Whenever I take up a new activity I immediately ask myself several questions: “What is smartest way to approach this? What mistakes do people often make? What is commonly known about it? What isn’t commonly known, but should be?”
When I first began drinking, my approach was not particularly sophisticated. I had two main rules:
- Drink one glass of water for every alcoholic beverage consumed.
- Learn to make drinks yourself. Homemade cocktails are both cheaper and tastier, and light beer is terrible.
Since then, as I have become more interested in the realm of health optimization, biohacking, and human physiology in general, I have learned a tremendous amount about how alcohol actually impacts our systems. Yes there are some minor health benefits, but overall it’s pretty scary stuff. But knowledge is power, and over the years I have developed a system for drinking that allows me to still experience the physical and social benefits whilst mitigating as many of the downsides as possible.
I’ve decided to share my evolving collection of research here for those fellow nerds who have an unhealthy relationship attachment style to PubMed. For those who don’t care about the “How” of hangover prevention and just want to skip to the practical dirty deets, go here:
For those fellow data junkies, enjoy!
- 1 The Basics of Alcohol Metabolism
- 2 How It Impacts The Body
- 2.1 Oxidative Stress
- 2.2 Cognitive Impact
- 2.3 Urination
- 2.4 Blood Flow
- 2.5 Magnesium Depletion
- 2.6 Glutathione / Antioxidant Depletion
- 2.7 Lipid Peroxidation
- 2.8 Congeners
- 2.9 Disruptions to Your Stomach Lining, Blood Vessels, and Blood Sugar
- 2.10 Inflammation
- 2.11 Glutamine Rebound
- 2.12 Biomarkers
- 2.13 Sleep
- 2.14 Health Risks
- 2.15 The Hangover Threshold
- 3 Mitigating its effects
- 3.1 Diet
- 3.2 Supplements
- 3.2.1 Curcumin
- 3.2.2 Vitamin C
- 3.2.3 Vitamin D
- 3.2.4 Zinc
- 3.2.5 N-Acetyl Cystine (NAC)
- 3.2.6 Green Tea (Extract)
- 3.2.7 Japanese Raisin Tree Fruit Extract
- 3.2.8 Milk Thistle
- 3.2.9 B-Vitamins
- 3.2.10 Prickly Pear
- 3.2.11 Korean Pear Juice
- 3.2.12 Red Ginseng (Panax ginseng)
- 3.2.13 L-Ornithine
- 3.2.14 Siberian Ginseng
- 3.2.15 Future Cures
- 3.2.16 NOTES
- 3.3 WARNINGS
- 4 Health Benefits of Alcohol
- 5 Resources
The Basics of Alcohol Metabolism
After consumption, alcohol is mostly absorbed in the upper GI tract and then enters the liver via the portal vein. However, contrary to popular belief, some of it still does reach the distal small intestine, and concentrations close to the colon within an hour of drinking 2.5 standard drinks (0.8g/kg) were shown to reach 200mg/ml.
The majority of alcohol metabolism occurs in cells called hepatocytes, contained in the liver. At lower levels of consumption (average of 2 drinks), the body breaks down the alcohol through a process called oxidative conversion, where the enzyme alcohol dehydrogenase (ADH) turns it into the toxic compound acetaldehyde. This is then converted into acetate by another enzyme, acetaldehyde dehydrogenase (ALDH). In each step, NAD+ is reduced to NADH, resulting in the production of some reactive oxygen species. This process typically results in few negative side effects. When larger amounts of alcohol are consumed, another metabolic pathway is used, known as the microsomal ethanol-oxidizing system, or MEOS (this pathway is also active for a small portion of light drinking), which produces a far greater quantity of reactive oxygen species. 
In addition to the liver, some enzymes for oxidative metabolism of alcohol are also present in the intestinal mucosa.
In addition, less commonly, nonoxidative alcohol metabolism occurs in the intestines via reactions with membrane phospholipids and/or free fatty acids. This alternative pathway may become particularly relevant when intestinal injuries occur after chronic alcohol consumption.
