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Give Yourself Gout For Fame And Profit

I.

Actually, no. You should not do this. Most of you were probably already not doing this, and I support your decision. But if you want a 2000 word essay on some reasons to consider this, and then some other reasons why those reasons are wrong, keep reading.

Gout is a disease caused by high levels of uric acid in the blood. Everyone has some uric acid in their blood, but when you get too much, it can form little crystals that get deposited around your body and cause various problems, most commonly joint pain. Some uric acid comes from chemicals found in certain foods (especially meat), so the first step for a gout patient is to change their diet. If that doesn’t work, they can take various chemicals that affect uric acid metabolism or prevent inflammation.

Gout is traditionally associated with kings, probably because they used to be the only people who ate enough meat to be affected. Veal, venison, duck, and beer are among the highest-risk foods; that list sounds a lot like a medieval king’s dinner menu. But as kings faded from view, gout started affecting a new class of movers and shakers. King George III had gout, but so did many of his American enemies, including Franklin, Jefferson, and Hancock (beginning a long line of gout-stricken US politicians, most recently Bernie Sanders). Lists of other famous historical gout sufferers are contradictory and sometimes based on flimsy evidence, but frequently mentioned names include Alexander the Great, Charlemagne, Leonardo da Vinci, Martin Luther, John Milton, Isaac Newton, Ludwig von Beethoven, Karl Marx, Charles Dickens, and Mark Twain.

Question: isn’t this just a list of every famous person ever? It sure seems that way, and even today gout seems to disproportionately strike the rich and powerful. In 1963, Dunn, Brooks, and Mausner published Social Class Gradient Of Serum Uric Acid Levels In Males, showing that in many different domains, the highest-ranking and most successful men had the highest uric acid (and so, presumably, the most gout). Executives have higher uric acid than blue-collar workers. College graduates have higher levels than dropouts. Good students have higher levels than bad students. Top professors have higher levels than mediocre professors. DB&M admitted rich people probably still eat more meat than poor people, but didn’t think this explained the magnitude or universality of the effect. They proposed a different theory: maybe uric acid makes you more successful.

Before we mock them, let’s take more of a look at why they might think that, and at the people who have tried to flesh out their theory over the years.

Most animals don’t have uric acid in their blood. They use an enzyme called uricase to metabolize it into a harmless chemical called allantoin. About ten million years ago, the common ancestor of apes and humans got a mutation that broke uricase, causing uric acid levels to rise. The mutation spread very quickly, suggesting that evolution really wanted primates to have lots of uric acid for some reason. Since discovering this, scientists have been trying to figure out exactly what that reason was, with most people thinking it’s probably an antioxidant or neuroprotectant or something else helpful if you’re trying to evolve giant brains. Other researchers note that in lower animals, uric acid is a “come out of hibernation” sign which seems to induce energetic foraging and goal-directed behavior more generally.

Some of these people note the similarity between uric acid and caffeine:

If uric acid had caffeine-like effects, then high levels of uric acid in the blood would be like being on a constant caffeine drip. The exact numbers don’t really work out, but you can fix this by assuming uric acid is an order of magnitude or so weaker than straight caffeine. Add this fudge factor, and Benjamin Franklin was on exactly one espresso all the time.

But you can’t actually be hyperproductive by being on one espresso all the time, can you? Don’t you eventually gain tolerance to caffeine and lose any benefits?

Although uric acid is structurally similar to caffeine, it’s even more similar to a chemical called theacrine. In fact, theacrine is just 1,3,7,9-tetramethyl-uric acid:

Theacrine (not the same as theanine, be careful with this one!) is a caffeine-like substance found in an unusual Chinese variety of tea plant. It’s recently gained fame in the nootropic community for not producing tolerance the same way regular caffeine does – see eg Theacrine: Caffeine-Like Alkaloid Without Tolerance Build-Up. This makes the theory work even better: Franklin (and other gout sufferers) were constantly on one espresso worth of magic no-tolerance caffeine. Seems plausible!

II.

This theory is hilarious, but is it true?

I was able to find eleven studies comparing achievement and uric acid levels. I’ve put them into a table below.

Study sample size finding significant at awfulness
Kasi 155 tenth-graders r = 0.28 w/ test scores 0.001 significant
Bloch 84 med students r = 0.23 w/ test scores 0.05 immense
Steaton & Herron 817 army recruits r = 0.07 w/ test scores 0.02 significant
Mueller & French 114 professors r = 0.5 with achievement-oriented behavior 0.01 astronomical
Montoye & Mikkelsen 467 high-schoolers negative result N/A unclear
Cervini & Zampa 270 children positive result unknown what even is this?
Inouye & Park ??? r = 0.33 with IQ 0.025 what even is this?
Anumonye 100 businessmen, 40 controls r = 0.21 with drive 0.05 immense
Ooki 88 twins r = 0.17 with 'rhathymia' 0.05 how is this even real?
Dunn I 58 executives positive ??? immense
Dunn II 10 medical students negative N/A astronomical

Nine out of eleven are positive. But I find it hard to be confident in any of them. Modern studies can be pretty bad, but studies from the 1960s ask you to take even more things on trust, while inspiring a lot less of it. Many of these studies were unable to find the outcomes that the others found, but discovered new outcomes of their own. Many failed to report basic pieces of information. The largest experiments usually found the least impressive results. Overall this looks a lot like you would expect from something forty years before anyone realized there was a replication crisis.

I also notice that the most positive studies compare business executives to people in other walks of life, and the least positive studies compare good students with bad students. Business executives get a lot of chances to differ from the general population – maybe they still eat more meat and richer food? Maybe they’re stressed and stress affects uric acid levels?

