Photo credit to Isabella Mendes
[Caption] Structure of alcohol, the smallest drug molecule at only 3 non-hydrogen atoms. Black, red, and white indicate carbon, oxygen, and hydrogen atoms, respectively.
This article will address several misconceptions about alcohol relevant to personal intake. What is alcohol and what physiologically interesting compounds besides ethanol are in alcoholic beverages? What is a hangover and how can it be avoided or cured? Is a glass of red wine per day healthy?
This article cites little original research. To write a proper literature review on subject matter of this breadth requires a far higher word count and more subject matter expertise than I have. Therefore, this article cites mostly review articles, peer-reviewed articles which present a subject matter expert's view of the state of the science.
Unlike the other articles on drugs, I discovered I was wrong on almost every question in this article as I did the research. Most of the questions addressed in other articles were interesting because I did not know anything about them. Prior to these articles I knew nothing about the relative rates of absorbtion of oral vs sublingual caffeine or the pharmacological variety of cannabinoid compounds. However, I was sure that all alcohols had an equal propensity for hangovers (provided they were dosed equally) and I was certain alcohol consumption, no matter how mild, was a net negative. Neither of these positions is supported by peer-reviewed studies. Correcting misapprehensions is a fundamentally different exercise than simply learning new information because old information must be unlearned before new information can be incorporated. The more confidence one has in their confusions, the more difficult this process is. Writing this piece forced my confidently-held misapprehensions to collide with reality more frequently than anything I have done in recent memory.
Ethanol was the first known chemical purposefully synthesized by early man [1]. Early fermentations are our species first known use of a reaction vessel (a container to hold the reactants of a reaction together and capture the products) and first known use of micro-organisms for chemical production (biochemical engineering). Obviously this was first done without any knowledge of chemistry or microbes but alcohol was our first step as a species between foraging for necessary chemical substrates and externally synthesizing them. It was also our species first step into addictive and intoxicating chemicals; alcohol is the oldest known drug of abuse. As all drugs of abuse have been at one time or another, alcohol has been banned by various governments throughout history including in the United States from 1920-1933, most western democracies in the early 20th century, and many, largely Muslim, countries in the present.
Alcohol is a cheap, ubiquitous drug in Western countries. It is a small molecule of two carbons, one oxygen, and six hydrogens. Unfortunately, "alcohol" means something different to organic chemists than it does in common parlance. An alcohol in chemistry is an oxygen and hydrogen bonded to something. In common usage, alcohol specifically refers to an oxygen and hydrogen bonded to ethane (a two carbon chain), see figure at top. An organic chemist refers to that specific alcohol as "ethanol", "ethyl alcohol", "grain alcohol", "drinking alcohol", or "EtOH". There is plenty of scientific literature which uses the term "alcohol" to refer exclusively to ethanol, particularly outside the field of chemistry (psychology, medicine, etc).
There are an infinite number of other molecules which could be bound to an OH. Chemists broadly refer to such molecules as "alcohols". They have a broad range of properties, some have pleasant tastes, some are exceptionally toxic, etc. Alcohols other than ethanol are present in low concentrations in most alcoholic beverages. Except in case of manufacturing errors, they are not present in high enough concentrations to directly cause psychological effects. However, they are responsible for variations in taste and there is evidence they mediate hangover symptoms, though hangovers are a complex multivariate pathology. This collection of non-ethanol alcohols are known as congeners in the beverage industry. For context, ethanol content in beverages is between 4% (light beer) and 40% w/v (distilled spirits); total congener content is between 0.01% and 0.1% w/v [2]. The congener concentration is two to four orders of magnitude lower than the ethanol concentration.
[Caption] Common congeners of alcoholic beverages. Acetaldehyde, ethyl formate, methanol, propanol, isobutanol, butanol, isopentanol listed in [2]. Acetone, isopropanol, 2-methyl-1-butanol, and 3-methyl-2-butanol from [3]. Furfural from [4]. Ethylene glycol is present in mismanufactured beverages but is not normally present in commercial products [3,5]. Acetaldehyde and acetone are both congeners and the metabolic products of ethanol and isopropanol, respectively.
