Safety From the Sunday Scaries
Using science to prevent spooky spirits from hanging over you.
No Morning-After Pains, No Liquid Courage Gains?
We’ve all been there before: lying in bed with our head pounding, our eyes begging the sun to come back later, and our stomach urging us to move to the toilet before the nachos, pizza, and potato chips from the night before find their way onto our pillow. Hangovers epitomize the give and take that is life, in that they remind us that all good things come at some type of cost. In this case, that good thing is the euphoria, socialization, and relaxation that comes from drinking alcohol, and the cost is the loss of productivity, digestive discomfort, emotional dysregulation, and outright pain that comes from a hangover. Whether it be by providing the confidence boost needed to hit on a stranger at a bar, relieving the stress of a hard day’s work, fueling a group tradition, or even supplying an excuse for lunacy, alcohol plays a major role in modern society; consequently, we have come to accept the headaches, nausea, and grumpiness that result from a night of drinking as worthy trade-offs for the benefits we reap from Natty Light’s and Jack Daniel’s alike. But, what if there was some way that we could reap those benefits without suffering through the negative consequences the morning after?
Seeing that the famed, “Halloweekend,” is approaching I figure it is about time that I do a deep dive on the science of hangovers and provide you with mechanisms and methods that you can leverage to escape the repercussions of a weekend of boozin’. I encourage you to read through the whole post, as understanding the science behind hangovers will help you implement your hangover prevention/treatment strategies; nonetheless, I imagine that some of you just want to cut to the chase, so feel free to skip to the, “Booze-Bag’s Delight,” section at the bottom of the post for the protocol summary.
Before we get started, here is a friendly disclaimer:
I am not an expert or a licensed medical professional, so nothing in this post is medical advice in any way, shape, or form. You are responsible for conducting your own research, consulting your doctor, and making your own choices.
The field of, “hangover science,” is small and receives little attention in comparison to more pressing areas of research, so many of the ideas below are theory-based.
This is all only my interpretation of the data, and — although it is backed by my understanding of biochemistry and physiology, as well as the publications cited below — you should take it with a grain of salt.
I am not in any way endorsing alcohol consumption.
So, what is a hangover? Similar to the concept I described in this post on cancer, we know hangovers for their dreaded symptoms and negative impacts, but most of us don’t think about them in terms of the physiological mechanisms associated with consuming alcohol. Sure, most of us are familiar with the idea that alcohol dehydrates us, and some may even know that this is because ethanol inhibits the antidiuretic hormone pathway; however, I predict few of us understand the remaining basics of alcohol metabolism, let alone its nuances and specifics. For that reason, we’ll start with a breakdown of how our body deals with alcohol, and the physiologic toll it acquires when doing so.
Devil’s Water 101
The Liver In Its Unnatural Habitat
In organic chemistry, the term, “alcohol,” refers to a chemical structure containing a hydroxyl group (an oxygen atom bound to a hydrogen atom) that is attached to a hydrocarbon chain containing one or more carbon atoms bound to hydrogen atoms. In terms of alcohol consumption, whenever we say, “alcohol,” we are referring to the molecule ethanol, which contains a 2-carbon hydrocarbon chain. The main pathway in ethanol metabolism consists of two steps:
Alcohol dehydrogenase (ADH) converts ethanol to acetaldehyde.
Aldehyde dehydrogenase (ALDH) converts acetaldehyde to acetic acid.
Although simple, this pathway exhibits significant physiological impacts, in that it alters the biochemical conditions in the liver and gives way to toxic by-products.
When breaking down ethanol, ADH and ALDH convert NAD+ to NADH, which leads to an increase in the NADH/NAD+ ratio within your liver cells. This ratio is important because it serves as an environmental sensor and notifies your cells of whether or not your body is in the fed state or the fasted state. If the NADH/NAD+ ratio is low, then your cells are, “under the impression,” that you are in the fasted state and biased towards catabolic processes, like breaking down stored fat and glucose. On the other hand, when the NADH/NAD+ ratio is high, the liver is switched into the fed state and biased towards anabolic processes, such as storing energy as glycogen, fatty acids, and triglycerides; additionally, during the fed state, the liver halts gluconeogenesis, the process in which your liver cells build molecules of glucose and dispense them into the bloodstream to stabilize your blood glucose levels. By altering the NADH/NAD+ ratio in your liver cells, ethanol metabolism can lead to additional physiological consequences, such as increasing lactic acid concentrations in the blood and reducing your kidneys’ abilities to filter and excrete uric acid from your blood; however, these side-effects of alcohol consumption are less discussed in the scope of a hangover.