What about the list of very famous people with gout? I agree it’s a lot of people, but what’s the base rate? Kings were born to their position, so we have no reason to think they were especially high achievers (someone in their family might have been, but that gene could have gotten pretty diluted). Since so many kings got gout, this suggests rich old people in the past had gout pretty often regardless of achievement. Also, this was before people invented good medical diagnosis, so probably arthritis, injuries, and any other form of joint pain got rounded off to gout too. What percent of rich old people in the past had some kind of joint pain? I’m prepared to guess “a lot”.

The biochemists report equally confusing results around the uric acid / caffeine connection. Caffeine mostly works by antagonizing adenosine, a chemical involved in sleepiness. According to Hunter et al, Effects of uric acid and caffeine on A1 adenosine receptor binding in developing rat brain, uric acid does not affect adenosine, and so probably does not have a caffeine-like mechanism of action. On the other hand, caffeine probably has a small additional effect on catecholamine (eg dopamine, norepinephrine) release, and a different paper finds that uric acid does share this mechanism. So it doesn’t have caffeine’s main effect, but it does seem to have some kind of mild stimulant properties.

Given this level of uncertainty around every step in the hypothesis, I would describe any link between uric acid and achievement as kind of a stretch at this point. I feel bad about this, because it’s an elegant theory with mostly positive studies in support, but I’m just not feeling like it’s met its burden of proof.

III.

But some recent research is trying to bring this field back from the dead. At least this is what I get from Ortiz et al, Purinergic System Dysfunction In Mood Disorders, which synthesizes some more modern evidence that “uric acid and purines (such as adenosine) regulate mood, sleep, activity, appetite, cognition, memory, convulsive threshold, social interaction, drive, and impulsivity”. It argues that we know there are neurorecptors for adenosine (another similar-looking molecule) and ATP (adenosine triphosphate, the body’s main form of chemical energy). These seem to be involved in depression and mania, in the predicted direction (manic people have too much ATP, depressed people have too little, and treatments for both conditions seem to normalize ATP levels). These results seem to be daring someone to make up a theory where mania is just too much chemical energy floating around, but if Ortiz et al are doing that, it’s sandwiched in between so many dense paragraphs on receptor binding that I can’t make it out.

More interesting for us, uric acid is related to all these chemicals and also seems to be involved in mania. See eg de Berardis et al, Evaluation of plasma antioxidant levels during different phases of illness in adult patients with bipolar disorder, which finds that uric acid is elevated in manic patients, and the more manic, the higher the uric acid levels. And Machado-Vieria claims to have gotten pretty good results treating bipolar mania with allopurinol, a gout medication that decreases uric acid – and the more the allopurinol decreased uric acid, the better the results. There’s also a little evidence that depressed people have lower uric acid than normal. None of this is a large effect – there are still a lot of depressed people with higher-than-normal uric acid and a lot of manic people with lower – but it’s around the same size as all the other infuriatingly suggestive effects we find in psychiatry that never lead to overarching theories or go anywhere useful.

Future studies should try to replicate the link between uric acid and mania, and come up with a better understanding of why it might be true – maybe since uric acid is a decay product of ATP, the body interprets it as a sign that energy is plentiful? They should try to explain away anomalies – if gout is maniogenic, how come so many people with gout are depressed? Is it just because having a painful illness is inherently depressing? And then it should investigate how mania bleeds into normal personality. Is someone with slightly higher uric acid a tiny bit hypomanic all the time?

If they can fill in all those steps, I’ll be willing to take a fresh look at the old papers linking gout and achievement. Until then, you should probably hold off on eating megadoses of venison to become the next Ben Franklin.

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95 Responses to Give Yourself Gout For Fame And Profit

  1. Le Maistre Chat says:

    In 1963, Dunn, Brooks, and Mausner published Social Class Gradient Of Serum Uric Acid Levels In Males, showing that in many different domains, the highest-ranking and most successful men had the highest uric acid (and so, presumably, the most gout). Executives have higher uric acid than blue-collar workers. College graduates have higher levels than dropouts. Good students have higher levels than bad students. Top professors have higher levels than mediocre professors. DB&M admitted rich people probably still eat more meat than poor people, but didn’t think this explained the magnitude or universality of the effect. They proposed a different theory: maybe uric acid makes you more successful.

    Was this a wasted opportunity to rename it urich acid?

    • OutsideContextProblem says:

      Venison may cause it, but poor people can’t eat too much because it’s a little deer.

      • Filareta says:

        On the other hand, among foods and drinks there is nothing more egalitarian than a beer.

  2. gwern says:

    Jensen mused a bit about uric acid. I’m not particularly convinced; it hasn’t passed any rigorous experimental trials, or even racked up somewhat-less-confounded correlational evidence like twin comparisons AFAIK. I tried out 500mg inosine supplements once, but I didn’t notice anything except possibly a mild stimulation, and the reports of kidney stones are pretty scary, so I dropped it.

  3. Douglas Knight says:

    Also, this was before people invented good medical diagnosis

    Ancient diagnosis was pretty good. And since it was centered around urine, gout should have been the easiest thing to diagnose. Indeed, wikipedia quotes Celsus:

    Again thick urine, the sediment from which is white, indicates that pain and disease are to be apprehended in the region of joints or viscera

    • Yashabird says:

      I wonder how commonly court physicians would ask the king about his sexual dalliances…

      I mean, gonorrhea can cause arthritis as well as “thick urine” with white sediment, and I don’t know any reason to think kings wouldn’t get a little gonorrhea to go with their gout.

