83 pointsby swah5 hours ago18 comments
  • keepamovin3 hours ago
    I take pentoxyfylline (a synthetic substituted xanthine, caffeine is a natural substituted xanthine) occasionally as a nootropic and supplement for vascular health and anecdotally for me it has several nice caffeine like properties without the jitters/ long tail, sleep effects etc.

    I find the listed side effects don’t happen for me besides occasional flush/blush. Which at my age is more like youthful vigor.

    Caffeine is is 1,3,7-trimethylxanthine, pentoxyfylline is 3,7-dimethyl-1-(5-oxohexyl)xanthine.

    Good effects are: sustained mental clarity, focus and energy with a smoother more stable baseline than caffeine’s bursty performance; good sleep, but strangely you can also stay up, if you prefer; feeling similar to “after exercise”. Half life is listed as under 1 hour, but beneficial effects can be felt for half a day after 400mg (a standard dose). So maybe there’s something like metabolite dynamics occurring here too.

    This ends my erowid/hive style “trip/nootropic” report ;)

    • ronjakoi3 hours ago
      You should start a xanthina where you serve various xanthinated beverages.
    • qingcharles38 minutes ago
      Pentoxyfylline is prescription in the USA?
  • drakonka5 hours ago
    I think it is already pretty widely recognized that caffeine can disrupt sleep taken even as early as 6 or 7 hours before bed. I usually don't drink coffee or caffeinated tea after 12 for this reason. Caffeine also has many other known benefits, possible beneficial effects on all-cause mortality, etc, and I'm not sure if we have any research showing the same benefits coming from paraxanthine. Seems like potentially a bit of a waste just to be able to get the stimulant effect a couple of hours closer to sleep time.
    • mapt4 hours ago
      This is a distinct claim. Caffeine can disrupt sleep even 48 hours later, a little bit; It is traditionally modelled with an elimination half-life of 5 hours, meaning 1/2 effect at 5 hours, 1/4 effect at 10 hours, 1/8 effect at 15 hours, an exponential decay curve.

      The claim being made is that due to cascading decay of a secondary metabolite that does a lot of the work producing the clinical effect, caffeine elimination is a much more linear, slow process that only reaches half effect at around 10 hours and 1/4 effect at 17 hours, 1/8 effect at 23 hours.

      • mememememememo4 hours ago
        This may explain why cold turkey effects for me take 24h to start
        • ectospheno4 hours ago
          I went decaf drinks only back in 2024. I was fine and thinking “what’s the big deal” until day three. I will never forget that day. So horrible.

          Still decaf only. Has been a pretty positive change for me. Kicked the soda habit completely. Sleep is better. I find I’m even all day. I generally only get tired when I’m bored.

      • malfist3 hours ago
        Just because the halflife leaves a measurable amount in your system, doesn't mean that that amount is enough for measurable outcomes.

        In your example, a 200 mg caffeine intake in the morning, least to 100mg at noon, 50mg at 5PM, 25mg at 10PM. Yes that means you still have 25mg of caffeine. But it's unlikely to have an outcome you can measure since it's below a minimum threshold.

        • Mezzie2 hours ago
          This depends on your genetics - there are different groups of caffeine metabolizers. I'm in the group that's super sensitive to caffeine and I can feel effects from less than 20mg.
  • bensyverson5 hours ago
    This article makes the case for paraxanthine supplements; 80% of caffeine is metabolized into paraxanthine anyway, and it turns out paraxanthine behaves a bit more like we (apparently wrongly) assume caffeine works.

    But the real question is: does it taste as good as espresso?

    • nlitened4 hours ago
      > does it taste as good as espresso?

      Coffee is an acquired taste, I think. People conditions themselves to like the bitter taste of coffee over time. I remember hating the taste of coffee (or beer, for example) in childhood.