The alcohols collectively called congeners are chemically similar and, with the exception of methanol, heavier than ethanol. Therefore, when separated by distillation, all the non-methanol-congeners appear below the ethanol in the distillation column. This collection of non-methanol-congeners are known as fusel alcohols, fuselol, or fusel oils. Not conincidentally, some congeners are themselves drugs of abuse for alcoholics. Methanol was used in the 1920s to dilute ethanol and increase profits for bootleggers. It works well enough until the methanol:ethanol ratio grows too high and the methanol blinds or kills the drinker. Isopropanol is perhaps the least toxic intoxicating alternative to ethanol, safer than methanol or ethylene glycol (which is also deadly and commonly available in the form of antifreeze). The perponderance of medical articles on the distinctive features and treatment of isopropanol and ethanol poisoning is itself evidence of the frequency of isopropanol poisonings [6], though how many are deliberate is unclear. At least one case report exists of deliberate repeated isopropanol ingestion by a 43-year-old Polish man leading to poisoning [7]. Isopropanol is safer than other ethanol substitutes because it is metabolized to acetone. Acetone is one of the ketone bodies, a group of molecules produced by the liver in response to fasting (among other situations). Ketone bodies are consumed by other organs of the body for energy. The cellular machinery for digesting ketones like acetone can render small amounts of acetone harmless. The medical standard of care for isopropanol poisoning is largely supportive since it is deeply uncomfortable but not acutely dangerous [8].
The presence of congeners raises some questions: why does the methanol not poison everyone as it did in bad batches of moonshine during prohibition? are congeners impurities? or extra flavor? The first question is a matter of concentration. To approach the threshold dose for methanol-induced blindness, one would have to consume approximately 10 bottles of wine [9]. Alcohol is far from my favorite drug but that seems ambitious even for professional winos. Even if it were possible to drink that much wine, methanol toxicity would likely not be a problem. The ethanol in the wine would offer a protective effect from the methanol by slowing the metabolism of methanol into toxic metabolites. Furthermore, the ethanol in the wine would be lethally toxic (making any methanol blindness the least of one's problems). As for the impurities vs flavor question, that depends on the beverage. Port wines, beers, and brandies have the highest congener contents which are prized for their flavor profiles. Vodka and gin distillers view congeners as contaminants to be removed [2] and therefore have about one order of magnitude less congener than brown liquors. To the extent congeners modulate the effects of alcohol hangovers, liquors with lower congener content will produce less severe hangovers (see below).
The hallmark symptoms of a hangover are headache and fatigue but may also include increased light/sound sensitivity, red eyes, muscle aches, thirst, elevated systolic blood pressure, tachycardia, tremor, sweating, dizziness, vertigo, depression, anxiety, and irritability. Symptoms usually begin within hours of drinking cessation as the blood alcohol concentration (BAC) begins to fall, peak as the BAC approaches 0, and resolve within 24 hours. Because of the overlap between alcohol withdrawl symptoms and hangovers, alcohol withdrawl is sometimes proposed as the hangover mechanism. Hangovers, unlike alcohol withdrawl, are not associated with hallucinations and seizures, have a shorter duration (hours versus several days for withdrawl), and are not lethal (unlike withdrawl, which can be lethal in extreme cases) [10].
[Caption] Artist rendering of blood alcohol concentration curve showing the drink phase and elimination phase. Ethanol follows zero order kinetics at BACs sufficient for intoxication and first order kinetics at low concentrations. [11] contains typical experimental BAC curves which are qualitatively similar. Hangover duration from [10].
The constellations of symptoms of a hangover are the result of several mechanisms working simultaneously: (1) dehydration, (2) hypoglycemia, (3) sleep disruption, (4) actions of toxic metabolites, (5) actions of toxic impurities and their toxic metabolites, and genetic predispositions which are poorly understood (and not addressed here). There is conflicting evidence on which mechanism is dominant as it appears to be situationally dependent. However, the hangover state is currently understood as a product of these mechanisms.
(1) Dehydration is the most treatable cause of hangover symptoms. Alcohol is a diuretic (agent that causes urination). Excess urination disturbs the salt balances in the blood so the dehydration problems cannot be solved simply by drinking water [10]. Vomiting and diarrhea common in heavy bouts of drinking also exacerbate electrolyte imbalances.
(2) Hypoglycemia is partially responsible for the lethargy of a hangover [12]. Therefore, remedies that increase electrolyte and sugar intake as well as water are more effective than water alone. Gatorade or cookie plus lots of water are more curative than water alone.