    • Null42 says:

      Everyone knows the ‘mellitus’ in ‘diabetes mellitus’, which is what everyone thinks of when you say ‘diabetes’, refers to ‘sweet’, as in the taste of the urine, right?

      There’s a diabetes insipidus that produces dilute, tasteless urine.

  4. Majuscule says:

    Why all the studies on teenagers and children? Were they just testing uric acid and achievement? It would be interesting to find the test subjects now, who are probably at least in their 50s and older, and see who got gout.

    Also, can we venture any guesses on why gout afflicts three times as many men as it does women? And when women do get gout it tends to be in advanced age and require more uric acid than in men. Do women just eat less venison or is there something protective at work? (I am aware of potential CW pitfalls here.)

    • dyfed says:

      Is it at all controversial or CW to say that on average men eat meat in greater quantity and frequency? It doesn’t have to be game meat to have a lot of uric acid; game organ meat is just the fastest way to get gout, not the only way.

      In response to a comment immediately below, I agree that some people are genetically predisposed to gout, but don’t consider this a significant number of historical gout sufferers based on the evidence we have. As diets have changed over time, gout prevalence has decreased dramatically, which we shouldn’t expect to see if most cases of gout are genetic in origin.

      It is much more likely that today’s gout cases are those who are so exaggeratedly predisposed to it that they require great dietary intervention as opposed to, say, simply not eating deer kidneys at every other meal.

      • caryatis says:

        Women definitely eat less meat, and drink less beer and alcohol on average.

        • But women are also lighter on average, and I would expect it to be the ratio of amount eaten to amount of eater that mattered.

          • Estera clare says:

            IIRC men have more muscle mass per pound of body weight and therefore need more calories per pound than women, all else being equal, since muscle takes more energy to maintain that fat. I don’t know if body composition plays a role in uric acid buildup, though.

  5. Kevin says:

    It’s unfortunate that this post perpetuates the (at best) questionable claim that gout is mostly caused by diet. In fact, it’s primarily genetic, and I unfortunately have multiple genes associated with it. As a gout sufferer, I avoid organ meat, but otherwise to control it with dietary changes would be more expensive both monetarily and in terms of quality of life than allopurinol, which costs $3–5/month and has virtually no side effects. That it’s hereditary is of course a major confound for any studies trying to associate it with positive characteristics (fame, productivity, etc.). However, the anti-correlation with depression is interesting; I’ve been told I’m remarkably non-depressed for my intelligence level.

    • Barry says:

      This is a good point. There was a lot of people marrying close relatives in medieval times and right up to the 19th century. I think Jane Austen married her first cousin. I wonder if that increased the chances of people getting the gout.

    • Deiseach says:

      A couple of years ago I had what I am assuming was gout in one of my feet. (I’m assuming because I didn’t go to the doctor about “Doctor, I have a pain in my toe”). I don’t think it was diet or alcohol related, and I do think the high uric acid level was to do with some minor kidney troubles I was also having at the time.

      It eventually cleared up, but I have no reason to think it was linked with high achievement in the “this is natural stimulant” fashion, and it was inconveniently painful and restrictive (I could just about hobble along when walking). I think this is one of those odd “sales of ice-cream and divorce rates go up at the same time” kind of correlations.

      • Null42 says:

        It’s probably one of these annoying things where it results in high achievement for 5% of sufferers and is enough to produce a correlation but not enough for having gout to actually be a good thing.

    • tgb says:

      This is good news from a research perspective – should be possible to do a Mendelian randomization study on the causal effects of uric acid! The UK Biobank has blood urate measures and some basic cognitive tests and mental illness history (as well as the genetic sequencing). Should be do-able if urate is a good enough measure for this.

      ETA Here’s a study proposal for MR with urate and gout causing metabolic syndrome, and it seems to have been published here. You’d “just” have to change the phenotype you’re associating it to.

    • drethelin says:

      Just to back up that gout is not caused by “diet” or at least not in the ways people think it is, I was diagnosed with gout (I’m 32 now but this was a few years ago) at a surprisingly young age, but I’ve actually had far fewer attacks when I’m eating MORE meat. I’ve had multiple attacks triggered (seemingly) by actually cheating on my mostly-meat diet with large amounts of carbs/sugar.

      My personal theory is that, since gout is an issue of crystals precipitating out of solution in your blood, that the real issue is dehydration. When you eat large meals (like the royal feasts of a king) with a lot of sugars in them, your cells tend to take up a lot of water, thus making your blood less able to contain the crystals. This also helps explain why drinking a lot of alcohol can trigger gout onsets. If I make sure to drink a ton of water, I can eat a diet consisting of 1-2 pounds of meat a day and still not have gout attacks.

      It’s also possible blood filtration for purines is impacted by obesity in a way that’s not actually connected to the purines in the food you eat.

      Of course this could all be bullshit.

      • Kevin says:

        I also think dehydration plays a big role. I, too, was diagnosed at a young age, about 28. My father, 30 years older, was diagnosed shortly afterward. Obviously, that’s unusual.

        One major difference between my life and his: I travel internationally for work frequently, while he mostly worked for domestic companies. It’s easy to get dehydrated on long flights. I think this made a significant difference. Most flareups came shortly after a trip, also. Now, I make sure to drink as much water as possible on flights.

        I also drink tart cherry juice, which has significant anti-oxidants and has been clinically shown to reduce flareup duration and intensity. With daily allopurinol, I haven’t had any symptoms for the past year.