      • anarazel4 hours ago
        Weirdly enough, I loved coffee from the first time I tried it, at maybe 13. Even though, looking back, it must have been terrible coffee, it was at something vaguely model UN like thing our entire class went to in an overnight trip. Obviously not enough sleep was had. A vending machine (in the late 90s) provided coffee...
        • _glass4 hours ago
          Yes, I also tried coffee first time when in England when 13, and it was like a revelation. I understand that beer and cigarettes are an acquired taste, they tasted terrible, but coffee was a love at first sip.
        • xnorswap4 hours ago
          > it must have been terrible coffee

          Douglas Adams nailed the quality of tea from a vending machine, "almost, but not quite, entirely unlike tea", and that era of coffee machines weren't much better at coffee.

      • Xcelerate4 hours ago
        I’ve heard that bitterness affects children more intensely. So I wonder how much of it is an acquired taste vs bitterness just becoming “milder” over time.
        • yonaguska4 hours ago
          My three year old loves the taste of matcha. Even when I don't prepare it quite right and it turns out very bitter. He's pretty picky about near everything else. I think it's acquisition through mimicry.
          • altairprime4 hours ago
            Matcha is one of the more concentrated amino acids drinks you can make; given how hungry I remember being as a kid, I bet it tastes like liquid gold. And if you’re in a climate that tolerates rhododendrons you can plant a camellia sinensis bush for it straight from the vine as a bridge from matcha to steeped tea, steaming and roasting, etc.
            • dpark2 hours ago
              > Matcha is one of the more concentrated amino acids drinks

              Matcha is virtually entirely water. Multiple sources say that matcha has about 270 mg of amino acids per serving. Even if matcha powder were 100% amino acids (which would taste vile), a 2g serving would still be 2g.

              Milk has about 4.5 grams of amino acid content per 100g (less than half a cup).

              • altairprime2 hours ago
                Yes, that’s one of the reasons dairy matcha lattes taste so good: not only is it more densely amino, but it’s also more broadly amino (e.g. milk is not particularly high in L-theanine), and the sweetness of the milk offsets the bitterness of the matcha, which lets you ramp up the density further beyond 2g if you like.
                • dpark2 hours ago
                  What I mean to say is that matcha is almost devoid of amino acid content. It’s basically a small cup of water. The small amounts of various compounds may have some beneficial effects, but amino acids are abundant in many foods and drinks. You don’t need to get them in micro doses from matcha.

                  Matcha may be tasty. It’s not a good source of aminos.

      • coldtea2 hours ago
        >Coffee is an acquired taste, I think

        Billions all over the world managed to acquire it just fine.

        If that's an acquired taste, I doubt 99% of drinks that aren't an acquired taste would do much better, assuming there's anything doing better than coffee to begin with.

        Not even Cola and tea come close.

      • bensyverson4 hours ago
        It's definitely an acquired taste. But an espresso doesn't have to be overwhelmingly bitter! It can be almost sweet if it's extracted well.
        • lamasery4 hours ago
          Regular coffee, too, can be very delicate, minimally bitter, giving herbal or strong tea-like notes, among other things.

          I've not gotten that kind of profile out of anything but fairly-expensive beans roasted within the last couple of weeks, though. I've never seen it out of even mid-priced beans, nor anything nationally distributed. It's practically a totally different drink from what you get if you ask for a coffee in most contexts.

          Iced coffee and cold brew are also fairly different. I find middling beans can make a much milder and more pleasant cold brew coffee than hot. Tiny (like, a teaspoon) splash of cream or milk and it takes the bitter edge all but completely off, to my taste anyway.

          • bensyverson3 hours ago
            > I've not gotten that kind of profile out of anything but fairly-expensive beans roasted within the last couple of weeks, though.

            Good beans will last more than 2 weeks, but yes—just as you wouldn't judge all sushi based on gas station sushi, we shouldn't judge coffee based on months-old pre-ground grocery store roasts.

            • DougMerritt7 minutes ago
              > we shouldn't judge coffee based on months-old pre-ground grocery store roasts.

              Next you'll be claiming that we shouldn't judge sushi based on months-old grocery store sushi.

      • altairprime4 hours ago
        I now like bitters and soda, and I didn’t like bitter as a kid, so I think there might also be shifts in favor of bitter unrelated to coffee. Perhaps the same thing that leads people to appreciate spicy or sour as experiences broaden.
        • DougMerritt5 minutes ago
          Years ago, somewhere I read that children have a genetically-based urge to avoid bitter flavors, since they may signal natural poisons, whereas adults can judge better, so the urge is lessened.