Types of Alcohol
Congeners are minor compounds other than ethanol that occur naturally in alcohol beverages as a result of distilling and fermenting processes. They tend to be present in larger quantities in the darker colored liquors, and often may increase the overall toxicity level of the beverage, resulting in more severe hangover symptoms.
Which alcohol to choose?
One study compared vodka vs wine vs beer, all consumed over 20 minutes on an empty stomach. Peak BAC (Cmax) was significantly higher (p < 0.001) after vodka/tonic (77.4 ± 17.0 mg/dl) than after wine (61.7 ± 10.8 mg/dl) or beer (50.3 ± 9.8 mg/dl) and was significantly higher (p < 0.001) after wine than beer. The time to Cmax occurred significantly earlier (p < 0.01) after vodka/tonic (36 ± 10 minutes) compared to wine (54 ± 14 minutes) or beer (62 ± 23 minutes). 
- Natural wine was shown to have a lower impact on BAC vs conventional wine. 
- Bourbon was shown to produce worse hangover symptoms than vodka 
- Wine and spirits were shown to have a greater diuretic effect than water or beer 
How It Impacts The Body
Acute and chronic ethanol treatment has been shown to increase the production of reactive oxygen species, lower cellular antioxidant levels, and enhance oxidative stress in many tissues, especially the liver. Ethanol-induced oxidative stress plays a major role in the mechanisms by which ethanol produces liver injury. 
The metabolism of ethanol to acetaldehyde and the further metabolism of acetaldehyde to acetate by aldehyde oxidase generates free radicals (reactive oxygen species), such as the superoxide anion and hydrogen peroxide, which in the presence of transition metal ions generate the hydroxyl radical which attacks acetaldehyde with acetyl and methyl radical formation.. These may contribute to alcohol-induced injury and carcinogenesis . It also results in DNA cleavage .
Alcohol use is associated with a diverse array of behavioral effects, including intoxication, motor incoordination, cognitive impairment, and tolerance and dependence. These effects are likely due to its actions on multiple brain proteins and ion channels. Gamma-aminobutyric acid (GABA) is the primary inhibatory neurotransmitter in the central nervous system (CNS). Gamma-aminobutyric acid type A (GABAA) receptors seem to occupy a central role in mediating the effects of ethanol in the CNS. This is especially likely to play a role in the development of alcohol dependence and tolerance.. Intoxicating concentrations (5–50 mM) of ethanol were shown to enhance the function of GABAA receptors .
Alcohol consumption also triggers a release of dopamine, leading to increased mood elevation. It also raises glutamine levels (a natural stimulant).
One study showed that every gram of alcohol consumed per day was linked to 0.02 years of brain aging — that's about a week of additional aging in the brain. Cumulatively, people who reported drinking every day or on most days, had about 5 months (0.4 years) of additional aging in their brains compared to people who were the same chronological age as them, but reported less frequent drinking
Alcohol inhibits the pituitary gland's secretion of vasopressin, an antidiuretic hormone that keeps you from urinating unintentionally (it is then actually increased post-drinking). When this enzyme is suppressed, water is sent right to your bladder (along with electrolytes) to be excreted, causing you to urinate more often. This can lead to dehydration.
- It was found that drinking 1L of beer increased urine production when subjects were properly hydrated but not when already dehydrated 
At intoxicating levels, alcohol is a vasodilator (it causes blood vessels to relax and widen), but at even higher levels, it becomes a vasoconstrictor, shrinking the vessels and increasing blood pressure, exacerbating such conditions as migraine headaches and .
- Regular or light-to-moderate alcohol intake increases vasorelaxation and may suppress elevated blood pressure, whereas chronic heavy alcohol consumption may raise blood pressure, causing various clinical conditions. 
- Alcohol acts acutely as a Mg diuretic, causing a prompt, vigorous increase in the urinary excretion of this metal along with that of certain other electrolytes.
- With chronic intake of alcohol and development of alcoholism, the body stores of Mg become depleted.
Glutathione / Antioxidant Depletion
When alcohol reaches the liver it gets broken down into acetaldehyde, a compound up to 30 times as toxic as alcohol itself. This then gets broken down down with the enzyme acetaldehyde dehydrogenase and glutathione, turning it into acetate. Drinking too much alcohol depletes the body’s stores of glutathione, allowing for a build-up of acetaldehyde and therefore negative impacts on the body such as hangover symptoms. 