  6. lotard says:

    Mice without uricase die young with kidney problems. But they also might have some protection against a model of Parkinson’s as opposed to mice expressing artificially high levels of uricase. Finally, mice with one of two uricase copies inactivated live longer, have higher running endurance and some resistance to stroke. While I won’t link purported selection for loss of uricase in primates to longer life or lower likelihood of Parkinson’s (little if anything could select for that in the past), the last publication might be onto something. They do have to supplement mice diet with allopurinol to keep them alive and the publication did appear in a journal I’ve never heard of (Neurobiology of Aging), but hey, it’s not my field.

  7. [Thing] says:

    The connection with meat consumption reminded me of a recent Rolf Degen tweet:

    “The majority of studies, and especially the higher quality studies, showed that those who avoided meat consumption had significantly higher rates or risk of depression, anxiety, and/or self-harm behaviors.” https://tandfonline.com/doi/full/10.1080/10408398.2020.1741505

    Too bad all the meat-processing plants are closing down due to COVID-19, but maybe after civil society collapses I can join a cannibal cult or something.

    • Anteros says:

      My expectation would be that those who have a high level of anxiety are more likely to become vegetarian.

      • flame7926 says:

        Also I would expect anyone with any type of eating disorder or even semi-disordered eating behavior is more likely to become vegetarian (see eg. this small study). Say ~5% of the American population is vegetarian (3.4% based off a 2015 Harris poll adjusted for growth). 10% of Americans have an eating disorder (seems high, maybe an expansive definition). According to above study, half of them have at some point been vegetarian. Say 12.5% were, 25% are, 12.5% are going to be. That means vegetarians with eating disorders account for 2.5% of the American population, so I would imagine the co-occurance of eating disorders, anxiety, depression etc. accounts for most of the original findings.

  8. chaosmage says:

    The only person with gout I know is also that rare-ish kind of person that needs only four hours of sleep per night function normally. I wonder if there’s a connection there. Many very successful people needed little sleep, including Caesar and Napoleon IIRC.

    • HomarusSimpson says:

      My ex wife was prone to gout (unusual for a young-ish woman as others have noted) and she was a dormouse, seemed to be able to sleep for 10-11 hours a day

  9. Goedel says:

    There is a nice Scientific American article looking at the uricase mutation in apes and linking it to Fructose processing and fat storage.

    Fructose seems to raise uric acid similar to the purines found in meat. There are some cohort studies looking at sugar sweetened beverages (raise uric acid) and comparing them to diet sodas (don’t raise uric acid).

    The rich used to consume way more sugar than the rest of the population.

  10. ChelOfTheSea says:

    No idea if this is even remotely plausible as an alternative, but by sheer coincidence five minutes after reading this article I ended up reading about a Molybdenum-containing enzyme (xanthine oxidase) whose activity is apparently sensitive to the concentrations of Molybdenum in your blood. It’s responsible for purine metabolism, as relevant here the metabolism of xanthine to uric acid. Higher molybdenum -> more activity of said enzyme -> more uric acid. It’s already a target of several anti-gout medications for this purpose.

    Molybdenum’s dietary sources? Meat and cereal grain (which covers all four of your diet items, including the beer) – and a dietary source for a rare and not especially well-regulated mineral would explain the sex differences, too, since men tend to eat more than women.

    So there’s my wild, crazy, totally unfounded speculation of the day derived from nothing but reading two articles within ten minutes.

  11. c1q says:

    The Atlantic suggests that early Americans consumed prodigious amounts of meat, 1.75x to 2x as much as modern Americans, mostly in the form of wild game: https://www.theatlantic.com/health/archive/2014/06/how-americans-used-to-eat/371895/

    • ADifferentAnonymous says:

      Now we know the real reason America became the richest and most powerful nation on Earth!

    • Bunthut says:

      The article says:

      he publication of The Jungle, Upton Sinclair’s fictionalized exposé of the meatpacking industry, caused meat sales in the United States to fall by half in 1906, and they did not revive for another 20 years.

      It also has a graph (technically meat consumption rather than sales) which doesn’t show that drop at all.

    • c1q says:

      Odd counterexample: Benjamin Franklin claimed to be vegetarian, yet suffered from gout, and also accomplished exactly one Benjamin Franklin’s worth of great acts in 84 years of life.

  12. Act_II says:

    It’s often fun to see what happens when you try to reverse causal links like this, but I think it’s almost always destined to be unfruitful. Still, an interesting post.

  13. Chris Phoenix says:

    Typo: “realized their was a replication crisis” <- there

    Edit: Scott, feel free to delete this comment.

  14. a real dog says:

    Anecdata : two most manic, high-achieving individuals in my friend group are both hyperuricemic. I thought this is a coincidence, but now I wonder.

  15. HarmlessFrog says:

    Gout is a disease caused by high levels of uric acid in the blood. Everyone has some uric acid in their blood, but when you get too much, it can form little crystals that get deposited around your body and cause various problems, most commonly joint pain. Some uric acid comes from chemicals found in certain foods (especially meat), so the first step for a gout patient is to change their diet. If that doesn’t work, they can take various chemicals that affect uric acid metabolism or prevent inflammation.

    Gout is traditionally associated with kings, probably because they used to be the only people who ate enough meat to be affected. Veal, venison, duck, and beer are among the highest-risk foods; that list sounds a lot like a medieval king’s dinner menu.

    Purines are in just about everything that has DNA. Meat is unfairly blamed for gout, even though you can get gout even if you are a vegan. If meat, per se, caused gout, then you’d see extreme levels of gout in most hunter-gatherer societies, which on average consume(d) a lot of meat. If anything, looking at the risk factors for gout, it looks like just another member of the metabolic syndrome family. Just a result of rich people being able to get too fat to be healthy.