          (And even if that source were true, that wouldn't make the genetic effect an absolute; it would depend on individual genetics and the variable expression of those genes. And probably on the individual's experience, either as a child or as an adult.)

      • em-bee3 hours ago
        but why? i have to add so much milk and sugar to mask the bitterness that, combined with the negative effects, i asked myself, why do i even bother? i might as well just drink hot milk with sugar instead. now i only drink coffee if i need the energy and waking effects and nothing else sugary is available, which happens once a year, at most.
        • integralid3 hours ago
          This is not universal. I only drink espresso without sugar or milk, because I love the taste of a strong coffee.
      • nightski4 hours ago
        That is entirely dependent on your diet as a child. I know children that love bitter or sour/fermented foods. Not to mention they dislike things that are overly sweet.

        I wouldn't be surprised if all tastes are essentially "acquired".

    • hk__23 hours ago
      > But the real question is: does it taste as good as espresso?

      I don’t know where you live, but in Italy it’s extremely difficult to find a good espresso; you must go in "specialty coffee" places to taste real coffee, as all the bars use cheap coffee that tastes burnt. Ironically, it’s a country that takes pride in its coffee "tradition" but doesn’t know what coffee tastes like. The experience is the same in France, without the "tradition" thing.

    • ortusdux4 hours ago
      I'd imagine it would not be hard to breed/engineer a coffee plant that produces more paraxanthine than caffeine. The plants take 5 years to mature so getting a crop to market would take a while though.
    • m4633 hours ago
      I accustomed myself to drinking coffee black. Then decaf. And later I tried camomile tea.

      I found the need I really needed satisfied was a warm cup of something to curl my hands around in the morning, and they all worked after I let them. ymmv.

    • Sharlin4 hours ago
      I can understand espresso being drunk for many reasons, but none of them are "tasting good".
      • bensyverson4 hours ago
        I actually envy you, because having my first truly good espresso was an experience I wish I could relive
      • 0xbadcafebee4 hours ago
        Cafes that care about their coffee can have very good tasting espresso, but cafes that don't care will produce burnt bitter water. There's also Cafecito, which is basically liquid crack.
        • jjk166an hour ago
          > There's also Cafecito, which is basically liquid crack.

          Is that a warning or an endorsement?

  • georgewsinger3 hours ago
    I'm surprised the author didn't mention the other argument for paraxanthine being less addictive than caffeine: it has a less acute/peaky curve of adenosine blocking.

    I'm not a biologist, but I'm under the impression that your body uses the heuristic of "the more acutely a neurotransmitter is suddenly flooded into our system, the more of a homeostatic counter-response we're going to launch in the form of things like dopamine downregulation (etc, depending upon what neurutransmitter we're talking about)".

    I'm not entirely sure this is true, but it seems to be corroborated by other researchers (e.g. Anna Lembke in her book Dopamine Nation, which isn't about caffeine though).

    This is why substances like theacrine claim to offer even less tolerance than paraxanthine: it has a super gradual adenosine-blocking curve, with super long half-life (like 12-16 hours, IIRC). So when you take one theacrine, you won't notice it for hours, but its effects will last longer than one day (though I forget what its interaction with sleep is supposed to be?).

  • cjbgkagh4 hours ago
    There are some fairly common genes that can drastically effect the strength and duration of caffeine so your experience may vary. For me the effect is very strong and one cup lasts all day, even as a habitual consumer.
    • oasisbob4 hours ago
      Great point. I'm a fast metabolizer, it's highly individualized.
  • bembem_c3 hours ago
    Pharmacokinetics (in this case: half-life in the central(venous) compartment, totally neglecting the distribution to the site of primary activity, the CNS) is only half of the truth.

    You have to consider pharmacodynamics: where is the site of action located, where are the receptors located. And how well do caffein and paraxanthine distribute to this compartment.

