Journal of Clinical Medicine Article The Inflammatory Response to Alcohol Consumption and Its Role in the Pathology of Alcohol Hangover 1,2, 1, 3 Aurora J.A.E. van de Loo y , Marlou Mackus y, Oran Kwon , Illathu Madhavamenon Krishnakumar 4 , Johan Garssen 1,5, Aletta D. Kraneveld 1 , Andrew Scholey 6 and Joris C. Verster 1,2,3,* 1 Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, 3584CG Utrecht, The Netherlands; [email protected] (A.J.A.E.v.d.L.); [email protected] (M.M.); [email protected] (J.G.); [email protected] (A.D.K.) 2 Institute for Risk Assessment Sciences (IRAS), Utrecht University, 3584CM Utrecht, The Netherlands 3 BioFood Laboratory/BioFood Network, Department of Nutritional Science and Food Management, Ewha Womans University, Seoul 120-750, Korea; [email protected] 4 Akay Natural Ingredients Private Limited, Ambunad Malaidumthuruthu, Cochin, Aluva, Kerala 683561, India; [email protected] 5 Global Centre of Excellence Immunology, Nutricia Danone Research, 3584CT Utrecht, The Netherlands 6 Centre for Human Psychopharmacology, Swinburne University, VIC 3122 Melbourne, Australia; [email protected] * Correspondence: [email protected]; Tel.: +313-0253-6909 Both authors contributed equally to the manuscript. y Received: 30 May 2020; Accepted: 30 June 2020; Published: 2 July 2020 Abstract: An increasing number of studies are focusing on the inflammatory response to alcohol as a potentially important determinant of hangover severity. In this article, data from two studies were re-evaluated to investigate the relationship between hangover severity and relevant biomarkers of alcohol metabolism, oxidative stress and the inflammatory response to alcohol. Hangover severity was significantly and positively correlated with blood concentrations of biomarkers of the inflammatory response to alcohol, in particular, Interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α) and C-reactive protein (CRP). At 4 h after alcohol consumption, blood ethanol concentration (but not acetaldehyde) was significantly and positively associated with elevated levels of IL-6, suggesting a direct inflammatory effect of ethanol. In addition, biomarkers of oxidative stress, i.e., malondialdehyde and 8-isoprostrane, were significantly correlated with hangover severity, suggesting that oxidative stress also contributes to the inflammatory response. The timing of the assessments suggests initial slow elimination of ethanol in the first hours after alcohol consumption. As a consequence, more ethanol is present in the second half of the night and the next morning, which will elicit more oxidative stress and a more profound inflammatory response. Together, these processes result in more severe hangovers. Keywords: alcohol; hangover; ethanol; acetaldehyde; acetate; oxidative stress; malondialdehyde; 8-isoprostane; cytokines; C-reactive protein 1. Introduction 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]. Reviews on the pathology of alcohol hangover [3–5] suggest that, although research is limited, both alcohol metabolism and the immune system play an important role in the development of alcohol hangover. The role of alcohol metabolism and oxidative stress are J. Clin. Med. 2020, 9, 2081; doi:10.3390/jcm9072081 www.mdpi.com/journal/jcm J. Clin. Med. 2020, 9, 2081 2 of 12 discussed elsewhere in detail [6]. These analyses revealed that higher blood concentrations of ethanol (but not acetaldehyde) and oxidative stress (a combination between depletion of antioxidants and an increase in free radicals, originating in the liver) were associated with having more severe hangovers. These processes are determined by the ethanol elimination rate. In other words, fast elimination of ethanol was associated with experiencing less severe hangovers [7]. The current analysis aimed to further elaborate the role of immune responses elicited by alcohol consumption in the development of the alcohol hangover. A possible role of the immune system in the pathology of alcohol hangover was first hypothesized in the 1980s [8,9]. Kaivola et al. [8] examined the effects of tolfenamic acid on alcohol hangover in n = 30 social drinkers. Tolfenamic acid is a non-steroidal anti-inflammatory drug (NSAID), and prostaglandin (PG) is an inhibitor used for the treatment of pain, and as such, it could be hypothesized that the drug would be helpful in mitigating related hangover symptoms. From n = 10 subjects, blood samples were also taken, and prostaglandin PGE2, PGF2α, thromboxane B2 (TXB2) and 6-keto PGF1α were determined at 0, 5, 10 and 20 h after drinking. Subjects rated the efficacy of the drug on an 11-point scale ranging from “very ineffective” to “very effective”, with