This time last year, I posted one of Shortcut U’s first and – to this day – most popular deep dives, Safety From the Sunday Scaries, in which we covered alcohol metabolism 101 and explored some of the literature on hangovers. Since then, I’ve come across some more interesting data and information on the subject; additionally, some of my favorite voices in the field of health have recently posted content around drinking and the morning-after effects. For these reasons, on this year’s Halloweekend – a time classically associated with alcohol consumption – I bring to you the first ever Shortcut addendum, continuing last year’s discussion on alcohol’s effects on the body, hangovers, and theoretical ways to reduce both.
Check out Dr. Peter Attia’s recent article discussing Myrkl – a new anti-hangover supplement in the UK – which inspired my deep dives on the publications discussed below.
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. I am not in any way endorsing alcohol consumption.
Check out my reference list for this post here.
L-Cysteine
As we covered last time, when it comes to hangover causes, there are a host of biochemical and physiological suspects to blame. Cysteine, an amino acid commonly found in eggs and involved in a plethora of biological processes, theoretically can neutralize two of these suspects: acetaldehyde and inflammation.
The first step in the majority of alcohol metabolism involves alcohol dehydrogenase (ADH) oxidizing ethanol to acetaldehyde, an inflammatory molecule and known carcinogen. (III) Next, aldehyde dehydrogenase (ALDH) continues the process by converting acetaldehyde to the less toxic acetate; however, if large amounts of alcohol are consumed, or if an individual is genetically predisposed to rapid ADH and/or slow ALDH functioning, the aforementioned metabolic process can become backed up and blood acetaldehyde concentrations elevated. (III, VI) When this happens, proteins can bind to the acetaldehyde molecules via interactions with certain amino acids, one of which is cysteine. (II, III) This acetaldehyde neutralization offers a potential mechanism through which cysteine could alleviate the effects of alcohol consumption and potentially the hangover symptoms that follow (II); however, the aforementioned adducts can elicit an inflammatory response – exemplified by the host immune system generating antibodies specific to those adducts – adding to the already boisterous storm of inflammation that accompanies alcohol consumption. (III)
For this reason, I personally favor the idea that cysteine’s supposed impact on alcohol consumption and hangover development is through replenishing glutathione (GSH), the body’s most powerful antioxidant. As I alluded to above, ethanol metabolism produces a host of reactive oxygen species (ROS) — chemically active molecules that disrupt and destabilize normal biochemistry — which are then counteracted by GSH and other antioxidants (III, VII); consequently, GSH stores can be depleted following alcohol consumption. (III) One theory proposes that cysteine, as the precursor for GSH, is a viable option for reversing this depletion (IV, V); interestingly, health professionals utilize cysteine to resolve this same physiological issue during acetaminophen (Tylenol) overdoses where GSH is depleted via different metabolic pathways. (IV, V)
Regardless of the mechanism, results from this 2020 study suggest that supplementing L-cysteine (one form of the amino acid) orally per day can reduce nausea, headache, and overall hangover symptoms following consuming 1.5 g/kg of alcohol — the equivalent of about 6, 7, and 8 standard alcoholic drinks for individuals weighing 120 lbs, 150 lbs, and 170 lbs, respectively. (I) The results are in the form of Likert scores on a 1-10 scale, in which the subject responds to a statement (i.e. I have a headache) with answers ranging from, “strongly disagree,” to “strongly agree.” To clarify, a 2 on this scale is equivalent to a, “strongly disagree,” response, and a 4 is equivalent to a, “disagree,” response. Now, the study used a crossover design with 3 trials, so each subject completed a drinking/hangover trial with placebo, 600 mg L-cysteine supplementation, and 1200 mg L-cysteine supplementation, each of which was separated by a 1-week washout period. Here’s an analysis of the results, along with visual representations of the data:
Notably, both supplementation groups exhibited non-trivial relative and absolute risk reductions for all of the assessed symptoms – aside from Group 1’s minor improvements on overall hangover – with the overall trend showing a dose-response relationship where the higher dose of L-cysteine led to greater reduction in risk. Additionally of note, zero subjects taking 1200mg of L-cysteine experienced nausea the next morning. Though the trend for headache results was not statistically significant, the large effects on relative and absolute risk reduction – exemplified by the fact that only one subject scored above a 4 – suggest that the small sample size of 19 subjects could be hiding the statistical significance of the results. Of course, as with all research, this study does have limitations, the largest, in my opinion, being that the supplement also contained vitamins B1, B2, B3, B6, B7, B9, B12, and C, all of which could have confounded the outcomes. (I)
Now, this is only one study, but, when combined with other clinical applications of N-acetyl-cysteine (NAC; another form of the amino acid) and mechanistic reasoning, it appears that taking a cysteine supplement could reduce hangover risk and severity. (I) In addition, via their effects on glutathione levels, cysteine supplements could, in theory, provide benefits even during light alcohol consumption that does not pose a heavy hangover risk but still negatively impacts health through inducing inflammation.
