Alcohol Hangover: Underlying Biochemical, Inflammatory and Neurochemical Mechanisms

Emily Palmer; Robin Tyacke; Magdalena Sastre; Anne Lingford-Hughes; David Nutt; Roberta J. Ward

Disclosures

Alcohol Alcohol. 2019;54(3):196-203. 

In This Article

Abstract and Introduction

Abstract

Aim: To review current alcohol hangover research in animals and humans and evaluate key evidence for contributing biological factors.

Method: Narrative review with alcohol hangover defined as the state the day after a single episode of heavy drinking, when the alcohol concentration in the blood approaches zero.

Results: Many of the human studies of hangover are not well controlled, with subjects consuming different concentrations of alcohol over variable time periods and evaluation not blinded. Also, studies have measured different symptoms and use varying methods of measurement. Animal studies show variations with respect to the route of administration (intragastric or intraperitoneal), the behavioural tests utilised and discrepancy in the timepoint used for hangover onset. Human studies have the advantage over animal models of being able to assess subjective hangover severity and its correlation with specific behaviours and/or biochemical markers. However, animal models provide valuable insight into the neural mechanisms of hangover. Despite such limitations, several hangover models have identified pathological changes which correlate with the hangover state. We review studies examining the contribution of alcohol's metabolites, neurotransmitter changes with particular reference to glutamate, neuroinflammation and ingested congeners to hangover severity.

Conclusion: Alcohol metabolites, neurotransmitter alterations, inflammatory factors and mitochondrial dysfunction are the most likely factors in hangover pathology. Future research should aim to investigate the relationship between these factors and their causal role.

Introduction

Alcohol hangover is defined as the experience of various unpleasant physiological and psychological effects that follow the consumption of high quantities of alcohol. The symptoms occur several hours after alcohol consumption, ~10h, (typically after a blood alcohol content, BAC, is >0.08%) (Verster et al., 2014). Hangovers can last for several hours or even more than 24 h. Over 47 symptoms of hangover were identified (Penning et al., 2012), the most common symptoms being tiredness, headache, nausea and impaired attention (van Schrojenstein Lantman et al., 2017a, 2017b, 2018). Several of these symptoms also occur during alcohol withdrawal in dependent drinkers, when they are more severe and of longer duration, in addition to other symptoms such as severe anxiety and tension, negative emotional state, sweating and seizures (De Witte et al., 2003). Hangover also cause several neurocognitive impairments related to executive function (impairment of attention, memory and psychomotor skills) (Gunn et al., 2018) as well as everyday tasks such as driving (Mackus et al., 2016). These cognitive impairments can reduce overall performance resulting in increased accidents (Cherpitel et al., 1998), workplace absenteeism (Verster et al., 2010) and reduced productivity (Gjerde et al., 2010). Reduced productivity has a huge overall impact on society; in 2010, the US Centre of Disease Control and Prevention estimated that alcohol hangovers cost ~$179 billion (Sacks et al., 2015).

Despite having a large health and economic impact and the potential for scientific understanding and remediation, little is understood about the biochemical and neurochemical changes that occur (Verster et al., 2010). The symptoms of hangover begin several hour after the drinking session concludes, possibly when BAC falls to very low residual levels (Ylikahri et al., 1974a; Kim et al., 2003a; 2003b; Penning et al., 2010a, 2010b) or even approaches zero (van Schrojenstein Lantman et al., 2016). However, a range of biochemical and neurochemical parameters will have altered prior to the occurrence of hangover symptoms, the intensity of such alterations could reflect the severity of the hangover.

Common factors which may contribute to hangover severity are outlined in Table 1A. However, only a few have been correlated with hangover severity (Penning et al., 2010a, 2010b). Furthermore, Penning et al. (2010a, 2010b) suggested that immune factors might correlate with hangover severity since this was reduced by the inhibition of prostaglandin synthesis. Factors that have been identified as contributing to hangover severity but not being the sole mechanism of action are outlined in Table 1A. Symptoms of dehydration and sleep disturbances are commonly reported in subjects experiencing hangover, when changes in various hormones, e.g. vasopressin and cortisol, electrolytes and glucose content may be involved. Meanwhile genetic factors, e.g. individual difference in the propensity to experience hangover and of being resistant to hangover, are also important. Between 5% (Kruisselbrink et al., 2017) and 23% (Howland et al., 2008) of the population are reported to be hangover resistant and may therefore be worthy of further investigation to identify biochemical and neurochemical differences between such populations after alcohol ingestion. Some studies have indicated that urinary ethanol concentrations significantly correlates with a variety of hangover symptoms, including, nausea, concentration problems, sleepiness, weakness, apathy, sweating, stomach pain, thirst, heart racing, anxiety and sleep problems in hangover-sensitive individuals (Van de Loo et al., 2017). Ethyl glucuronide and ethyl sulphate, non-oxidative minor metabolites of ethanol metabolism (>0.1%) correlated with urinary ethanol concentration but not with overall hangover severity (Mackus et al., 2017b). Others found no correlation between breath alcohol content and hangover severity, in either hangover sensitive or hangover insensitive individuals (Mackus et al., 2018). It therefore remains to be investigated whether changes in ethanol elimination rates may be responsible for reducing hangover severity.

Other compounds within alcoholic beverages, specifically congeners, are also known to contribute to hangover severity Table 1B. Congeners are substances that are produced during distillation and fermentation, and may contribute to the symptoms of hangover induced by ethanol. High concentrations of congeners are present in red wine and dark spirits, e.g. brandy, and lowest in clear spirits such as vodka. A high content of congeners possibly results in a more severe hangover although the effect of ethanol itself will have a considerably stronger influence on hangover severity than congener content (Rohsenow and Howland, 2010; Rohsenow et al., 2010). The list of congeners includes amines, amides, acetones, acetaldehyde, polyphenol, methanol, histamines, fusel oil, esters and tannins although the contribution of each compound to alcohol hangover is unknown. Methanol is considered to be a major contributor to the symptoms of hangover (Bendtsen et al., 1998). Alcohol dehydrogenase, ADH, will metabolise methanol at a slower rate than ethanol, to form formaldehyde and formic acid both of which are highly toxic and may contribute to hangover. Young-Sup et al. (2005) assayed blood methanol in humans 13 h after ingestion of 1.5 g/kg ethanol and identified a positive correlation between methanol concentration and a subjective hangover scale. A highly significant correlation was found between the presence of headache, nausea and vertigo and urinary methanol concentration in subjects 6–11 h after ingestion of 50–80 g ethanol (Bendtsen et al., 1998), but not in other studies (Mackus et al., 2017a). Further studies on the role played by methanol on hangover severity are clearly warranted.

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