A standardized extract of the fruit of Hovenia dulcis alleviated alcohol-induced hangover in healthy subjects with heterozygous ALDH2: A randomized, controlled, crossover trial

Highlights

• The anti-hangover effect of HDE was tested on healthy subjects with heterozygous ALDH2.

• Headache, dizziness, nausea, and weakness were significantly alleviated.

• The favorable effect appeared to be associated with inflammation w/o endotoxemia.

• The magnitude of effects might be different in subjects with CYP2E1 polymorphism.

Abstract

Ethnopharmacological relevance

Hovenia dulcis, known as the oriental raisin tree, is mainly found in East Asia. It has long been used as traditional folk remedies for alcohol intoxication.

Aim of the study

To examine the anti-hangover effect of Hovenia dulcis Thunb. fruit extract (HDE) in a randomized controlled crossover trial.

Materials and methods

Twenty-six eligible male adults with heterozygous ALDH2 (23.7±0.3 years old) consumed 360 mL of Korean Soju (50 g alcohol) together with HDE (2460 mg) or matched placebo with subsequent crossover. The blood samples were taken at baseline and 1, 4, and 12 h post-treatment.

Results

Blood alcohol, acetaldehyde, and total hangover scores were highest at 1 h post-treatment with no difference between groups, but declines in hangover symptom scores were significant in the HDE group compared to the placebo group. Significant differences between groups were also observed on interleukin (IL)-6, IL-10, IL-10/IL-6 ratio, and aspartate aminotransferase levels, but not on endotoxins. Pearson correlation analysis revealed a positive correlation between total hangover symptom scores and IL-6 and IL-10 level. Further analyses by CYP2E1 polymorphism at rs10776687, rs2031920, rs3813867, and rs4838767 alleles showed a reversed association, suggesting that CYP2E1 polymorphism might be an effect modifier.

Conclusions

The results suggest that a favorable effect of HDE on alcohol hangovers might be associated with enhancing homeostatic regulation of inflammatory response. The magnitude of impact might be different in the presence of CYP2E1 polymorphism.

Introduction

There is no consensus on the definition of an alcohol hangover. However, an alcohol hangover is generally recognized as unpleasant symptoms occurring after the consumption and full metabolism of alcohol. Although a hangover might be considered trivial, it has substantial economic consequences due to decreased productivity and increased risk for injury in the workplace (Wiese et al., 2000). Frequent hangovers are also associated with increased cardiovascular and psychomotor morbidity (Kauhanen et al., 1997). The high prevalence of alcohol hangover is becoming a more important issue: over 75% of people who consume alcohol have reported that they have experienced a hangover at least once. Interestingly, hangovers are substantially more common in light-to-moderate drinkers than in heavier drinkers (Wiese et al., 2000). Therefore, comprehensive approaches in managing hangovers are required.

However, few trials have been performed to investigate the effects of foods and their constituents on alcohol hangovers. Although studies have investigated the anti-hangover effects of red ginseng (Lee et al., 2014), artichoke (Pittler et al., 2003), or Opuntia ficus-indica (Wiese et al., 2004), questions remain regarding the mechanisms of their effects. Ingested alcohol is metabolized into acetaldehyde by alcohol dehydrogenase (ADH), cytochrome P450E1 (CYP2E1) and catalase; then, acetaldehyde is oxidized into acetate primarily by aldehyde dehydrogenase (ALDH) (Zakhari, 2006). Many studies have reported that acetaldehyde (Bogin et al., 1987) or congeners (the byproducts of individual alcohol preparation) (Duhamel et al., 1984) might be associated with the frequency and severity of alcohol hangovers. Recent studies began to reveal that alcohol consumption may activate inflammation by either causing a dysfunction in the gut barrier and allowing bacterial products to enter the liver via the portal vein (Lippai et al., 2014, Zhou et al., 2003) or causing CYP2E1-induced reactive oxygen species (ROS) production in the liver (Prat et al., 2009). Furthermore, substantial individual differences were reported in alcohol hangovers and may be partly due to genetic polymorphisms in alcohol metabolic enzymes (Slutske et al., 2014). However, our current knowledge is still fragmented, and various ideas need to be connected.

Hovenia dulcis, also known as oriental raisin tree, is a perennial woody deciduous member of Hovenia genus in the family Rhamnaceae and mainly found in East Asia. It has traditionally been used as an anti-hangover herbal medicine (Shen et al., 2012), but this effect has not yet been confirmed in controlled human trials. Recently, studies began to report effects of the fruit of Hovenia dulcis on hepatoprotective activity in alcohol-induced liver injury mice (Wang et al., 2012); and suppression of lipopolysaccharide-stimulated inflammatory responses in Raw 264.7 cells (Park et al., 2016). Based on these findings, we hypothesized that a freeze-dried aqueous extract of the fruit of Hovenia dulcis Thunb. (HDE) might decrease the symptoms of alcohol hangover. To test this hypothesis, we experimentally induced hangovers and evaluated the effects of HDE on the severity of alcohol hangovers in a randomized crossover trial. Furthermore, to explore the underlying mechanism, we limited the subjects to men with heterozygous ALDH2; measured plasma endotoxin, its related proteins, and inflammatory cytokines over time; and determined the association with total hangover score. Finally, we evaluated the possible moderating influence of CYP2E1 polymorphism on the suggested relationships.