Booze Brains
Although ethanol metabolism mainly occurs in the liver, alcohol consumption leads to physiologic effects throughout the rest of the body as well. Ethanol’s effects on your brain are most notable, as they breed the psychological, social, and emotional changes we seek when grabbing a, “Busch Latte,” or, “Rum N’ Coke.” These behavioral changes stem from ethanol inhibiting the prefrontal cortex (PFC) — the region of the brain that is responsible for decision making, judgment, planning, and action-inhibition — and result in the silly, compulsive, and sometimes unwise choices we make after downing a few drinks; interestingly, it is the incomplete development of the PFC that causes the similarly poor decision making and judgment in teenagers, and it is the ethanol-induced lack of action-inhibition in the PFC that makes alcohol a desired social lubricant.
In addition to its effects on the PFC, ethanol impacts the brain through its interactions with neurotransmitters and their receptors. Namely, ethanol acts as an agonist to gamma-aminobutyric acid (an inhibitory neurotransmitter, known as GABA) and an antagonist to glutamate (an excitatory neurotransmitter), and it increases neural concentrations of serotonin (a neurotransmitter associated with satisfaction and content) and dopamine (a neurotransmitter involved in motivation and reward). Through its many interactions with neurotransmitters and their receptors, ethanol generally turns down the action-inhibitive and cognitive portions of the brain, which are involved in memory, restraint, and motor function, and it turns up the portions involved in pleasure-seeking, relaxation, and impulsivity.
Lastly, ethanol influences the endocrine system by inhibiting the hypothalamic-pituitary axis from secreting antidiuretic hormone (also known as vasopressin) into the bloodstream. Typically, the posterior pituitary gland secretes antidiuretic hormone when your blood is over-concentrated or low in volume; consequently, your kidneys retain water during their filtering process, which dilutes your blood and restores its volume. By inhibiting antidiuretic hormone secretion, ethanol acts as a diuretic and causes your kidneys to excrete water in dilute urine, which is evidenced by your clear urine and frequent need to urinate when you drink alcohol — commonly known as, “breaking the seal.”
Fireball Blood
On top of the physiologic effects of high ethanol concentrations in the brain and the blood, the high acetaldehyde concentrations in your blood that result from alcohol consumption influence your physiology as well. Unlike ethanol, acetaldehyde cannot cross the blood-brain barrier (BBB) — a protective filter that dictates what molecules can traverse between your blood and your brain — so it does not exhibit neurocognitive effects; instead, acetaldehyde exhibits its effects by activating an inflammatory immune response. This immune response consists of a cytokine storm, in which your innate immune system — check out this post to learn more about the branches of the immune system — floods your body with macrophages and prostaglandins in an attempt to neutralize the toxic acetaldehyde molecules.
This inflammation is propagated by large doses of alcohol, as your liver resorts to activating the microsomal ethanol oxidizing system (MEOS) to metabolize the excess ethanol, during which reactive-oxygen-species (inflammatory by-products of metabolism, known as ROS) further damage your liver and provoke your already rampant immune response. ROS and inflammation are typical aspects of human physiology that your body counteracts with antioxidants, such as glutathione, vitamin C, and vitamin E, which neutralize the aforementioned inflammation; however, many of these antioxidants are water-soluble, and your body excretes them in your urine. Due to the increased urination that results from alcohol consumption, concentrations of water-soluble vitamins and minerals decrease in your body when you drink, leaving the remaining antioxidants to be overused and depleted amidst your body’s battle against acetaldehyde-induced inflammation.