- Reactive oxygen species are generated during ethanol metabolism. It plays a major role in ethanol-induced oxidative stress, which may be additionally enhanced by depletion of antioxidant defense system and in consequence by an imbalance between pro-oxidants and antioxidants.
- Chronic ethanol consumption by well-nourished rats for 6 wk increased enzyme activities related to the recycling and utilization of glutathione in the liver. 
- The liver level of all non-enzymatic antioxidants(GSH, ascorbate vitamins A, E and b-carotene) were shown to be decreased in mice after chronic alcohol consumption.
NOTE:Women have less acetaldehyde dehydrogenase and glutathione than men, which may lead to their being more susceptible to the effects of alcohol.
Giving ethanol to rats caused significant increase in the level of lipid peroxidation products measured as thiobarbituric reactive substances. 
Congeners are ingredients produced as byproducts of distillation and fermentation. They include acetaldehyde, acetone, tannins, and some flavorants. Congeners are thought to worsen the effects of a hangover and are found in greater amounts in darker liquors (such as brandy, whiskey, and red wine) than clear liquors like vodka or gin. One study showed that hangovers tended to be worse after drinking whiskey than after drinking vodka 
Disruptions to Your Stomach Lining, Blood Vessels, and Blood Sugar
Alcohol irritates the stomach lining and leads to increased stomach acid production. This can cause nausea, vomiting, and stomach pain. Alcohol can also lead to dips in your blood sugar level, leading to shakiness, fatigue, mood swings, and seizures. It can also cause your blood vessels to expand, sometimes triggering headaches.
Ethanol consumption leads to an accumulation of NADH. This high concentration of NADH inhibits gluconeogenesis by preventing the oxidation of lactate to pyruvate. In fact, the high concentration of NADH will cause the reverse reaction to predominate, and lactate will accumulate. The consequences may be hypoglycemia and lactic acidosis.
Both the oxidative and the nonoxidative metabolites of ethanol can affect the epithelial barrier of the small and large intestines, thereby contributing to GI and liver diseases. It can also contribute to increased permeability of intestinal mucosa  as well as disruptions to the immune system . It can even lead to gut dysbiosis and bacterial overgrowth
Alcohol provokes the body's inflammatory response, triggering the immune system and provoking hangover symptoms including memory problems, decreased appetite, and trouble concentrating.
- After drinking 1.5g/kg ethanol, blood levels of inflammatory cytokines IL-10, IL-12, and IFN-gamma were significantly increased during the hangover state compared with the concentrations in normal conditions.
- Another study showed that within 2 hours of alcohol intake, levels of IL-1Ra (an anti-inflammatory cytokine) were elevated and remained so throughout the 12 hour assessment period 
Alcohol inhibits glutamine, which normally acts as a natural stimulant in your body. This one reason why alcohol has a depressive or sedative effect.During alcohol consumption glutamine production is suppressed, then after you stop drinking, the body works overtime to increase glutamine levels, which can result in frequent wake ups during a night's sleep after you drink. A normal night of sleep averages 6-7 REM cycles. After drinking, this is reduced to an average of 2-3 cycles. This glutamine rebound may contribute to the tremors, anxiety, fatigue, restlessness, and even increased blood pressure that are often felt during a hangover.
- Hormones: Alcohol affects levels of insulin, cortisol, testosterone, aldosterone, and growth hormone
- Neurotransmitters affected by alcohol are epinephrine (adrenaline) and norepinephrine (noradrenaline)
- Alcohol can also cause hypoglycemia.
Alcohol decreased sleep efficiency and rapid eye movement sleep, and increased wake time and next-day sleepiness. 
- Chronic alcohol use can lead to a disruption of the body's circadian rhythm, which in turn can lead to many other health consequences such as increased gut permeability 
- Chronic use can lead to pancreatic enzyme insufficiency 
- Decreases retinol and retinol-binding protein (RBP4) levels in the body, which can increase risk of deficiency 
- Decreases folic acid (Vitamin B9) levels, which in turn can lead to elevated homocysteine 
- Uptake of ascorbic acid by pancreatic acinar cells is negatively impacted by chronic alcohol exposure. 