subjects rating the treatment as significantly more effective than placebo. The same study further showed a significant reduction in the severity of several hangover symptoms after drug administration, with headache, dry mouth and thirst being the most drug-sensitive items. Alcohol consumption significantly increased PGE2 and TXB2 concentrations (the placebo condition). Administering tolfenamic acid partly counteracted the observed increments. No significant changes in PGF2α and 6-keto PGF1α were observed over time, and tolfenamic acid had no significant effect on these assessments. Paratainen [9] reviewed the evidence for the role of prostaglandins in hangover, which at that time was limited to the study by Kaiviola et al. [8]. The review concluded that alcohol has an effect on prostaglandin synthesis, which can be counteracted by a prostaglandin inhibitor such as tolfenamic acid. It took 20 years for other studies to confirm that alcohol consumption is accompanied by an immune response, and that elevated levels of cytokines in blood and saliva may be related to the presence and severity of the alcohol hangover. Kim et al. [10] demonstrated an inflammatory response accompanying alcohol consumption that was significantly associated with next-day hangover severity. In their study, twenty male Asian subjects had an evening of alcohol consumption (soju, a distilled beverage of Korean origin), which was compared to an alcohol-free control day. The following morning, blood samples were collected for determination of cytokine concentrations. The hangover scale consisted of two subscales, computing sum scores of ratings of subjective hangover symptoms (i.e., thirst, tension, depression and general discomfort, rated by the participant) or somatic hangover symptoms (i.e., paleness, tremor, perspiration, nystagmus, vomiting and general appearance, rated by two psychiatrists). On the hangover day, compared to the alcohol-free control day, significantly increased blood concentrations were found for interleukin (IL)-10, IL-12 and interferon-gamma (IFN-γ), whereas no significant changes were observed for IL-1β, IL-4, IL-6 or tumor necrosis factor-alpha (TNF-α). Furthermore, the increase in IL-12 and IFN-γ correlated significantly with overall hangover severity. Significant correlations with subjective hangover scale scores were found for difference scores (D, alcohol-control day) D IFN-γ, and significant correlations with somatic hangover scale scores were found for D TNF-α and D IL-12. Wiese et al. [11] examined the effects of Opuntia ficus indica (OFI) (prickly pear) on alcohol hangover, administered 5 h before alcohol consumption. OFI is used as a dietary supplement for its antioxidant and anti-inflammatory properties [12]. The authors concluded that the alcohol hangover is mediated by an inflammatory response, as they observed significant correlations between blood C-reactive protein (CRP) concentration and hangover severity. After placebo treatment, CRP levels rose by 50%, accompanied by experiencing an alcohol hangover. After administering OFI, no inflammatory response was seen (CRP levels did not differ from placebo) and several hangover symptoms were alleviated. J. Clin. Med. 2020, 9, 2081 3 of 12 George et al. [13] examined the effects of a new hangover treatment (Phyllanthus amarus, PHYLLPROTM, 750 mg/day, administered for 10 days) on hangover severity. Phyllanthus amarus is traditionally used in India for the treatment of hepatitis and jaundice, and for general liver health, and its reported effectiveness is most likely due to its antioxidant properties [14]. George et al. assessed a variety of blood cytokines the day following alcohol consumption, and hangover severity reported 10 h after drinking. In this study, IL-8, IL-10 and IL-12p70 levels were increased significantly in the active group, denoting an anti-inflammatory effect of the treatment compared to the placebo treatment alcohol challenge. Unfortunately, the authors did not report correlations between inflammatory markers and the presence or severity of alcohol hangover. Van de Loo et al. [15] examined cytokine concentration in saliva. n = 36 healthy social drinkers (18 to 30 years old) participated in a naturalistic study. Based on lifetime self-report, at screening, subjects were allocated to a hangover-sensitive group (those who reported having hangovers), or the hangover-resistant group (those reporting never having hangovers despite consuming large quantities of alcohol). The morning following an evening of alcohol consumption and an alcohol-free control day, saliva samples were collected, and cytokine concentrations were assessed. Significant increases