Alcohol hangovers as a predictor of the development of immune-related chronic diseases

Abstract

The alcohol hangover is defined as 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 (Verster, Scholey, et al., 2020a). December 2021, the Classification and Statistics Advisory Committee (CSAC) of the International Classification of Diseases – 11th revision (ICD-11) adopted this definition and reclassified the alcohol hangover as a separate child entity to alcohol intoxication. Over the past 15 years, research on the pathology and treatment of alcohol hangover has attracted increased attention. There are, however, still major gaps in knowledge regarding its etiology and pathology. Both require further research to enable the development of effective and safe treatments to prevent or reduce the alcohol hangover.

Contrary to popular belief, the alcohol hangover is not caused by dehydration, and the consumption of water is not effective in reducing or preventing a hangover (Mackus et al., 2024). Instead, Turner et al. (2024) concluded that inflammation and associated oxidative stress together represent the main causes of the alcohol hangover. In their review, Turner et al. (2024) synthesized existing data and confirmed previous publications that reported a critical role of inflammation and alcohol metabolism in the pathology of the alcohol hangover (Mackus et al., 2020a; Van de Loo et al., 2020). Turner et al. (2024) applied the Brandford-Hill criteria to demonstrate the connection between inflammation, oxidative stress, and the alcohol hangover. This is a major strength of their review. In addition, the authors discussed the role of alcohol congeners and alcohol-associated perturbations in the microbiome, electrolytes, and sleep architecture in the development of inflammation. Turner et al. (2024) concluded that, “hangover frequency and severity may be predictors of the development of later alcohol-related diseases.” They further suggested that treatments that prevent or reduce the inflammatory response to alcohol, such as nonsteroid anti-inflammatory drugs (NSAIDs) and probiotics, may prevent hangovers or reduce their severity.

Indeed, moderate to high alcohol consumption leads to an inflammatory response which may result in hangovers. As discussed by Turner et al. (2024), several studies have demonstrated elevated blood, saliva, and urine levels of inflammatory biomarkers (e.g., Interleukin (IL)-6, C-reactive protein (CRP), and tumor necrosis factor (TNF-α) during the hangover state; e.g., Kim et al., 2003; Merlo et al., 2023; Van de Loo et al., 2021). These findings correspond with reduced self-reported immune fitness during hangover (Merlo et al., 2023). Although not fully elucidated, the role of oxidative stress in the pathology of alcohol hangover is supported empirically (Mackus et al., 2020a), and there is an established bi-directional relationship between sleep quality and immune functioning (Dickstein & Moldofsky, 1999). The relationship between immune function and congeners is less clear. As suggested by Turner et al. (2024), it is apparent that prospective studies are needed to enhance our understanding of how different factors contribute to the inflammatory response to alcohol consumption, the development of alcohol hangovers, as well as their contribution to the development of systemic inflammation.

Turner et al. (2024) also raise the possibility of alcohol disrupting the integrity of the intestinal epithelium, which functions as a line of defense preventing the entry of toxins and immune cells. While healthy epithelial cells are tightly interconnected, frequent alcohol exposure weakens this intestinal barrier, resulting in a so-called ‘leaky gut’ through which immune cells and bacterial antigens can enter the body (see Figure 1A). Through the gut-brain axis, the inflammatory response to alcohol also affects the brain. Here, in conjunction with the ethanol that crosses the blood-brain barrier, it triggers the onset of the alcohol hangover.

Turner et al. (2024) concluded that ‘hangover frequency and severity may be predictors of the development of later alcohol-related diseases’, with systemic inflammation as the primary contributor. Indeed, adequate immune fitness, that is, the capacity of the body to respond to health challenges (such as infections) by activating an appropriate immune response, is a critical determinant of health and disease (Verster et al., 2023). Experiencing hangovers has been associated with both reduced immune fitness and systemic inflammation (Merlo et al., 2023). The latter is illustrated in Figure 1B,C, showing hypothetical drinking data from two individuals.

Figure 1B shows the drinking data of an individual who has a light to moderate pattern of alcohol consumption, including occasionally experiencing hangovers. This pattern is unlikely to lead to the development of chronic systemic inflammation. The occasional hangover will correspond with a rise in levels of immune biomarkers (e.g., cytokines) and oxidative stress, but these will return to the normal range once the hangover wears off. However, in individuals who consume alcohol at higher levels and experience hangovers more frequently (see Figure 1C), the inflammatory response is no longer a discrete event. Instead, these individuals are at risk of developing a state of continuously increased levels of inflammatory markers, remaining above the critical level, and leading to a state of chronic systemic inflammation.