    Anecdotally, I haven’t eaten non-trivial amounts of plant-based foods in like a year and a half, and I don’t have gout. My uric acid is below saturation, (5.4 to 6.7 mg/dl across five measurements within the last year or so).

    • Lambert says:

      Mycoprotien-based meat substitutes (Quorn) need to be processed to remove all the nucleic acids, lest it give everyone gout. Not sure how much of it is left.

  16. kaakitwitaasota says:

    Have any of these studies controlled for meat consumption? As you note, meat consumption leads to higher levels of uric acid, and brains seem to really like meat–I find I think considerably more clearly when I have a bit of beef in the morning. If it’s meat consumption that helps, then we might expect higher uric acid levels to be a side effect of that relationship, but the observed relationship between uric acid levels and achievement would be fuzzy and noisy, which is what we see.

  17. matkoniecz says:

    typo?

    before anyone realized their was a replication crisis

    their -> there

  18. Tony says:

    https://www.youtube.com/watch?v=lnKdvwngRdM

    “L. Amber O’Hearn – My case against uricase: a critical examination of hypotheses”

  19. Cerastes says:

    Just an FYI, the other major lineage that lost uricase was the Sauropsids (birds, reptiles, extinct parareptilia), where it was associated with water conservation – being able to excrete uric acid lets you save a TON of water, which helps today (reptiles are a HUGE part of desert fauna) but was especially important in the hot, arid Permian. Co-incidentally, apes lack uricase and started to diverge during the Miocene, as the planet got cooler but also dryer (retreat of tropical rainforests).

  20. dusty_yeti says:

    John Cade discovered lithium as a treatment for mania in the 1940s when looking for a uric acid-lowering agent in guinea pigs.

    • Student says:

      Specifically he was collecting urine from people with psychiatric illnesses and injecting it into the abdominal cavities of Guinea Pigs. Supposedly urine from people with mania was particularly toxic when instilled in this fashion, but could be blunted by lithium carbonate.

      https://www.nature.com/articles/d41586-019-02480-0

      • deciusbrutus says:

        Wait, there are consistent detectable differences in the urine of people with mania? Is that true of other psychiatric illnesses?

        • Student says:

          One would think so if the original research was valid. I’m curious if it could have been someone stumbling across the right answer for the wrong reasons.

          If urine of those in a manic episode was so different, couldn’t it be used for diagnostic purposes?

          It seems odd.

  21. Lambert says:

    It’ll probably just turn out that there’s some gene that regulates both brain growth in utero and uric acid levels or something.

  22. John B says:

    The association of gout with rich men was noted long ago and mocked by skeptics who thought doctors used that term to flatter their patients; Lord Stanhope once wrote, “gout is the distemper of a gentleman—whereas the rheumatism is the distemper of a hackney coachman.” See https://benedante.blogspot.com/2013/01/what-happened-to-gout.html

    • wanda_tinasky says:

      Came here to say this. And testosterone levels rise in response to success, which would seem to explain the gout thesis. Women seem like the obvious control here. Are there any studies which investigate the correlation between success and gout in women?

  23. Yashabird says:

    I’ve been following a number of the “Purine Hypotheses” on neuro(-evolutionary) development for a while now. In med school, I took a personal interest in Lesch-Nyhan Syndrome (and, in the process, shorthand-conceptualized Lesch-Nyhan as “severe, congenital gout”), because it seemed that I personally shared with Lesch-Nyhan kids their characteristic constellation of: developmental difficulties, including 1.) high trait irritability, 2.) problems with speech acquisition, 3.) motor symptoms localizable to the basal ganglia, 4.) social aggression, and 5.) compulsive self-injurious behavior – with the specific hallmark of repeatedly seeking sharp pain to one’s own lips and fingertips in order to self-soothe. It was somewhat eerie for me to find myself (over-)identifying with the intellectually disabled, as Lesch-Nyhan sufferers often are (and I don’t use “sufferer” lightly in their case), but the qualitative neurological commonalities between myself and the overwhelmingly hyperuricemic were rife and compellingly specific.

    It was already a long-standing question for me, how these neuro symptoms, apparently attributable to hyperuricemia, might be related to human cognition, because, though I suppose I was a generally weird kid, I shared many of my personal quirks with other members of the pretty large family I have to compare myself with. Two areas where I am very obviously and measurably an outlier within my own large family, though, are 1.) my motor symptoms (which are generally pretty classic for Tourette’s), and 2.) my outlier performance on a lot of cognitive tests.

    To my tentative intuition…informed by the above: uric acid probably doesn’t function so much as a classical “stimulant” as it does as an irritant. I’m using “irritant” loosely here, because I’m probably conflating “high trait (developmental) irritability” with the electroencephalographic sense of “cortical irritability,” but I’d like to be able to make that leap between psychological and neurological irritability, because I think it might be reasonable to posit some perhaps-complex relationship between high trait irritability and one’s position along a “Social Class Gradient of Serum Uric Acid Levels in Males”…and, however that relationship plays out, the neurodevelopmental perspective should be helpful in sussing out the mechanism.

