Since the beginning of time, mankind has yearned to drink a cup of coffee at 5 PM and go to sleep at 10.
asserted
mankind → yearn → 10
Here’s a simplified diagram of caffeine metabolism:
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diagram → ’ → metabolism
Caffeine is converted to a different stimulating chemical called paraxanthine by a liver enzyme called CYP1A2, over a half-life of ~5 hours.
asserted
Caffeine → convert → hours
Then the same enzyme converts paraxanthine into other non-stimulating chemicals that don’t matter, over a half-life of about three hours.
asserted
that → convert → hours
Kman on Less Wrong has graphed the total effective concentration over time:
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Kman → graph → time
Over the course of hours, the liver converts caffeine into paraxanthine.
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liver → convert → paraxanthine
These are (by assumption) equally potent, so total effective concentration (the dashed red line) goes down slowly.
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concentration → go → assumption
(Why does it go down at all?
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it → go → ?
Because of the simplification in the diagram above: only about 80% of caffeine is converted to paraxanthine; the rest is converted to other, less active metabolites.)
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rest → convert → metabolites
By hour ten, paraxanthine predominates, the liver is mostly converting paraxanthine to other non-stimulating chemicals, and effective concentration continues to decrease.
asserted
concentration → predominate → chemicals
In this model, we see that the effective half-life of caffeine is close to ten hours1!
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life → see → hours1
What if we want it to be less?
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it → want → ?
There are three levers we can pull: the enzyme, the metabolite, and the starting chemical.
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we → be → ?
The Enzyme
CYP1A2 is a cytochrome enzyme, part of a large and venerable family that has been protecting your ancestors from toxins since you were all sea slugs.
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you → protect → toxins
The more CYP1A2 you have, and the better it works, the faster you eliminate caffeine and all its active byproducts.
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you → have → caffeine
A tree in China called Tetradium ruticarpum produces fruits containing the chemical rutaecarpine, whose only notable characteristic is that the liver hates it.
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liver → call → it
Feed it to rats, and their livers will go into overdrive, producing more and more CYP1A2 to tear up the intruder.
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livers → feed → intruder
Give those rats caffeine, and the newly-CYP1A2-enriched rats will metabolize it much faster than usual.
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rats → give → it
At last, our goal of drinking coffee at 5 and falling asleep at 10 appears to be in sight!
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goal → drink → sight
Of course, it would be irresponsible to go straight from these rat results to trials in humans, by which I mean you can buy it for $26.99 on Amazon.
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you → go → Amazon
Does this work?
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this → work → ?
It’s unclear how long it takes rutaecarpine to take effect2, but we know from Estari et al that by three hours after dosing, CYP1A2 is elevated to 3x its normal level3.
uncertain
CYP1A2 → ’ → level3
If you take the rutaecarpine three hours before the caffeine, your metabolism might look like this:
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metabolism → take → this
The total process, from caffeine to paraxanthine to inactive metabolite, goes from 8 hours to 4!
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process → go → 4
If we accept as a rule of thumb that most people can sleep after one full effective concentration half-life has elapsed, then this suggests the 5 PM → 10 PM plan could work.
uncertain
plan → accept → thumb
It even leaves some margin of error in case you forget to take the rutaecarpine until an hour or two after the coffee; the enzymes ramp up fast.
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enzymes → leave → coffee
Amazon supplement reviews are always implausibly positive, but for what it’s worth, they seem to agree that this does its job:
This stuff is great.
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stuff → ’ → job
I use it for special environments/days (usually work-related) when I need to have some caffeine later in the day.
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I → use → day
I’m someone who is naturally affected dramatically by caffeine, so if I have so much as a black tea at 3 PM on a regular day, I’ll have a hard time falling asleep at the right time that night.
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I → ’m → time
But with [rutaecarpine], if I need to, I can even have a coffee at 8 or 9 PM and still fall asleep, if I take this about two hours before I want to fall asleep.
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I → need → this
For a while, a few years ago, I used this almost daily, in order to be able to regularly have caffeine late into the day.
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I → use → day
These days, I use it more sporadically, as I generally only drink tea now, not coffee (which is better for my overall mood (less anxiety)); but this is still super useful for those times when I have to be alert in the evening.
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I → use → evening
If you induce your enzymes this way, they’ll still be induced the day after, and the day after that.
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they → induce → that
So all the coffee you drink over the next two days will leave your body twice as fast.
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you → drink → body
If you try to drink twice as much coffee, you will learn that metabolic curves are more complicated than that, and spend the next hour bouncing off the walls.
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curves → try → walls
If you try to divide your coffee into smaller doses throughout the day, sorry, metabolic curves are still more complicated than that and the effects will be unpredictable.
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effects → try → that
There is some amount and schedule of coffee-drinking that will get you about the same effects you had before, at the same time, but it probably depends on your personal metabolism, and it’s up to you to discover it.
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it → be → it
(this also means that CYP1A2 itself will build up in a complicated way; if you take this medication daily, the effect will be stronger after a week than it was the first day, and it’s up to you to navigate this.)
Second, there are rumors that rutaecarpine causes liver injury.
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rutaecarpine → mean → injury
This is maybe the least surprising side effect ever for a chemical whose whole mechanism of action is to provoke the liver so strongly that the liver builds lots of new metabolic enzymes to destroy it extra fast.
asserted
liver → provoke → it
But the magnitude could range from trivial to life-threatening, so we should examine it in greater depth.
uncertain
we → range → depth
…and 125 more, not listed.