    Soiler: Most metabolites are more hydrophilic than respective parent compounds (biological sense of metabolism: to increase renal clearance of xenobiotics). Therefore, receptor affinity alone tells you little about the relative contribution of any metabolite for the pharmacological effect observed.

    And to complicate things even more: Long-half life metabolites are only ONE potential reason for prolonged biological effects.

  • blitzar4 hours ago
    Its like a 45 minute decay - Im not shaking the cup's shaking. I can quit anytime I want, I just dont want to.
    • supliminal4 hours ago
      forehead twitch

      sips half cup

      BASED

  • sharpshadow3 hours ago
    Fun fact smoking reduces caffeine half-life up to 50% by upregulating the enzymes which break it down, which affect paraxanthine as well.
    • R_D_Olivaw2 hours ago
      Smoking in general? Tobacco specifically?
  • charles_f4 hours ago
    That's an interesting takes. I found it quite suspicious at first, especially because it doesn't present well the myths that it's trying to debunk: are we talking abouy caffeine half life or its effects; and is that 5h half life related to the metabolism of caffeine, or related to its effects.

    It looks like pharmacokinetics (ie how long caffeine stays in blood) is what's been studied mostly, and that's where the 5h timeline is coming from. I couldn't find papers on the timeline of pharmacodynamics of caffeine (how long it has effects).

    That's an interesting gap this article is underlining!

  • uticus5 hours ago
    > Importantly, the primary metabolites also block adenosine receptors.

    Biochemistry is rarely a one-and-done event it would seem.

  • mannyv2 hours ago
    FYI you can't patent a supplement. You can, however, be the only manufacturer because nobody else noticed it.
  • siliconc0w4 hours ago
    Nicotine is also a nice alternative to coffee. I still drink coffee but past late morning I'll usually reach for nicotine because the effect is much shorter.

    It also has neuro-protective effects if you're an older gentleman.

    • vrganj4 hours ago
      It's also cripplingly addictive. Ask me how I know.
      • unmole3 hours ago
        > It's also cripplingly addictive.

        That very much depends on the medium. It's virtually impossible for a nicotine naive individual to get addicted to losenges or gum.

        • coffeeindex27 minutes ago
          I’m going to need a source on that
  • meitham5 hours ago
    I haven’t come across lesswrong before! Great site and this caffeine article is great presentation of data.
    • OuterVale5 hours ago
      I feel it my due diligence to advise you that LessWrong is closely associated with the rationalists and all that comes with them. It is worth doing a tad of research into the rationalist community and Eliezer Yudkowsky before going too deep down the LessWrong rabbit hole. https://en.wikipedia.org/wiki/Rationalist_community
      • yehoshuapw4 hours ago
        Regardless of the community,

        Harry Potter and the Methods of Rationality is worth a read.

        https://hpmor.com/chapter/1

        Or a listen: https://hpmorpodcast.com/?page_id=56

        • fwip3 hours ago
          I found it pretty boring, to be honest. Felt like an excuse for the author to show off how smart they thought they were, without really any skill at characterization or meaningful plot.

          And like, I'm not a writing snob. I read fanfic by amateur authors. But HPMOR just doesn't do much of anything interesting.

          • stratos123an hour ago
            There's lots of valid critiques of HPMOR (I recently reread it and the early chapters are painfully obnoxious), but I think "no meaningful plot" and "doesn't do anything interesting" are objectively false. It has like a dozen interacting plotlines, and is massively different from any other HP fanfic and most media in general. It is popular for a reason. If you dropped it early, I'd encourage you to try again.
      • embwbam4 hours ago
        One can take many good ideas from less wrong, yudkowsky et al without adopting a rationalist identity. Sure, it attracted wackos and they made a cult or two. But that could happen to anyone!
        • specialist3 hours ago
          > without adopting a rationalist identity

          Aha: "identity". You nailed the misgivings I couldn't articulate. Thank you.

      • Zababa4 hours ago
        >the rationalists and all that comes with them.

        What does that mean?