    Because Tourette’s is characterized by underdevelopment of certain parts of the basal forebrain (along with secondary compensations in the development of other neurological circuits), and because underdevelopment of the basal ganglia is also a very common finding in “severe, congenital gout,” here are two quick excerpts from Oliver Sack’s lovely story Witty Ticcy Ray, which I venture may support a role for uric acid in guiding human cognitive evolution through its “irritant” insults on neurodevelopment, perhaps specifically within the basal forebrain:

    The ‘It’ in Tourette’s, like the ‘It’ in Parkinsonism and chorea, reflects what Pavlov called ‘the blind force of the subcortex’, a disturbance of those primitive parts of the brain which govern ‘go’ and ‘drive’. In Parkinsonism, which affects motion but not action as such, the disturbance lies in the midbrain and its connections. In chorea – which is a chaos of fragmentary quasi-actions – the disorder lies in higher levels of the basal ganglia. In Tourette’s, where there is excitement of the emotions and the passions, a disorder of the primal, instinctual bases of behaviour, the disturbance seems to lie in the very highest parts of the ‘old brain’: the thalamus, hypothalamus, limbic system and amygdala, where the basic affective and instinctual determinants of personality are lodged. Thus Tourette’s – pathologically no less than clinically – constitutes a sort of ‘missing link’ between body and mind, and lies, so to speak, between chorea and mania.

    Between 1973 and his death in 1977, I enjoyed the privilege of corresponding with the great neuropsychologist A.R. Luria, and often sent him observations, and tapes, on Tourette’s. In one of his last letters, he wrote to me: ‘This is truly of tremendous importance. Any understanding of such a syndrome must vastly broaden our understanding of human nature in general … I know of no other syndrome of comparable interest.’

    Maybe I’m wrong to claim hyperuricemia as of specifically comparable interest in elucidating “human nature in general,” but under a neurologist’s rubric, the overlap of expression and evolutionary implications at these two extremes of pathophysiology doesn’t seem immediately dismissable.

    • noyann says:

      To my tentative intuition…informed by the above: uric acid probably doesn’t function so much as a classical “stimulant” as it does as an irritant. I’m using “irritant” loosely here, because I’m probably conflating “high trait (developmental) irritability” with the electroencephalographic sense of “cortical irritability,”

      This irritation should respond to pregabalin and similar substances that lower the excitability of neurons. In the other direction, someone here reported severe aboulia after pregabalin. An irritation—aboulia axis would be relevant for success in life.

    • Murphy says:

      Came here to mention lesch nyhan syndrome.

      For context it’s slightly nightmare fuel.

      Kids with the disorder often do things like chew off their own lips or fingertips.

      The mutations that case it are well known: SNP’s that break the HPRT1 gene .

      As such kids with it have very high levels of uric acid.

      Mutations in the HPRT1 gene cause Lesch-Nyhan syndrome. The HPRT1 gene provides instructions for making an enzyme called hypoxanthine phosphoribosyltransferase 1. This enzyme is responsible for recycling purines, a type of building block of DNA and its chemical cousin RNA. Recycling purines ensures that cells have a plentiful supply of building blocks for the production of DNA and RNA.

      HPRT1 gene mutations that cause Lesch-Nyhan syndrome result in a severe shortage (deficiency) or complete absence of hypoxanthine phosphoribosyltransferase 1. When this enzyme is lacking, purines are broken down but not recycled, producing abnormally high levels of uric acid.

      kids with the disorder have a somewhat extreme urge towards self-mutilation along with moderate cognitive difficulties.

  24. Lancelot Gobbo says:

    Currently enjoying my first episode of gout, which is a consequence of a gentle, slow-motion tumour lysis syndrome as ibrutinib attacks my relapsed CLL. Have treated gout dozens of times in others, and seeing how annoying my left 1st MTPJ has become even though it is not hot, red and shiny, I feel sorry for those for whom it went full-blown before they limped into the office. Now on the cure being worse than the disease front, I asked an ex-colleague (I’m retired) for some colchicine. I grew up knowing the regime of “Take 2 and then one every two hours until you are better or you can’t stand the diarrhoea”, but as years went by I switched along with everyone else to the “Take 2 and then 1 twice a day till better”. Seems that one a day is more than my guts like, and I even wake up with a raw oesophagus despite omeprazole. This stuff is damn good at putting the brakes on cell division!
    Traditionally, gout was felt to be a disease of the wealthy, and getting it required a rich diet and an excess of alcohol. But there was a good deal of reporting bias in that, as the poor didn’t see doctors, and even if they had, would history recall their gout as opposed to that a a famous (and famously grouchy when suffering) person? The complete failure of low-purine diets to alter the incidence in sufferers (and who lives on sweetbreads, banana skins and anchovies anyway!), and the discovery of different forms of xanthine oxidase was what transformed our understanding. If you inherit a more active form of xanthine oxidase, you get gout more easily. Get it often enough, and it’s worth swallowing a xanthine oxidase inhibitor each day (allopurinol). I have never had gout till now, but nor has anyone in my family, and this is only the second time I have killed of millions of white cells in a hurry (and guess what? Last time I was put on allopurinol prophylactically). None of this alters the hypothesis that uric acid might have some unseen effects on life outcomes, and that is interesting.

  25. ambimorph says:

    Hi, I think I have an answer to this dilemma.

    I gave a talk about the evolutionary puzzle of humans having high uric acid last year at the Ancestral Health Symposium, and a short, less detailed abstract in the Journal of Evolution and Health. Both are titled “My case against uricase: a critical examination of the hypotheses.”

    The TL;DR is that there is mass confusion about hyperuricemia (which isn’t sufficient for gout, by the way!) due to the fact that metabolic syndrome is *one* cause of it, and that cause is associated with gout and bipolar disorder. However, in the *absence* of metabolic syndrome, high UA appears to be an advantage (as is seen in some cognitive and neurological conditions). In the talk I explain more and give some cross-species analysis. The abstract is more focused on refuting the argument that high UA in the absence of high carbohydrate intake can cause metabolic syndrome.