- After chronic ethanol consumption, the activity of the MEOS increases, with an associated rise in cytochrome P450, especially CYP2E1.
- Catabolism of retinol is accelerated resulting in its depletion
- Metabolism by CYP2E1 results in a significant release of free radicals which, in turn, diminishes reduced glutathione
- Individuals with sleep apnea often experience longer and more severe apneic episodes and hypoxia, or oxygen deprivation, after drinking alcohol.
Acetaldehyde can break and damage DNA within blood stem cells, permanently altering the DNA sequences within these cells. This can lead to the development of certain types of cancer. 
The Hangover Threshold
- Hangover threshold: 1g ethanol per kg bodyweight. 
- 1 drink = 14g ethanol.
Mitigating its effects
- One study found that tributyrin, a triglyceride fat found in butter, prevented alcohol-induced tight-junction disruption, which in turn protects against intestinal hyperpermeability.
- Another study found that saturated long-chain fatty acids (SLCFAs), which are found in peanut oil, coconut oil, and dairy products, are produced far less in mice fed ethanol. This was accompanied by lower levels of tight-junction proteins in the gut. Supplementing with SLCFAs fixed this problem, raising levels of tight-junction proteins, as well as preventing gut dysbiosis.
- In contrast, another study showed that consumption of unsaturated fats alongside alcohol actually increases intestinal permeability.
Drinking on a Full Stomach
Food in the stomach before drinking not only leads to a lowering of the peak BAC and diminishes the feelings of intoxication, but also boosts the rate of ethanol metabolism. One study showed that total BAC when drinking on a full stomach was 64% that of drinking after an overnight fast. The mean rate of disappearance of alcohol from the blood was also between 36-50% faster after eating.
Several rodent studies indicate that the consumption of oats may help to limit alcohol's negative effects on the digestive system. One showed that oat-fed rats had lower endotoxin levels, another showed that alcohol-fed rats given oat supplementation showed fewer signs of gut inflammation and alcohol-induced hyperpermeability than rats fed alcohol and regular rat chow. A third showed that supplementation with 'glutamine', an amino acid found in oats, lowered alcohol-induced intestinal leakiness and lessened alcohol-induced liver damage.
- Co-administration with curcumin significantly and dose-dependently prevented all the behavioral, biochemical and molecular alterations in rats chronically administered ethanol 
- Curcumin attenuates alcohol-induced liver injury via improving mitochondrial function and attenuating endoplasmic reticulum stress and inflammation. 
- low doses of curcumin may protect against liver damage caused by chronic alcohol intake and a high-fat diet partly by modulating the alcohol metabolic enzyme activity, the antioxidant activity and the lipid metabolism. 
- One study with guinea-pigs fed alcohol showed that those with the highest tissue concentration of vitamin C proved to have significantly decreased residual levels of ethanol and acetaldehyde in the liver and the brain. In contrast, other studies have shown that chronic alcohol use tends to lower Vitamin C levels.
- Vitamin C supplementation has been shown to increase glutathione levels when there is a pre-existing Vitamin C deficiency 
Higher vitamin D levels in the bloodstream correlated with increased resistance to intestinal injury.
Chronic alcohol use has been associated with zinc deficiency, and feeding zinc-deficient mice a zinc-deficient diet showed an increased intestinal permeability and higher plasma endotoxin levels .
N-Acetyl Cystine (NAC)
Take ~600mg at least 30 minutes before drinking. NAC is a form of the amino acid cysteine. Both it and Vitamin C (ascorbic acid) are precursors to glutathione and have been shown to break down the acetaldehyde that causes many hangover symptoms.
- It was shown to protect against alcohol-induced liver damage in mice when used as a pre-treatment. It may actually worsen the damage when taken post-drinking. 