Boozin’ With Bacteria
Of course, if you really don’t want a hangover, you can follow the age-old recommendation: don’t drink. Or, as those behind this new anti-hangover product propose, you could modernize that recommendation to, “don’t absorb the alcohol.” More specifically, I’m referring to the idea of leveraging genetically engineered bacteria with ADH and ALDH capabilities to metabolize alcohol in your gut before your body absorbs it. (VI, VII) Now, while it could theoretically minimize or eliminate your hangover, using this approach would also mean sacrificing your drinking buzz, along with all of the other commonly desired side-effects of alcohol consumption. So, if you’re after some meaningful degree of drunkenness, metabolizing alcohol in the gut with these microbes is not ideal; however, if you want to consume alcohol for celebration, social reasons, or the taste alone without the inebriating effects, this probiotic idea is interesting. And, this is the main idea behind Myrkl, the anti-hangover supplement mentioned above. But are its self-proclaimed miracle mechanisms adequately justified by science? Let’s break down some of the data.
Like most research, the groundwork for degrading alcohol with recombinant bacteria – microbes genetically engineered with certain capabilities, in this case with ADH and ALDH functionalities – starts with in-vitro and animal studies. This study did both, examining the alcohol metabolizing abilities of recombinant ADH/ALDH bacteria in solutions of varying temperature and pH, as well as in live mice following a week of receiving injections of both alcohol and the special bacteria. (VII) In the former experiments, the bacteria were able to metabolize large percentages of ethanol – greater than 60% – at body temperature and pH ~5.5, which is slightly more acidic than the 6-7.4 pH’s found in the intestines; however, their rate of ethanol breakdown significantly decreased to ~22% at pH 2-3 – similar to the acidity of the stomach – and dropped to ~5% or less when interacting with ethanol concentrations greater than 20%. (VII) With that said, when tested in living mice, the recombinant bacteria significantly reduced blood alcohol content by ~45% compared to mice that received the alcohol injections with no bacterial treatment. (VII) In addition, the mice receiving the bacterial treatment showed significantly better measures of inflammation and liver damage – defined by inflammatory markers, antioxidant concentrations, and liver enzyme concentrations – than the alcohol-only mice. (VII) Of note, the mice received 5.6 grams of alcohol per kilogram of bodyweight per day for 8 days, which is roughly equivalent to 22, 27, and 31 standard alcoholic drinks per day for individuals weighing 120 lbs, 150 lbs, and 170 lbs, respectively. (VII) So, though the in vitro data causes some skepticism about the practicality of this probiotic approach, when combined with the animal data, there appears to be some potential for these microbes to reduce both alcohol absorption and some of the negative physiologic consequences of drinking. The real question is how do the human studies compare?
