (American Psychiatric Association, 2013). Clearly, hangover does not involve the complications of addiction which contribute to the psychological impacts of withdrawal and there are differences between the symptoms experienced (notably the lack of relapse, seizure and delirium). Therefore, further research is required to investigate if there is a similarity in the underlying neuroadaptive mechanism (potentially the upregulation of glutamate receptors) between the occurrence of these symptoms. This could provide a critical insight into the type and extent of damage that even short-term consumption of alcohol could be causing to our bodies.

The mechanisms of hangover damage proposed above are further complicated by the fact that hangovers vary greatly between individuals and some may not experience them at all (Verster et al., 2014a). Further research is needed to determine exactly what this damage is and if the body’s sensitivity or resistance to hangovers works to compound or remedy the problem. Recent investigations have suggested that there is individual variability to an individual’s sensitivity to alcohol hangovers, with around 10% of drinkers reporting to be resistant to hangovers even after high levels of consumption (estimated BAC < 0.18%) (Kruisselbrink et al., 2017; Verster et al., 2014a). Further research into metabolism difference between hangover-sensitive and -resistant individuals could hold the key to revealing its underling mechanism. Resilience and self-reported immune status have already been investigated as potential causes of inter-individual variation in hangover variability but were not shown to correlate with hangover severity (Mackus et al., 2018, van Schrojenstein Lantman et al., 2018b).

This suggests that additional investigations are required to identify why some individuals experience incapacitating symptoms following only a few drinks compared to those whose experience no negative symptoms. The topic of variation in hangover sensitivity or resistance has also raised the question amongst researchers of whether or not hangover sensitivity could predict future tendencies towards developing alcohol dependence. A recent study suggested that familial risk of alcohol use disorder was not associated with hangover severity but was associated with frequency (Stephens et al., 2017). This could indicate that there may be a genetic link between hangovers and familial history of alcohol use disorder. Additional studies are required to clarify this relationship and also that of hangover variability and its potential as a risk factor for developing dependence.

Another area of great interest is that of adding ingredients such as the extracts of DIOSCOREA OPPSITA, astragalus membranaceus, tartary buckwheat, fructus crataegi, pueraria, etc. to alcohol to reduce hangover, . This has been done in China by Jing Brand Co., Ltd with some of their high-end spirit liquors (which are called health liquors). These ingredients are derived from the centuries-old Chinese herbal pharmacopeia and as well as adding a distinctive flavour to the spirits which may help reduce hangover. Research into this possibility is currently ongoing at the Imperial College.

Conclusions

Hangover is a massive health and economic problem in most developed countries including China. To mitigate these harms, we need to properly understand alcohol hangover, so it is critical that research first addresses its underlying mechanism. If hangovers are caused by damage to tissues, this research should identify the type of tissues which are damaged and how this occurs. Research is needed to determine if multiple occurrences of this short-term damage may impact health. This will also help identify if this could be prevented, thereby identifying a potential therapeutic to avoid the unwanted symptoms. As yet there appear to have been no brain imaging studies, either fMRI or PET, on the mechanisms of hangover in humans, which is surprising given the scale of the impact of this syndrome.

Research should also seek to understand how the frequency and severity of hangovers experienced by individuals may contribute to longer term damage to health or influence disease progression. This knowledge may help researchers to understand the inter-individual variability in hangover susceptibility and what this might mean for the health of those individuals from different genetic and ethnic backgrounds. Further research in the field of alcohol hangovers is hampered by several limitations which need to be overcome. Therefore, alongside the research described above, further investigations into establishing the best tests and models for alcohol hangover are required.

It is clear that a better understanding of alcohol hangover is needed so that we can recognise the damage we may be doing to ourselves and how best to avoid it, or even protect against it. Ultimately, alcohol hangover and the search for a so-called ‘cure’ have in the past called in to question a moral issue. However, research is suggesting that the alcohol hangover is not merely a reflection of over indulgence but also a representation of the repetitive damage that we may be inflicting on our bodies. The economic impacts are also enormous and overall hangovers present an important yet largely overlooked issue for most countries.