- One human study showed no significant hangover improvement after ingestion of 600mg NAC post-drinking, however this would seem to make sense given that it would need to be consumed in advance of the drinking to properly upregulate glutathione production while the alcohol is in the system 
- NAC supports glutathione synthesis when the demand for glutathione is increased, as during the metabolism of acetaminophen. The same effect was observed when glutathione levels were depleted in HIV patients . However, NAC had no effect on plasma glutathione in the absence of increased stress on the glutathione pools. 
- NOTE: While NAC seems to be one of the most commonly recommended hangover-cure supplements, after doing a deep dive into the research it seems like there is no human clinical evidence towards its efficacy specifically for hangovers. It does seem to help with liver function in patients with fatty liver disease, but also might delay liver recovery when used in a prolonged fashion.
Green Tea (Extract)
Gamma-glutamyl transferase (GGT) is a marker of ethanol toxicity in cells. A compound in green tea called (-)-epigallocatechin gallate (EGCG) was shown to limit ethanol toxicity. EGCG failed to prevent the intracellular glutathione loss caused by ethanol, but it appeared to be a strong GGT inhibitor.
- Chronic consumption of alcohol increased serum ALT levels, liver levels of TNFalpha protein, as well as accumulation of protein adducts of 4-hydroxynonenal, a product of lipid peroxidation and an index of oxidative stress. All of these effects were significantly blunted by the consumption of green tea extract.
- The therapeutic effect of green tea is due to its containing catechins having polyphenolic structure, especially with two hydroxyl groups in B ring of catechin molecule. These compounds possess the ability of preventing oxygen radical formation, by inhibiting the activity of enzymes participating in their generation.. It also induces a number of enzymes, including antioxidant enzymes such as glutathione peroxidase, catalase, quinone reductase and glutathione transferase.
- Drinking green tea increased the level of GSH, vitamin E, b-carotene and total antioxidant status in comparison with the control group 
- In rats on a high fat diet, green tea administration prevented ethanol-induced increases in 4-HNE adducts to liver proteins and significantly decreased ethanol-induced liver necrosis 
Japanese Raisin Tree Fruit Extract
- Works to lower the negative impact of alcohol via regulation of lipid and inflammation metabolism. Fruit water extract (FW) and seed ethanol extract (SE) of Hovenia dulcis Thunb administered at300 and 500mg/kg/day while mice were being fed 36% calories from alcohol reduced hepatic lipid contents and droplets, serum lipid concentration and inflammatory markers. It also lowered plasma alcohol and acetaldehyde levels, hepatic enzyme activity and protein expression of CYP2E1.
- Another study with humans showed a significant decrease in hangover symptoms as well as lowering of inflammatory markers interleukin (IL)-6, IL-10, and IL-10/IL-6 ratio. Dosage used was 2460mg of Hovenia dulcis Thunb. fruit extract (HDE) after consumption of 50g alcohol (~3.5 drinks worth).
- Lowered serum alcohol concentrations in mice by upregulating ADH and ALDH 
- It might be able to counteract the effects of alcohol intoxication itself, by interfering with the way alcohol impacts GABA and the Central Nervous System 
- Silymarin, derived from the milk thistle plant, Silybium marianum, has been used in traditional medicine as a remedy for diseases of the liver and biliary tract. Medicinal use of milk thistle as a liver-protecting herb dates back to the earliest Greek references to the plant. The mechanisms involved in silymarin’s hepatoprotective effects mainly include antioxidant, anti-inflammation, and antifibrotic activity.
- In a rodent study, silymarin was shown to work alongside Vitamin C to limit ethanol toxicity, both being more effective as a preventative treatment as compared to a curative. 
- Another study showed that silymarin protects against hepatic lipid peroxidation induced by acute ethanol intoxication 
- Mice given large doses of ethanol (5g/kg) showed significant liver injury: prominent hepatic microvesicular steatosis with mild necrosis and an elevation of serum ALT activity, induced a significant decrease in hepatic GSH in conjunction with enhanced lipid peroxidation, and increased hepatic TNF production. All of these factors were attenuated by almost 40% with the administration of 200mg/kg silymarin .
- All-cause mortality reduced by 50% in patients with alcoholic liver disease taking Milk Thistle 
Especially B1 and B6 . B2 involved in glutathione recycling.