Pick Your Poison
In regards to what you drink when considering the causes of a hangover, the main concern is congeners, or additional chemicals produced during ethanol production. When metabolized, these congeners activate an inflammatory response in the body and can give way to harmful byproducts; particularly, methanol, an alcohol-containing a single-carbon hydrocarbon chain, is injurious to the body because it gets metabolized into formaldehyde, a known toxin. In this study, there was a roughly 136% relative increase in hangover scores for the subjects drinking bourbon in comparison to those drinking vodka; however, the subjects drinking vodka still had a 242% relative increase in hangover symptoms in comparison to the subjects drinking the vodka placebo, so the congener content did not entirely account for the hangover symptoms. That being said, other data also shows that the discrepancies between classically high-congener alcohol — like red wine, and rum — and those with lower congener content are not as large when viewed through standard drink quantities. In other words, the difference in congener content between one standard drink worth of beer and one standard drink of whiskey is not as large as the difference in congener content between 100 grams of beer and 100 grams of whiskey.
Now, some people still claim to experience different hangover sensitivity when consuming different alcoholic beverages, such as the feared wine hangover, and others even claim to experience different types of drunkenness when drinking different alcoholic beverages; therefore, it may require some experimenting to determine how the type of alcohol you drink affects your body.
The Keys to Hangover Free Degrees
Now that you are familiar with the physiological consequences of your tequila shots and cabernet sauvignon, we can dive into some interventions that, in theory, can blunt the side-effects of alcohol consumption that lead to a hangover. After reading through some of the hangover literature, exploring alcohol-related pathways, and investigating the common hangover symptoms, I have devised five main hangover causes:
Dehydration
Inflammation
Sleep disturbance
High ethanol concentrations in the blood and brain
High acetaldehyde concentrations in the blood
Each of these potential causes is backed by mechanisms and research that either correlate with hangover sensitivity or insinuate such a correlation through biological and biochemical theory. I will break down each potential cause below, including potential actions you could take in an attempt to mitigate the hangover symptoms that might result from the aforementioned causes.
“I need water, but I can’t reach the bed stand.” - an internal hungover dialogue.
In terms of public perception, I find that dehydration is viewed as the main culprit when it comes to hangovers; however, many of the studies I read either implied a minimal or incomplete relationship between dehydration and hangover sensitivity. In addition, if you take a step back and view the situation logically, the argument for dehydration as a main cause of hangovers weakens. If dehydration is a main cause of hangovers, then why does drinking beer — a beverage that is 90% water or more — give you a hangover? Although ethanol acts as a diuretic, its effects on your kidney function are partial, not absolute, so drinking large quantities of water in beer should theoretically counterbalance at least some of that beer’s diuretic effects. Also, if dehydration is the key to hangovers, why don’t we feel hungover when we get dehydrated from athletic activity or low water intake? I am willing to bet that the average American walks around under-hydrated most of their days, so why do they not experience hangover symptoms on a daily basis? Yes, dehydration outside of drinking alcohol can cause headaches and fatigue, but it does not typically cause the remaining symptoms of a hangover, so there seems to be at least one other cause of said symptoms. Lastly, if preventing a hangover was as simple as drinking water, wouldn’t everybody just drink some water every time they went out to party to avoid the painful wake-up the following morning?
Now, there are some arguments supporting dehydration’s effects on hangover sensitivity, such as the idea that dehydration could lead to a high ethanol and acetaldehyde concentration in your blood. If this is correct, then drinking water during and the morning after drinking could help to dilute those concentrations. Finally, dehydration could contribute to a hangover by depleting your body of necessary water-soluble vitamins and minerals.
With all of this taken into account, here are my thoughts on how you might counteract dehydration’s potential hangover effects.
Drink water leading up to the period when you consume alcohol, so you are already well-hydrated by the time the ethanol-induced diuresis kicks in. Drinking water while you consume alcohol could help as well, but the more alcohol you consume, the less water you will retain, so it is likely more effective to drink water prior to a bout of drinking.
Follow the age-old recommendation to separate your alcoholic drinks with water. This will regulate how quickly you consume alcohol and reduce the tsunami of ethanol that might otherwise crash on your liver.