        • kreyenborgi4 hours ago
          Probably referring to https://en.wikipedia.org/wiki/TESCREAL

          or, if you don't buy into the "they're all the same" arguments, at least beware of the arguments against utilitarianism https://en.wikipedia.org/wiki/Utilitarianism

          • Zababa4 hours ago
            Yeah but like:

            >Writing in Asterisk, a magazine related to effective altruism, Ozy Brennan criticized Gebru's and Torres's grouping of different philosophies as if they were a "monolithic" movement. Brennan argues Torres has misunderstood these different philosophies, and has taken philosophical thought experiments out of context.[21] Similarly, Oliver Habryka of LessWrong has criticized the concept, saying: "I've never in my life met a cosmist; apparently I'm great friends with them. Apparently, I'm like in cahoots [with them]."

            The people that coined TESCREAL seem to not really be related to rationalists, and seem to have coined a term for "those vaguely related ideas from people that do some stuff we consider wrong and we consider bad". "Evil people from San Francisco" could work just as well I think.

            And wait, shouldn't I beware arguments for utilitarianism rather than against? If that's what you meant yeah I agree, especially pushed to the extreme it leads you in very weird places.

            • tasty_freeze4 hours ago
              I know nothing about the drama, but treating "utilitarianism" as if it is one thing or that a particular person or group's position is identical to utilitarianism seems ironic in the context. It is like claiming all pizza is bad because I went to dominoes and didn't like the experience.
            • SmirkingRevenge4 hours ago
              I'm not sure what the parent meant by "beware arguments against utilitarianism" - there is nothing wrong with arguing for or against utilitarianism. It's a popular moral philosophy.

              You should beware of bad utilitarian arguments though, which is where you often get the real "gotta break a few eggs to make an omelette" kind of arguments that justify all manners of atrocity in service of some narrow hypothetical future good.

              Like when Marc Andreessen says we should consider anyone who would do something to slow down or regulate AI advancement murderers of future humans. Bad utilitarianism right there.

              Proper utilitarians are concerned with the net difference between all positive and negative consequences of actions.

              • tasty_freeze3 hours ago
                People often think they have mic-dropped utilitarianism by saying things like, "Oh, so if two people get a lot of joy by beating up a third person, that is ethical because it is overall net positive?"

                A few things wrong with that. First is there is no net happiness formula which utilitarians are proposing. Peter Singer has said more than once that he weights suffering far, far higher than happiness.

                Second is that every ethical system has screw cases which make the system look messed up. "Do unto others..." it terrible if you are talking about masochists.

        • WBrentWilliams4 hours ago
          Quick Wikipedia search: https://en.wikipedia.org/wiki/Zizians

          Like any group of humans, there are power structures and edge cases that can lead to horrific outcomes. Giving the person that posted the warning the benefit of the doubt, I think what they are saying is that "Rationalist does not necessarily mean positive for humanity, nor even no harm for humanity". This holds for all religions and religion-like movements, of which Rationalism, in this sense, is one.

          • Zababa4 hours ago
            I think this holds for basically all movements in which case, I don't really understand the need to flag that website over any website.

            Edit: though I don't want to diminish that this specific group is a cult with classical cult techniques like sleep deprivation and with the disastrous consequences often associated with cults.

            > They claim to practice unihemispheric sleep (UHS), a form of sleep deprivation intended to "jailbreak" the mind, which they believe can enhance their commitment to their cause.[

            • eightysixfour4 hours ago
              > I think this holds for basically all movements in which case, I don't really understand the need to flag that website over any website.

              Because it uses the language and thinking patterns of the Rationalists, it serves as a strong indoctrination tool. The site itself isn't bad but, as someone who flirted with those communities as a result of the site, I think the warning is deserved.

              • Zababa3 hours ago
                If you feel like the warning is deserved, and have personal experience, yeah then fair enough. I personally live in the "periphery" (read: not in Berkley or SF or New York) so I think I may see way less of the good and the bad.
        • tbrownaw4 hours ago
          It's a particular variety of "everyone else is wrong (and maybe a bit stupid)".

          Like, sure, sometimes you get popular nonsense like recovered memories or accidental fires can't be as hot as intentional fires or shaken-baby syndrome or bite-mark analysis. But a lot of times, everyone isn't wrong and you've just overlooked something critical or misdefined the problem.

