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 ;)
Do you know how much it affects your deep sleep duration?
People who drink caffeine at night may claim to be able to sleep still, but they will find that deep sleep stages are shorter, which is significant because it may be the most important type of sleep.
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.
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.
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.
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.
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.
Decaf only is great for coffee lovers. Instant decaf is of course just a way to spoil perfectly good hot water. But decaf beans from a good roaster are good then grind and make what you desire - espresso, pour over, french press, moka etc.
The point is to communicate that it's not a steep step change. In the original caffeine-only model, it's a smooth exponential decay function. There is still measurable caffeine in your blood N hours later, at levels approximately 1/(2^(N/5)) as high as the peak concentration.
In the new model, it's still smooth decay, but it's a compound exponential decay which is spread out over a longer time period, and close to linear for a while after that, before going on a longer exponential decline.
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?
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.
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...
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.
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.
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.
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.
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.
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.
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.
> 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.
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.
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.
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?).
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.
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.
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!
I used to drink two double-espressos (technically a latte with a double-espresso in it) a day -- one in the morning, one early afternoon -- for many years.
~5 years ago I stopped drinking the afternoon coffee, and have subjectively noticed improvements in my sleep -- less wakeful in the night. It also fits better with my sleep habits, where when I was younger I commonly worked past midnight whereas now I'm asleep by 10 pm and wake up early.
I still drink the morning coffee and I wouldn't switch to another stimulant because the main reason I drink coffee is because I enjoy drinking coffee :)
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...
Very interesting! An aside and fishing lazily: I am one of those people where caffeine has a very strong and long lasting effect. I don't have caffeine after about 9am or it affects my sleep that night. I love drinking coffee, and fortunately for me it seems like decaf got way better and widely available recently. Did something happen there?
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.
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.
105 comments
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 ;)
Great book.
People who drink caffeine at night may claim to be able to sleep still, but they will find that deep sleep stages are shorter, which is significant because it may be the most important type of sleep.
I did this for a while working nights until I caught on. The nights I didn't have a can were much better.
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.
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.
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.
Maybe preground OK for non-espresso too?
The literature for AASM protocols suggests 41 hours without caffeine is enough to safely control for those potential effects
In the new model, it's still smooth decay, but it's a compound exponential decay which is spread out over a longer time period, and close to linear for a while after that, before going on a longer exponential decline.
But the real question is: does it taste as good as espresso?
> 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.
> 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.
>
Coffee is an acquired taste, I thinkBillions 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.
> 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.
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.
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?).
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.
> Importantly, the primary metabolites also block adenosine receptors.
Biochemistry is rarely a one-and-done event it would seem.
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!
~5 years ago I stopped drinking the afternoon coffee, and have subjectively noticed improvements in my sleep -- less wakeful in the night. It also fits better with my sleep habits, where when I was younger I commonly worked past midnight whereas now I'm asleep by 10 pm and wake up early.
I still drink the morning coffee and I wouldn't switch to another stimulant because the main reason I drink coffee is because I enjoy drinking coffee :)
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...
It also has neuro-protective effects if you're an older gentleman.