Consume some electrolytes and water-soluble vitamins prior to, during, and/or after drinking to mitigate the depletion of these molecules that results from ethanol-induced diuresis. By consuming electrolytes, you could also counteract that diuretic effect by encouraging your body to retain water to balance out the now higher concentration of solutes in your blood.
“Am I hungover, do I have COVID-19, or is this a typical shitty morning?” - the modern booze-bag.
As I mentioned above, alcohol consumption can lead to an inflammatory immune response in a drinker’s body, which is likely due to the acetaldehyde build-up following said alcohol consumption and possibly due to congeners in alcoholic beverages. Researchers have linked this inflammatory response to hangover outcomes in multiple publications, so it appears that it has at least some impact on whether or not you wake up wishing you spent the previous night on the couch watching re-runs of Lost instead of on the tail end of a waterfall in a game of Kings Cup. For this reason, researchers have hypothesized that raising levels of antioxidants, such as vitamin C, vitamin E, and glutathione, in the body could lighten the blow of ethanol metabolism. Due to its direct involvement in acetaldehyde metabolism and its particular antioxidant strength, glutathione seems particularly promising in regards to this hypothesis; however, glutathione is poorly absorbed in the digestive tract, so N-acetylcysteine (NAC), a precursor for glutathione, is typically utilized to raise endogenous glutathione levels. Some studies have tested the impact of antioxidant supplementation on hangover sensitivity and found minimal impact; nonetheless, the relatively strong evidence suggesting inflammation plays a role in the hangover process — as well as the results demonstrating that glutathione and vitamin E levels are depleted in subjects following alcohol consumption — implies that further and better research may reveal that supplementing with the aforementioned antioxidants decreases hangover sensitivity. For this reason, here are my theoretical propositions for how you can mitigate the inflammatory symptoms of a hangover:
Consume vitamin C, vitamin E, and/or NAC supplements prior to, during, and after a night of drinking.
Avoid NSAID’s, as some of them can damage the lining of your stomach, and most of them will add to the metabolic stress already drowning your liver.
“Did you go out last night? You look like shit.” - the fake work colleague pretending to care about you, while they relish your hungover suffering.
In recent years, an abundance of evidence has strengthened the argument that sleep plays a critical role in our health — if you are looking to learn more about this argument or sleep in general, check out this post. Unfortunately for those of us drawn to the bottle, sleep’s critical role is disturbed following alcohol consumption, as ethanol’s interactions with neurotransmitters and their receptors disrupt normal brain activity during sleep. Specifically, ethanol’s role as a glutamate antagonist is problematic for sleep, in that it creates a glutamate pressure and build-up that leads to overly excitatory signaling once the ethanol wears off. This bias towards excitatory signaling can disrupt your brain activity during sleep and your quality of sleep as a consequence. Considering poor sleep is connected to a host of health issues, it is possible that alcohol’s detrimental effects on sleep may contribute to hangover sensitivity. This idea is supported by the common anecdotes that describe individuals sleeping in or taking naps to recover from a night of drinking. Here are some suggestions regarding sleep that, in theory, could improve your hangover outcomes:
Go to bed around the same time every single day, and wake up around the same time every single day. If you are out late every weekend, then, according to neuroscientists Matthew Walker and Andrew Huberman, it will benefit you to stay up late during the week as well. This will facilitate the development of your body’s circadian rhythm and prevent a night out on the town from you throwing you off of said rhythm.
If possible drink during the day or cut yourself off of alcohol early in the evening. This will move that glutamate-overload period either before you got to sleep or earlier in your sleep period.
I am not sure if this will play a role in regards to alcohol’s effects on the brain, but Andrew Huberman often touts magnesium threonate, theanine, and apigenin as the ideal concoction for encouraging inhibitory activity in the brain. It is possible that this concoction could increase GABA and serotonin activity in the brain and ward off the previously mentioned excitatory storm until you wake up. Check out this video to learn more about Dr. Huberman’s suggestion.
“Are we okay?” - Your liver and brain wondering if this is the end of the relationship.