          • jjk16631 minutes ago
            > Like, sure, sometimes you get popular nonsense like recovered memories or accidental fires can't be as hot as intentional fires or shaken-baby syndrome or bite-mark analysis. But a lot of times, everyone isn't wrong and you've just overlooked something critical or misdefined the problem.

            The older I get, the more I find that everyone is wrong. It's fucking astounding how much stuff either was never actually checked, or is true only under very select circumstances with those caveats being widely ignored. For example at work right now we have been using a test for 40 years that was developed around the idea that our product absorbed air - chemical variation would lead to extreme differences in results and you can't retest an item for at least 24 hours because it will still be affected. Turns out that none of that was true, all the error we were getting was from temperature change, the items can be retested after 45 seconds. 40 years and no one took 30 minutes to verify this claim which costs us millions of dollars per year. And this is just the example from this past week. I've probably seen several hundred such cases of completely unjustified claims being treated as gospel truth.

            I can't speak for the countless things I've never tested, but if nearly everything I do test is wrong, across numerous fields full of very intelligent people, it doesn't give me much confidence about everything else. We live in a world that values simplicity and confidence, not nuance and rigorous verification. I've gotten to the point where I don't trust anything without verification, not even my own past work.

          • iamnotherean hour ago
            > It's a particular variety of "everyone else is wrong (and maybe a bit stupid)".

            Gestures at the current state of the world

            Not that adopting rationalist modes of thinking will fix the problem, of course. Teach rationalist principles to an idiot and you will have a slightly more rational idiot, who will reason himself into absurdity. Teach them to a manipulative, amoral psychopath and you will have a more skillful manipulator.

            Rationalist principles and methods provide superior tools for thinking through some complex problems, but they say nothing about foundational ethics (other than pointing out possible sources for the many different systems of ethical beliefs). And they cannot be wielded effectively by people who lack the ability to decouple, to think abstractly, or to create extended “chains” of thoughts and keep them in working memory.

            One should be suspicious of anyone who claims that rationalism is a panacea, or alternatively that it is somehow a problem per se. It’s a neutral set of tools, a community who wants to improve those tools, and a small group hanging off the edge who have unrealistic and/or harmful views of how those tools should be applied. Unfortunately this third minority is presented by anti-rationalists as the core of rationalism. In reality, they are easily avoided unless you hold the same core values.

            (I say this as a long time observer who appreciates their work but does not consider myself a part of the “rationalist” community.)

        • mrguyoramaan hour ago
          https://en.wikipedia.org/wiki/Roko%27s_basilisk

          Imagine dressing Pascal's Wager up in blinking lights and considering yourself a rationalist.

          Yudkowsky banned discussion of it for 5 years because he considered it a threat

  • NoiseBert694 hours ago
    For me a coffee is more kind of a ritual addiction.
    • Xerox92134 hours ago
      Making coffee is often the only part of my day that I have control over.
    • bilsbie3 hours ago
      I switched to cocoa. Replaces the ritual at least. I still miss the boost though.
  • michaelcampbell5 hours ago
    This feels like a Gwern blog, or something he'd be interested in.
  • atlgator3 hours ago
    I generally avoid caffeine at all costs. I'm susceptible to SVT, and I want the Adenosine to work if I should need it. Caffeine blocks Adenosine receptors. But on the rare occasion I have a single can of caffeinated Diet Coke, I experience a crash 48 hours later so profound that I cannot get out of bed that day.
  • annoyingnoob4 hours ago
    Why change what works? Especially if you enjoy it.
  • fredgrott4 hours ago
    sight correction....caffeine impacts two neuron groups not just one!

    Dopamine and Noradrenaline

    For dopamine its the competitive for the adenosine part of the dopamine heretodimer....meaning it prevents adenosine from binding and closing the dopamine receptor....

    I use the effect on both dopamine and noradrenaline to assist in controlling my ADHD via more herb based means....

    But author is yes correct that the metabolism of caffeine in how it breaks down does make the half life of its effects longer than 5 hours...I combine my dose with green tea ECGC which gives me a good focus boost of 12-16 hours...