    [1] Talk
    [2] Journal abstract

  26. J.D. Sockinger says:

    Anybody know of a good source of the theacrine-containing tea? I’m interested in the tea itself, not the theacrine supplements. I spent a few minutes on Google and didn’t come up with anything promising. I’m surprised that it’s not easily available. You’d think there would be a market for it.

    • Lambert says:

      Sounds like it comes from Yunnan.
      So maybe a specialist pu-er exporter?
      It’d probably be ruinously expensive to import.

  27. Reasoner says:

    How about Uridine? It’s also used as a nootropic.

    Check the post count on this famous thread. I used to take that stack every so often, and I found it was incredible for reducing social anxiety. (From herbivore man to party animal after a week of administration; effects persisted a good while after stack is discontinued.) But I stopped when I saw this paper which said “pharmacological uridine may be carcinogenic”. There’s also this and this to worry me.

    Curious to hear any of your thoughts; I’m out of my depth evaluating the severity of these risks. Uridine is present in beer, so it can’t be that bad right? But better to stay on the safe side if its effects are amplified by the other components of that stack? But maybe the bad effects wouldn’t be amplified?

  28. wpidentity says:

    Well, I have self-experimentation proof! High achiever, got gout. Allopurinol lowers uric acid levels, and my career stalls, so that I finally just retired. QED.

    Personally, I prefer retired obscurity to intense pain, but maybe that’s just me.

    • Tarpitz says:

      You missed the killer achievement-preserving prophylactic: wearing socks indoors so your feet never get cold. I’ve managed to almost completely eliminate flare-ups since I realized this worked.

  29. Wency says:

    Fun anecdote: only person who has ever personally told me he has gout is a successful businessman with net worth of about $100MM, probably richest person I know personally.

    Overlapping with previous post, the drug to treat it can apparently be very expensive (he quoted me high 5 figures per year). He was telling me about his efforts to pick up insurance that covers it at a reasonable cost to him.

  30. Beans says:

    Some would call me high-achieving in my field, and over the last few years I’ve had some business with my left big toe joint that is consistent with a touch of gout, but I can’t objectively evaluate either of these things.

  31. Fun post, thanks.

    What about the list of very famous people with gout?

    There’s another obvious explanation which you touched on in mentioning base rates, but is worth making explicit: it’s not like there are gonna be lists of non-famous people with gout! ‘This guy called John had it, and his second cousin, and this other lady called Mary…”

    You could make the same kind of list for literally any attribute: in the absence of base rates, it would seem like an Intriguing Spooky Connection that all those rich/famous people were left-handed/Capricorns/suffered from IBS.

  32. Gerry Quinn says:

    I’ve had an occasional attack of gout since I was about 40. I haven’t done anything about it since it only hits occasionally. Mostly the big toes, once or twice a knee, the last attack was about three years ago in the fourth finger of my right hand. It’s very painful when it occurs, but it goes away – after a week there is at most some residual pain, though the finger joint stayed swollen for quite some time. I need more than that to throw myself upon the mercy of the medical profession.

    I eat plenty of meat and I drink more beer than doctors have recommended since Edwardian times, so I suppose I do nothing to upset standard hypotheses about its cause.

    • Carl Milsted says:

      Organ means have a lot more DNA than muscle meats. In the olde days the organ meats were more prized: more vitamins and more tender.

      Modern beer is filtered so you don’t get as much brewer’s yeast and in the olde stuff. I have given myself temporary gout by taking brewer’s yeast as a supplement or taking “natural” vitamins where had brewer’s yeast extracts. I also got gout once from drinking homemade wine — dregs not filtered out. No problems from store bought wine.

      • Rebecca Friedman says:

        In the olde days the organ meats were more prized: more vitamins and more tender.

        Where are you getting that from? Alternately, how old do you mean? I have done a great deal of reading old cookbooks, including ones that puff themselves up a great deal (“And here is a poem written about this dish! … Whereas this other poet, speaking of this dish, writes: “…” ) and I don’t think I’ve seen any evidence to that effect. Sugar, yes, meat-as-opposed-to-vegetables yes, rice yes if you get early enough, definitely an emphasis on the fineness and whiteness of sugar/flour, but organ meats as better than other meats no.

        Which doesn’t mean you’re wrong, what I’ve read is a tiny subset of what exists. But when and where are you thinking?

        • Gerry Quinn says:

          Organ meats are definitely less prized than they used to be, judging by the paucity of them on supermarket shelves. One of my local supermarkets still does lamb’s liver, the other has none. (Obviously there will still be some in processed meats and pies etc.)

          A few decades ago, you’d see at least liver and kidneys from several different species, along with tripe – and I think I’ve seen sheep’s hearts in a supermarket too.

          • Rebecca Friedman says:

            It’s a bit easier to find them in non-American grocery stores – I can get at least tongue, maybe a couple kinds, at least one kind of heart, I believe tripe, and I think a couple other things, at my local Chinese supermarket – and they do come with whole chickens, but yes. On the other hand, my understanding is that organ meats were pretty cheap back when they were more common – one of the ways to get some sort of meat if you didn’t have the budget for something fancy. I wasn’t personally making observations a few decades ago; does that match your experience?

            If so, have you considered the hypothesis that the majority of people haven’t gotten less fond of organ meats, they’ve just gotten more capable of affording meats they always liked better?

    • Acedia says:

      Are you unusually wealthy or successful?