As I described above, high ethanol and acetaldehyde concentrations play large roles in alcohol’s physiologic impact; furthermore, many researchers point at these impacts as the main drivers of hangovers. In addition to expert opinions, many studies have correlated blood ethanol and acetaldehyde peak concentrations, as well as the duration of time in which the concentrations are elevated, with hangover sensitivity. Interestingly, these impacts likely vary from one individual to another due to genetic variance in the genes for ADH and ALDH. Those of us with alleles — different versions of a gene — that breed efficient forms of ADH and ALDH likely metabolize ethanol more efficiently and without as many negative consequences as those of us with alleles that produce less efficient versions of those enzymes. This story gets more complex though, as the combination of a rapid ADH and a slow ALDH would lead to an overflow of acetaldehyde from the first step in ethanol metabolism, and a back-up of acetaldehyde from the second step; ultimately, this combination would theoretically result in amplified negative effects of consuming alcohol. In particular, individuals of Asian descent are more prone to inherit this disadvantageous combination of ADH and ALDH alleles, which is indicated by the severe effects, such as extreme flushing and nausea, that these individuals experience after drinking even one alcoholic beverage. Some data suggests that alleles for rapid versions of ADH are protective against the risk of developing alcoholism, and it would make sense that these alleles would also protect against some of ethanol’s negative cognitive impacts; however, these benefits would theoretically be countered by detriments if those people also had alleles for the slow versions of ALDH.
In light of their contribution to ethanol metabolism and their suspected roles in hangover sensitivity, it seems that altering ADH and ALDH activity could largely influence hangover risk and severity. In this study researchers examined how different foods and drinks impacted ADH and ALDH activity in vitro — in a petri dish in a laboratory, not in live humans. The tables below depict their results in terms of percentage change in ADH and ALDH activity after each ingredient was introduced to the respective enzymes.
Cheddar cheese, pear, tomato, cucumber, onion, lime juice, and coconut water each exhibited non-trivial increases in the activity of ADH, ALDH, or both, all of which are theoretically favorable in regards to hangover prevention. Similar to the concept above regarding the genetic aspects of ADH and ALDH activity, the ideal ingredient would be one that increases both ADH and ALDH activity, and the most harmful ingredient would be one that decreases activity in both enzymes or increases activity in ADH while decreasing activity in ALDH. The authors of the study utilized these results to select optimal ingredients for a hangover-prevention concoction, which ultimately consisted of 65% pear juice, 25% lime juice, and 10% coconut water. This concoction produced a net 23.31% increase in ADH activity and 70.02% increase in ALDH activity, which the authors deemed positive signs that the concoction could successfully prevent a hangover.
Kitchen or Laboratory?
As far as I have seen, the research on how different ingredients can affect ADH and ALDH in vivo — when conducted in a living human — does not currently exist, and the aforementioned in vitro data is still too weak to be conclusive. That said according to that data, consuming cheddar cheese, pear, tomato, cucumber, onion, lime juice, and coconut water before, during, and after a bout of drinking alcohol could speed up the ADH and ALDH activity in your liver; consequently, consuming these ingredients could mitigate hangover risk and severity.
I conducted a couple of informal experiments with some friends to test this hypothesis, but I found mixed results. For Trial 1, I had the subjects utilize the following protocol:
On the Day/Night of Drinking
Drink 0.5-1 gallon of water throughout the day before drinking.
Drink a glass of Gatorade powder mixed with water prior to drinking.
Drink a glass of pear juice, lime juice, and coconut water 15 minutes prior to drinking and again 2-3 hours into the drinking session.
Eat a cheeseburger with extra cheddar cheese and an egg (high in cysteine) prior to drinking.
Eat nachos with extra cheddar cheese and chunky salsa 2-3 hours into the drinking session.
The Morning After Drinking
Drink a glass of Gatorade powder mixed with water upon waking.
Eat 3 eggs (high in cysteine) with cheddar cheese and a berry smoothie 30 minutes after waking.