(3) Sleep disruption is caused by rebound-excitation-induced insomnia during the falling BAC phase [13]. Additionally, alcohol is often consumed in the evening and early morning hours leading to a disruption of circadian rhythms and shortening the time available for sleep. Sleep deprivation and hypoglycemia are the main contributors to hangover fatigue.
(4,5) Toxic metabolites, impurities, and their metabolites appear to play a role in hangover severity and justify some of the more counterintuitive hangover remedies. For example, the "hair of the dog that bit you" cure holds that a hangover is cured with more alcohol. Methanol modulated hangovers are particularly painful because the body metabolizes methanol to formaldehyde and formic acid which cause blindness and death in high concentrations. The metabolites are responsible for blindness and other toxicity associated with methanol poisoning. Ethanol competes with the enzymes that metabolize methanol preventing the build up of toxic methanol metabolites. Methanol concentrations linger much longer than ethanol [14] and its metabolism coincides with the symptoms of the hangover. Methanol appears to be only a mediator since it is possible to induce a hangover with laboratory pure ethanol (in the complete absence of methanol).
Ethanol is metabolized to acetaldehyde which is toxic but because acetaldehyde is a short-lived intermediate product, concentrations do not usually build to harmful levels. However, individuals with mutations in the acetaldehyde dehydrogenase enzyme experience harmful acetaldehyde concentrations after mild ethanol intake. This is the cause of "Asian glow," so called because of the red flushed face caused by the acetaldehyde and the frequency of acetaldehyde dehydrogenase mutations which affect 1 in 3 Asians. The acetaldehyde mechanism is currently the subject of some debate; no one debates whether it is toxic at high concentrations, just whether it is responsible for hangover symptoms in people with normal acetaldehyde dehydrogenase genes.
[Caption] Methanol pathway from [15], ethanol pathway from [10]. FTS is the aycronym for 10-formyl tetrahydrofolate synthetase. The metabolic pathways for ethylene glycol and isopropanol are longer but, like methanol and ethanol, the first step is mediated by alcohol dehydrogenase and the primary toxins are the metabolites.
Alcohol dehydrogenase is a pesky enzyme in poison control. It mediates the first step in the metabolism of ethylene glycol, methanol, ethanol, and isopropanol. All of those compounds are non-toxic until acted upon by alcohol dehydrogenase which turns methanol into formaldehyde, ethylene glycol into glycoaldehyde, and isopropanol into acetone. The current treatment for all such poisonings is ethanol or fomepizole. "Get drunk, the doctor needs you drunker if you're going to survive" is a hell of a prognosis, though in reality ethanol is administered by IV not by shot glass. In poisoning treatment, the goal with ethanol or fomepizole is to occupy the alcohol dehydrogenase and slow the rate of conversion of the poison to the toxic metabolite. That only works if the doctor makes the diagnosis quickly, otherwise the only treatment is hemodialysis (removal of the patient's blood, running it through a filter, and returning it) [16].
Most of these variables are things we cannot control or things we are deliberately chosing not to control (sleep scheduling, genetic predispositions to hangovers, amount consumed, etc). Congeners have not been conclusively shown to mediate hangover effects but there is a plausible mechanism by which they could and significant evidence in favor of that hypothesis. If we take as fact that congeners are partially but significantly responsible for hangovers, we would recommend drinking beverages with the lowest congener:ethanol ratio, see figure below. The degree to which this is sound actionable information depends on how much of your hangover is caused by the impurities in the beverages. This is doubtlessly an individual-specific situation but there is plenty of consistent evidence going back to the 1970s that low-congener beverages produce less severe hangovers [17].
[Caption] Congener to ethanol ratio (by mass) of popular commercial beverages as measured in 1981 [2].
Once hangover symptoms have arrived, the most successful treatments will address hypoglycemia, dehydration, and electrolyte imbalances via the intake of sugar, water, and salt (ie Gatorade). IV saline bags address both the dehydration and electrolyte imbalances, which is why they are popular among celebrities who can afford personal physicians and medical staff who have access to them. Caffeine is also commonly recommended to mask the effects of hypoglycemia and sleep deprivation. When caffeine is delivered via a sugar-filled coffee, the sugar also address the hypoglycemia. Regardless of what else is done, rehydration, rest, and the passage of time should cure most hangovers within 24 hours.
To prevent hypoglycemia or dehydration, one would need to drink/eat in a window starting several hours before the onset of symptoms and ending as symptoms subsided. As of this time, there have not been any carefully controlled studies attempting to pinpoint an optimum time within that window.