  33. Etoile says:

    It seems like for any effect where one gender is way more affected than the other, there should be an immediate check for the impacts of testosterone/estrogen/sex hormones? And, secondarily, to see whether the opposite gender with unusual amounts of the relevant hormone – in the case of gout, women with high testosterone — have a greater prevalence of the condition?

  34. AdventureTrevor says:

    Sorry for this zero-value-add comment, but in “…but I’m just not feeling like it’s met it’s burden of proof”, the second “it’s” should be “its”.

  35. zardoz says:

    Gout: it’s like sunlight in the body!

    Sorry.

  36. cxed says:

    Joint problems? My engineer perspective wonders about how much use the joint gets. In other words, maybe all the right chemistry is there, but if you don’t use the joints a certain way, problems arise. This is compatible with kings presumably needing to be less physically active. So shouldn’t exercise be considered? And not just from the normal limited “burns calories” perspective.

  37. liquidpotato says:

    This has GOT to be the weirdest thing I have ever read on gout.

    I have gout and it is just pure hell when it happens. Thankfully I’ve found a way to control it.

    Never thought I’d ever see a thing linking gout as possible correlation with improved mood and energy. Thanks for making my day. I just don’t know what to feel about it all.

  38. Steve Sailer says:

    When I was in high school, it was often said in textbooks that tuberculosis might have contributed to the genius of its many Romantic Era victims, such as Keats.

    For example, from the Journal of the American Medical Association in 1941:

    January 4, 1941
    Tuberculosis and Genius
    JAMA. 1941;116(1):85. doi:10.1001/jama.1941.02820010087041

    Abstract
    Again and again physicians have given thought to the possibility that illness, such as tuberculosis or even dementia paralytica or starvation or some other physical factor, might stimulate mental activity or even be an important factor in the production of genius. There has been, for instance, evidence to show that a crippling handicap may serve as an important factor in the development of ambition. Indeed, articles have been published to indicate that allergic children are brighter than nonallergic. In this book Dr. Moorman discusses the effects of tuberculosis as they modified the lives of a number of extraordinary workers in the field of letters. Obviously, a similar study might be made in relation to art, architecture, medicine or some similar activity. There are some who insist that tuberculosis acts particularly as a stimulus to the brain in the case of writers …

    • Steve Sailer says:

      In general, however, tuberculosis and gout were seen as ailments at opposite ends of a spectrum running from young / gaunt / artistic / genius to old / fat / unaesthetic / noncreative. Tuberculosis was seen as a disease plaguing young bohemian artists living in garrets, while gout afflicted the Pickwickian well-fed.

      • Steve Sailer says:

        Geoff Nicholson wrote about gout in the NYT in 2008:

        The received wisdom associates gout with debauchery and decadence. It’s supposed to afflict bloated, self-indulgent, post-middle-aged clubmen (never women) who slump in leather armchairs, gorging on grouse, port and Stilton and railing against youth and modernity. Definitely not people like me. …

        The roll call of famous gout sufferers is long and distinguished and includes Benjamin Franklin, Leonardo da Vinci, Martin Luther, Oliver Cromwell, Galileo, Theodore Roosevelt, Henry James, Benjamin Disraeli, Thomas Jefferson and Karl Marx. …

        As late as 1926, in his book “A Study of British Genius,” Havelock Ellis was happy to confirm the connection between genius and gout. It “occurs so often,” he writes, “in such extreme forms, and in men of such pre-eminent intellectual ability, that it is impossible not to regard it as having a real association with such ability.”

        … Perhaps Conrad avoided mentioning gout in his novels because it’s so frequently seen as a comic plot device. The fictional gout sufferer has historically been, and continues to be, a figure of fun rather than tragedy. Falstaff rails against it in “Henry IV, Part 2”: “A pox of this gout!” he says. Sir Leicester Dedlock in Dickens’s “Bleak House” is a laughable old aristo who regards gout as a painful but necessary, indeed a noble, part of his family inheritance. Gout pops up throughout P. G. Wodehouse as a nasty and disabling condition, but not something to be taken at all seriously.

        https://www.nytimes.com/2008/08/03/books/review/Nicholson-t.html

  39. PeterL says:

    There’s a simpler explanation: rich&successful people have until recently been fat – being fat has historically been a mark of success (it’s only recently that thinness has become a sign of wealth).
    There’s a link between obesity and the production of uric acid: https://www.jbc.org/content/288/38/27138
    So, the inference isn’t high uric acid -> success but rather:
    Success -> obesity -> high uric acid -> gout.

    (Also, ordinary people would not have had the details of their lives remarked upon, regardless of them having or not having gout.)

    Nice theory, though. It had me wondering whether my sensitivity to caffeine is related to my high uric acid levels …

    • Steve Sailer says:

      Did Newton have gout during his annus mirabilis of 1666-1667 or decades later when he was a rich, successful civil servant but past his scientific prime? Tuberculosis was notoriously a young genius’s disease. I doubt if tuberculosis made its victims more brilliant, but that was a popular theory back when both TB and gout were common, whereas I’ve never heard of people back then theorizing that gout made you smarter.

  40. jameverywhere says:

    Anecdotally, I’ve known four people with gout. One was a young college student of average intelligence and ambition, one was a severely disabled alcoholic, one was an overweight depressed homeless individual, and yet another was applying for disability for a combo of physical and mental ailments, including the gout.

    I’d personally always associated gout with poverty and poor health for this reason. I knew about the kings in the old days but I always figured they had gout because of obesity problems.

  41. Plumber says:

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