The results for Trial 1 were mixed and mostly negative, and I suspect the problem may have been both in the execution of the protocol and the protocol itself. Firstly, all but one of the subjects started drinking prior to eating the cheeseburger and drinking the concoction containing pear juice, coconut water, and lime juice; additionally, 3 out of 4 of the subjects were smaller females, so consuming the amount of food and liquid in the protocol alone could have lead to negative digestive symptoms. Those females woke up the next morning with hangovers subjectively equivalent to ones they would have otherwise received — granted, they did recall consuming considerably more alcohol than usual.
The one male subject, on the other hand, is large enough to handle all of those foods and drinks, and he did not start drinking until after he ate the cheeseburger and drank the pear juice, coconut water, and lime juice concoction. On top of closely adhering to the protocol, that male subject slept for 10 hours following his bout of drinking. In addition to being the only subject to report zero hangover symptoms the following day, he reported feeling better than he would have after a night without any alcohol consumption.
In light of the results from Trial 1, I implemented changes into the protocol for Trial 2:
Drink 0.5-1 gallon of water throughout the day before drinking.
Drink a glass of Gatorade powder, vitamin-C powder, pear juice, lime juice, and coconut water with one pill of N-acetyl-cysteine 15 minutes prior to drinking.
This simplified and less demanding protocol produced a positive result, albeit with the study containing only one subject. That subject was an average-sized male and reported similar feelings to the male from Trial 1: zero hangover symptoms the following day and improved subjective condition in comparison to what he would have felt after a night without any alcohol consumption.
Now, these experiments are certainly not up to NIH-standard, as they contain countless confounding variables and lack sufficient controls — such as the total quantity of alcohol each subject consumed, the type of alcohol each subject consumed, etc.; however, in combination with the previously described research, I feel they further support the hypothesis that hydration, electrolytes, antioxidants, and ingredients that facilitate ADH and ALDH activity have potential to improve hangover sensitivity.
Booze-bag’s Delight
If you’re reading this then you likely either just slaved through more hangover mechanisms and details than you know what to do with, or you skipped to the end thinking, “screw all that bull shit, I just want to get hammered, sing my heart out at karaoke, forget any of it ever happened, then wake up feeling half-alive in the morning.” Either way, you’re eager for the finale, so here is Chari’s Hangover Prevention Protocol, which could, in theory, help you escape the uncomfortable repercussions of a night out with the girls, a break-up blackout, a Thanksgiving boozefest, and anything in between.
(Side Notes: the highlighted bullet points are those that are most important in my opinion ; some of these bullet points are not mentioned above but are commonly proposed ways to avoid and treat hangovers; this protocol and post are not comprehensive, so there are likely additional hangover interventions that could work in theory)
Prior to Drinking
Drink 0.5-1 gallon of water throughout the day before drinking.
Drink a glass of Gatorade powder, vitamin-C powder, pear juice, lime juice, and coconut water with one pill of N-acetyl-cysteine 15 minutes prior to drinking.
Take some type of multi-vitamin, vitamin B-complex, or supplement that contains the water-soluble vitamins.
Eat something, so your stomach isn’t empty.
During the Drinking
Drink water throughout the drinking session and space out your alcoholic drinks.
Drink a glass of Gatorade powder, vitamin-C powder, pear juice, lime juice, and coconut water with one pill of N-acetyl-cysteine 2-3 hours into drinking. You can also use this concoction as a chaser, or incorporate it into a mixie.
Eat or drink something with electrolytes to encourage your body to retain water.
Avoid alcoholic drinks with higher congener content (depends upon your hangover sensitivity when consuming different types of alcohol)
Either drink during the day or stop drinking earlier in the evening to limit the negative impacts that alcohol has on your sleep.
The Morning After
Eat something to replenish your electrolytes and restore your blood glucose levels.
Drink water to dilute any remaining ethanol and acetaldehyde in your blood.
Drink an antioxidant smoothie with NAC, berries, turmeric, vitamin C powder, vitamin E, and any other antioxidants you have.
Take some type of multi-vitamin, vitamin B-complex, or supplement that contains the water-soluble vitamins.
Take a nap.
Drunk Nerds
If you’re a real alcohol and hangover nerd, and all of this information wasn’t enough for you, here are some additional resources that I found interesting during this deep dive. Also, if you test out any of the hypotheses mentioned above, let me know how it goes.