- Consuming 24g alcohol /day as vodka or red wine lowered serum vitamin B12 and folate concentrations in health males (as well as an increase in homocysteine). . It was also found to be deficient in many alcoholics 
- Moderate depletion of B12 status was shown after alcohol consumption in postmenopausal women.
- A study looking at rats fed alcohol + either a sufficient-vitamin or low-vitamin mixture found that in the sufficient-vitamin group there was no difference in B vitamin levels with or without alcohol, but in the low-vitamin group there was a decrease in the contents of vitamins B₁, B₂ and pantothenic acid in the liver, contents of vitamins B₁, B₂, B₆ and pantothenic acid in the blood, and lower excretion of all b-group vitamins in urine except for niacin. . This may
- Another study showed that ethanol consumption causes lowered plasma levels of pyridoxal 5'-phosphate, the coenzyme form of vitamin B6. Acetaldehyde acts by accelerating the degradation of intracellular pyridoxal phosphate.
- A study found that chronic alcoholic patients were deficient in folate, vitamin B6, thiamine (B1), and vitamin A.
Opuntia ficus indica (a cactus also known as prickly pear) - lowered CRP and cortisol levels, reducing risk of severe hangover by 50%. Increases heat shock protein production . Works even better with high congener counts, probably due to anti-inflammatory properties.
Korean Pear Juice
Reduced hangover symptoms, BAC, and acetaldehyde concentration. 
Red Ginseng (Panax ginseng)
- Reduces thirst, fatigue, concentration, and dizziness (anti-inflammatory).
- 32mg lowered BAC by ~25% at the 45 and 60 minute mark, no difference after that.AUC was ~20% lower. Plasma acetaldehyde went up by 30% and AUC by 25%. 40% reduction in hangover symptoms. 
- Increases the activity of ethanol dehydrogenase (a type of enzyme that helps convert ethanol to acetaldehyde) but may not increase the activity of aldehyde dehydrogenase (a type of enzyme that helps convert acetaldehyde to acetic acid)
Taking 400 mg ornithine after alcohol consumption improved various negative feelings and decreased the salivary stress marker cortisol the next morning. These effects were not caused by an increase in acute alcohol metabolism. (After drinking 0.4 g/kg body weight alcohol 1.5 hours before bed)
- This study was conducted on people with the flush response to alcohol (weak ALDH2 activity, leading to increased acetaldehyde concentrations in their system).
Also called Acanthopanax senticosus (PEA) or Eleutherococcus senticosus, this is a totally different plant from Red Ginseng. It doesn't have any impact on blood alcohol concentration (BAC), but alcohol's effect on glucose and C-reactive protein (CRP) level was significantly attenuated by PEA, and hangover symptoms were reduced. Therefore, PEA may have potential to reduce the severity of the alcohol hangover by inhibiting the alcohol-induced hypoglycemia and inflammatory response. 
- It has been shown to have anti-stress, antiulcer, anti-irradiation, anticancer, anti-inflammatory and hepatoprotective activities, etc 
- Another study showed that Nrf2 and the antioxidant enzymes were all increased significantly by medium and high doses of ASE–150 mg/kg and 300 mg/kg–but not 75mg/kg. 
Inspired by the metabolism of alcohol, a hepatocyte‐mimicking antidote for alcohol intoxication through the codelivery of the nanocapsules of alcohol oxidase (AOx), catalase (CAT), and aldehyde dehydrogenase (ALDH) to the liver, where AOx and CAT catalyze the oxidation of alcohol to acetaldehyde, while ALDH catalyzes the oxidation of acetaldehyde to acetate. This compound was shown to be quite effective at lowering BAC in mice. 
Taking these won’t stop you from getting drunk. It will just help your body to eliminate the toxic byproducts of alcohol processing in a more timely manner.
It is best to avoid using Tylenol (acetaminophen) as a hangover cure, as it puts added stress on the liver.
Health Benefits of Alcohol
- A study comparing red wine, beer, and vodka showed that all three provided similar protection against oxygen-induced increase in arterial stiffness, probably due to central vasodilatatory effect of alcohol itself, but only RW provided protection against oxygen-induced oxidative stress.