Figure 1B,C are hypothetical examples. In real life, there is significant variation between individuals in both ethanol metabolism and functioning of the immune system. For example, there are genetic differences in alcohol metabolism and hangover susceptibility. Other research has revealed that immune fitness is influenced by demographic factors such as sex and age, health status, and lifestyle. Therefore, more research is needed to further increase our understanding of how these various factors influence the relationship between alcohol consumption, experiencing hangovers, and the development of chronic systemic inflammation.

Turner et al. (2024) suggest a direct connection between the quantity of consumed alcohol and the development of hangovers. This is consistent with Van de Loo et al.'s (2017) finding of a significant correlation between hangover severity and ethanol concentration assessed in urine samples, although older research using blood samples reported no significant correlation with hangover severity (Ylikahri et al., 1974). Other research revealed that ‘drinking more alcohol than you usually do’ and ‘the level of subjective intoxication (drunkenness)’ were the best predictors of the presence and severity of hangovers, respectively (Verster, Kruisselbrink, et al., 2020b). Moreover, there is a consistent finding that 10%–20% of people report that they do not experience hangovers (i.e., hangover-resistant drinkers) while consuming the same amounts of alcohol as people who experience hangovers (i.e., hangover-sensitive drinkers) (Verster, Kruisselbrink, et al., 2020b). Turner et al. (2024) call for prospective studies to confirm the pathway from frequent hangovers towards the development of chronic systemic inflammation. Comparing hangover-resistant with hangover-sensitive individuals could provide important insight into the relative contribution of alcohol consumption levels, and the frequency of experiencing hangovers to systemic inflammation. Mackus et al. (2023) compared these groups and confirmed that the hangover-resistant group did not report any hangover symptoms the day after an evening of heavy alcohol consumption (except some low-level sleepiness that can be attributed to sleep loss and poor sleep quality). Conversely, the hangover-sensitive group reports a variety of hangover symptoms. The presence and severity of these symptoms varied across drinking occasions, without a clear dose-dependent relationship with the amount of alcohol consumed. With regard to immune functioning, Merlo et al. (2023) reported (after analyzing data from the same study population) that hangover-sensitive drinkers experience a significant reduction in self-reported immune fitness during the hangover state. Albeit statistically significant, the reduction of immune fitness in the hangover-resistant group was much smaller. In contrast, no significant differences in cytokine concentrations (IL-1β, IL-6, IL-8, and TNF-α) were found between the hangover sensitive and hangover resistant groups. Van de Loo et al. (2021) also reported no significant differences in cytokine concentrations between the hangover-sensitive and hangover-resistant drinkers. In both groups, there were significant increases in saliva IL-6 and IL-10 concentrations the morning after alcohol consumption. The changes in cytokine concentrations did not significantly correlate with hangover severity. Together, these findings suggest that also drinkers who do not experience hangovers may also be at increased risk of developing chronic systemic inflammation. Independent of being hangover-sensitive or hangover-resistant, higher quantity of alcohol consumption increases the likelihood of an inflammatory response. Thus, both quantity of alcohol consumed, and the frequency and severity of hangovers may play a role in the development of chronic systemic inflammation.

The fact that frequently experiencing hangovers is related to the development of chronic systemic inflammation has major health implications that should not be underestimated. Chronic systemic inflammation is one of the underlying causes of cardiovascular diseases, cancer, COVID-19, respiratory diseases, Alzheimer's disease, diabetes, liver disease, and kidney disease (Furman et al., 2019). Worldwide, these noncommunicable diseases (NCDs) account for 71% of all deaths (WHO, 2023a). In addition, the top 10 patient-reported signs and symptoms in primary care (by individuals without a chronic disease) (Finley et al., 2018), such as cough, fever, pharyngitis, and respiratory concerns, have all been related to systemic inflammation and reduced immune fitness (Wilod Versprille et al., 2019). Furthermore, the World Health Organization lists the harmful use of alcohol as a major preventable risk factor for developing chronic inflammation and NCDs (WHO, 2023b). Taken together, frequent and severe hangovers may increase the risk of susceptibility to a cluster of immune-related complaints or diseases.