de Faire Medical, the company behind Myrkl, touts this study, in which human subjects received a supplement containing both L-cysteine and recombinant bacteria similar to those from Lou and colleagues’ study mentioned above (VII), as proof of, “the first formula in history that breaks down alcohol effectively.” (VIII) At first glance, this appears to be true, as after taking two of the anti-hangover pills per day for a week, subjects in the experimental group exhibited a 70% relative reduction in area under the curve (AUC) of blood alcohol content compared to subjects in the placebo group. (VI) However, these headline statistics become significantly less impressive when held next to some of the finer details of the study. Firstly, with only 24 subjects to begin with, the study’s sample size was small, and it shrank further when 10 of the subjects (~42%) did not show a meaningful BAC response to the amount of alcohol consumed. (VI) This leads into the next limitation of the study: the low dose of alcohol consumption, which – to the researchers’ defense – was the amount allowed by the regulatory body overseeing the study. As compared to the relatively massive amount of alcohol administered in the previously mentioned mouse study, these human subjects consumed 0.3 g/kg of alcohol, which came out to 47-89 mL (roughly 1-2 shots) of vodka, depending on the size of the subject. (VI) Interestingly, in the conclusion, the authors cite an unpublished follow-up study, where people consumed a single dose of the anti-hangover supplement then drank twice as much alcohol (2-4 shots), after which, AUC of BAC was only reduced by 10% for subjects in the supplement group. (VI)
Where does this leave us? Well, the theory behind this probiotic solution appears solid and is strengthened further by the mouse data; furthermore, considering it is in its infancy, the human data also shows some promise, especially the large effects on AUC of BAC for those that experienced a meaningful rise in BAC. With that said, though it is tempting to fall head over heels for the enticing abstracts and headlines, we cannot extrapolate the human data beyond its limitations, which – in my opinion – are significant. Most notably, we should not look past the small quantities of alcohol used in the study from Pfützner et al. and the bacteria’s reduced effectiveness at high alcohol concentrations in Lou and colleagues’ experiments. Together, these factors remind us that this approach would really target those looking to drink a small amount of alcohol at one time anyways, as anybody looking to drink more heavily likely wouldn’t be looking to expunge the commonly sought after side-effects of alcohol. So, for you glass of wine with dinner and grab one beer with the gang folks, the day when you can have your drink of choice with diminished or even non-existent health consequences – the day when you can drink your booze and have it too, so to speak – may exist in the future. Only time and cleverly designed, thorough research will tell.
Huberman’s Hangover Help and Alcohol Explainer
It doesn’t take hanging around Shortcut U for long to learn that I am a fan of Dr. Andrew Huberman, a neuroscientist and professor at Stanford Medical School who continuously shares entertaining and understandable scientific breakdowns on his podcast, Huberman Lab. This past August, Huberman and his team explored all things alcohol, from the biological basis for the buzz to the physiological underpinnings of hangovers and other consequences of drinking. If you’re interested in a beginner’s guide to alcohol science that will quickly take you to the JV level, this is a podcast you’ll want to listen to. Here is a link to the whole podcast, along with my most notable takeaways and some clips from the episode:
Shortcut Takeaways:
Contrary to common belief, light alcohol consumption – ~7-14 drinks per week, whether distributed across the whole week or consumed at one time – has significant negative impacts on the body, especially the brain.
Although we most commonly associate alcohol with its acute effects on our brains while we drink, regularly consuming alcohol also impacts our brains when we aren’t drinking, in that it alters neural networks, biasing them towards greater impulsivity and stress. Interestingly, these effects can be reversed after ceasing alcohol consumption for several months.
Alcohol, being an antibacterial substance, has historically been used to disinfect wounds and sterilize medical equipment; similarly, consuming alcohol kills good bacteria in your digestive tract, which – considering all of the data connecting the status of the gut microbiota to health – is likely significantly detrimental to the body.
For every 10 grams of alcohol – about 1 standard alcoholic drink – consumed per day, your relative risk of cancer increases by 4-13%.