There is a class of alcoholic who constantly feels the need to justify their habit: "Red wine is good for you" or if you are this particularly enthusiastic reporter "A glass of red wine is just as good as an hour at the gym" (0:40). If that does not send your bullshit alarms into a deafening howl, you may find a photo of yourself next to the word gullible in the dictionary. Every non-drinking scientifically-literate person who hears that fact almost immediately dismisses it. Including me.
This skepticism is further cemented in STEM education. This example was given almost verbatim in college: "Reservatol and other antioxidants were isolated from wine in the 1990s and they showed promise when administered to yeast cultures but you'd have to drink a crate of wine to achieve that dose of reservatol. And the alcohol would kill you before the reservatol did any good. It is just the media dragging things way out of proportion to sell ads."
However, there are epidemiological long term studies which show some benefits to regular, low doses of alcohol. In fact, you can spend a day on PubMed and be hard pressed to find any evidence against the "glass of wine a day" recommendation. All the available, long-term epidemiological studies support it [18,19,20,21] though none of them persuasively untangle how much of the effect is red wine versus alcohol specifically. I have never been more surprised by a literature search in my life. The myth of the myth of red wine is the misconception among the educated that "red wine is healthy in moderation" is a myth.
[1] "Fermented beverages of pre-and proto-historic China," PNAS, vol. 101, pp. 17593—17598, 2004.
[2] "Congener contents of alcoholic beverages," Journal of Studies On Alcohol, vol. 42, pp. 1030—1037, 1981.
[3] "Volatile congeners in alcoholic beverages: analysis and forensic significance," Rom J Leg Med, vol. 18, pp. 265—70, 2010.
[4] "The role of beverage congeners in hangover and other residual effects of alcohol intoxication: a review," Current Drug Abuse Reviews, vol. 3, pp. 76—79, 2010.
[5] "Unwell after drinking homemade alcohol—A case of ethylene glycol poisoning," African Journal of Emergency Medicine, vol. 3, pp. 71—74, 2013.
[6] "Isopropanol poisoning," Clinical Toxicology, vol. 52, pp. 470—478, 2014.
[7] "Acute oral poisoning with isopropyl alcohol in alcoholics," Przeglad Lekarski, vol. 54, pp. 459—463, 1997.
[8] "Isopropyl alcohol poisoning," UpToDate.com, April 2019.
[9] "Estimations of the lethal and exposure doses for representative methanol symptoms in humans," Annals of Occupational and Environmental Medicine, vol. 29, pp. 44, 2017.
[10] "Alcohol hangover," Alcohol Health Res World, vol. 22, pp. 54—60, 1998.
[11] "Ethanol pharmacokinetics in white women: nonlinear model fitting versus zero-order elimination analyses," Alcoholism: Clinical and Experimental Research, vol. 24, pp. 1353—1362, 2000.
[12] "Metabolic Studies on the Pathogenesis of Hangover," European Journal of Clinical Investigation, vol. 4, pp. 93—100, 1974.
[13] "Sedative effects of ethanol at night.," Journal of Studies On Alcohol, vol. 52, pp. 597-600, 1991.
[14] "Elimination half-life of methanol during hangover," Pharmacology & Toxicology, vol. 60, pp. 217—220, 1987.
[15] "American Academy of Clinical Toxicology Practice Guidelines on the Treatment of Methanol Poisoning," Journal of Toxicology. Clinical Toxicology, vol. 40, pp. 415-46, 2002.
[16] "Treatment of ethylene glycol poisoning," American Family Physician, vol. 66, pp. 807—812, 2002.
[17] "Alcohol hangover: a critical review of explanatory factors," Human Psychopharmacology: Clinical and Experimental, vol. 24, pp. 259—267, 2009.
[18] "Contribution of red wine consumption to human health protection," Molecules, vol. 23, pp. 1684, 2018.
[19] "Red wine, resveratrol and atrial fibrillation," Nutrients, vol. 9, pp. 1190, 2017.
[20] "Wine and its metabolic effects. A comprehensive review of Clinical Trials," Metabolism, vol. 83, pp. 102—119, 2018.
[21] "Wine, beer, alcohol and polyphenols on cardiovascular disease and cancer," Nutrients, vol. 4, pp. 759—781, 2012.