Given the above, prevention of harmful drinking and experiencing fewer hangovers should be given the highest priority. Unfortunately, since the first use of alcohol, prevention measures to reduce alcohol consumption have had little success. In many countries, alcohol consumption is socially accepted, and hangovers are the most frequently reported negative consequence of overindulgence. Although not consistently found (Smith et al., 1988), experiencing hangovers does not seem to deter drinkers from consuming less alcohol on future drinking occasions (Mallett et al., 2006). In addition, with increasing frequency of experiencing hangovers, their severity (while correcting for the amount of alcohol consumed) also increases (Verster et al., 2019), suggesting reverse tolerance.

While alcohol researchers should continue to develop better strategies and therapies to reduce harmful drinking, we also agree with Turner et al. (2024) that adequate treatment of hangovers is warranted. Thus, effective and safe hangover treatments may prevent or reduce the inflammatory response associated with alcohol consumption. Turner et al. (2024) emphasize the microbiome as offering possibilities for the development of effective treatments for the hangover, for example in the form of probiotics. Also, drugs that potentially counteract the inflammatory response such as NSAIDs could be effective. Unfortunately, research in this area is limited. Turner et al. (2024) do not mention alternative strategies, such as treatments that aim to prevent or reduce the inflammatory response and oxidative stress by accelerating ethanol metabolism. When ethanol enters the brain, it is thought to elicit central inflammatory responses (Mackus et al., 2020a). These, in turn, cause cognitive hangover symptoms such as poor mood and memory deficits. In contrast, the major alcohol metabolite acetaldehyde is not capable of crossing the blood-brain barrier. As such, it can be hypothesized that treatments that accelerate ethanol metabolism will also reduce the presence and severity of these hangover symptoms. In this context, Mackus et al. (2020b) found a significant negative correlation between ethanol elimination rate and hangover severity. Only a few hangover treatments are aimed at directly reducing or preventing the inflammatory response elicited by alcohol consumption. For example, over 40 years ago, Kaivola et al. (1983) found that the non-steroidal anti-inflammatory drug (NSAID) tolfenamic acid, a prostaglandin inhibitor, significantly reduced hangover severity. A more recent pilot study in humans found positive results for SJP-001, a combination product of naproxen and fexofenadine (Verster, Dahl, et al., 2020c). However, this hangover treatment is not marketed yet, and these findings need to be confirmed in a placebo-controlled, randomized clinical trial with a greater sample size. Although some animal studies showed positive results for other compounds that accelerate ethanol metabolism or reduce the inflammatory response to alcohol consumption, these findings are yet to be confirmed in humans.

Taken together, there are currently no hangover products marketed whose efficacy is scientifically supported (Verster et al., 2021). We agree with Turner et al. (2024) that frequently experiencing hangovers increases the risk of developing chronic systemic inflammation and accompanying health risks. To support healthy aging and longevity, developing a safe and effective hangover treatment is therefore warranted.

Dr. Scholey reports personal fees from Bayer, Coca Cola, Danone, Delica Therapeutics, GlaxoSmithKline, Mars-Wrigley, Naturex, Nestlé, McCormick, Metavate Consultancy, PepsiCo, Pfizer, Pharmavite, REVIV, Sanofi, Verdure Sciences, and Wörwag Pharma outside the submitted work; and in the past 36 months Scholey has held research grants from Abbott Nutrition, Arla Foods, the Australian Research Council, Bayer, BioRevive, DuPont, Fonterra, GlaxoSmithKline, the High Value Nutrition Fund, the National Health and Medical Research Council, Nutricia-Danone, and Sanofi. Dr. Scholey is the Chief Scientific Officer for Ārepa Nootropics and is on the Scientific Advisory Board of Sen-Jam Pharmaceutical. He has stock from the Sen-Jam Pharmaceutical and Ārepa Nootropics. He has received travel support from the Ārepa Nootropics, Vitafoods, ILSI, and NutraIngredients. Dr. Verster reports personal fees from Eisai, KNMP, Med Solutions, Mozand, Sen-Jam Pharmaceutical, Red Bull, and Toast! outside the submitted work. Dr. Verster is on the scientific advisory board of Sen-Jam Pharmaceutical and Toast! He has stock from Sen-Jam Pharmaceutical. Dr. Verster has received travel support from Sen-Jam Pharmaceutical. Ms. Išerić has received travel support from Sen-Jam Pharmaceutical.