Since the beginning of time, mankind has yearned to drink a cup of coffee at 5 PM and go to sleep at 10. But now there’s an entire scientific subfield and several companies pandering to this absurd fantasy.
Here’s a simplified diagram of caffeine metabolism:
Caffeine is converted to a different stimulating chemical called paraxanthine by a liver enzyme called CYP1A2, over a half-life of ~5 hours. Then the same enzyme converts paraxanthine into other non-stimulating chemicals that don’t matter, over a half-life of about three hours. Kman on Less Wrong has graphed the total effective concentration over time:
Over the course of hours, the liver converts caffeine into paraxanthine. These are (by assumption) equally potent, so total effective concentration (the dashed red line) goes down slowly.
(Why does it go down at all? 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.)
By hour ten, paraxanthine predominates, the liver is mostly converting paraxanthine to other non-stimulating chemicals, and effective concentration continues to decrease. In this model, we see that the effective half-life of caffeine is close to ten hours1!
What if we want it to be less? There are three levers we can pull: the enzyme, the metabolite, and the starting chemical.
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. The more CYP1A2 you have, and the better it works, the faster you eliminate caffeine and all its active byproducts.
A tree in China called Tetradium ruticarpum produces fruits containing the chemical rutaecarpine, whose only notable characteristic is that the liver hates it. Feed it to rats, and their livers will go into overdrive, producing more and more CYP1A2 to tear up the intruder. Give those rats caffeine, and the newly-CYP1A2-enriched rats will metabolize it much faster than usual. At last, our goal of drinking coffee at 5 and falling asleep at 10 appears to be in 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.
Does 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. If you take the rutaecarpine three hours before the caffeine, your metabolism might look like this:
The total process, from caffeine to paraxanthine to inactive metabolite, goes from 8 hours to 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. 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.
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. I use it for special environments/days (usually work-related) when I need to have some caffeine later in the 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. 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. 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. 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. Honestly a game changer; highly recommend!
There are only two catches.
First, the half-life of CYP1A2 itself is about two days. If you induce your enzymes this way, they’ll still be induced the day after, and the day after that. So all the coffee you drink over the next two days will leave your body twice as fast. 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. 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. 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.
(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. 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. But the magnitude could range from trivial to life-threatening, so we should examine it in greater depth.
Tetradium fruit extract, confusingly called Evodia for irrelevant historical reasons, is used in traditional Chinese medicine. The traditional Chinese say to only use it for a few days or weeks at a time, not constantly over long periods. Some Chinese rodent studies suggest that Evodia harms the liver. Evodia contains many chemicals besides rutaecarpine, so this doesn’t necessarily implicate rutaecarpine. But it also doesn’t necessarily exonerate it.
On the other hand, Choi et al study rutaecarpine directly (in mice). Their endpoint is liver enzyme elevation, a common early signal of damage4, and they find no negative effects after seven days. They even find that the chemical mildly helps protect the liver against other things (plausibly through hormesis, where slightly stressing an organ activates its built-in protective response and makes it more resilient). Also, some Redditors mention taking rutaecarpine for long periods (several months to one year) without any issues.
However, three Amazon reviews (out of ~300) mention liver problems. One, an extreme and life-threatening case of liver failure, includes enough details that we may suspect that it was something else5. But two - cases of isolated liver enzyme elevation - do seem potentially related to the rutaecarpine. Here’s the one that included details:
I’ve tried these since coffee kept me up at night. They worked great!! I was scheduled for a blood test about a month after taking these, my results came back with very concerning, very very high liver enzymes. My doctor told me to stop taking anything in pill form, even Tylenol. I tried narrowing down what could be causing my liver enzymes to be so high. I googled the rutaecarpine(the main ingredient) and it says will Cause SEVERE Liver damage!!! I stopped taking this and was retested a week Later and my liver enzymes fell half way. I started taking my normal pill routine (without the daily decaffinate) Retested another week later, liver back to normal. So BEWARE of this product I can’t believe this is even allowed to be sold on Amazon
We should be careful drawing any conclusions from this limited evidence. Mouse studies don’t always extend to humans, traditional Chinese medicine is sometimes bonkers, and many reports of side effects on supplements are post hoc ergo propter hoc.
But all of this fits a common pattern of a medication which is “safe” for most people over a few days, but can cause some people drug-induced liver injury when taken consistently for weeks or longer. Since there’s lots of interpersonal variation, some people will get liver injury much faster, and other people can take it for years without getting it at all.
I took rutaecarpine 100 mg for three days. I didn’t notice any effect on my caffeine metabolism, but it was already pretty confusing and I ascribe no weight to this result. I tested my liver enzymes after three days, and they were normal.
Caffeine is metabolized into paraxanthine, supposedly an equally stimulating chemical. This suggests a new solution to our dilemma: just take the paraxanthine directly! Instead of superimposed half-lives of 5 hours + 3 hours before becoming inactive chemicals, you just get the half-life of 3 hours!
Capitalism has noticed this niche and leapt to fill it:
Consumer paraxanthine manufacturer Enfinity claims not just that their product has a shorter half-life, but also that it’s “cleaner”, with fewer jitters and a better headspace. And unlike rutaecarpine, a barely-tested plant-derived compound that could be horribly toxic, we can be nearly sure paraxanthine is safe - after all, 80% of the caffeine you drink turns into it, so you have lots of it in your body every day! Is this the answer?
Paraxanthine has only been available to consumers for four years, so the anecdotal evidence base is still building. kman on LessWrong tried it and reported the following:
Taking one or two capsules in the morning has a similar wakefulness-promoting effect to drinking a cup or two of coffee in the morning
I’ve taken one capsule around 4-5pm a handful of times, which did not interfere with going to sleep at 10-11pm
Taking a capsule at 7pm gave me enough energy to do some work in the evening, and did not interfere with going to sleep at 11:30pm
Subjectively the peak effects of 100mg paraxanthine feel similar or weaker than those of 100mg caffeine, while 200mg paraxanthine feels stronger than 100mg caffeine
The effects seem to peak within an hour of dosing (maybe 30-45 minutes)
I sometimes feel a bit of an energy crash 2-3 hours after dosing when I take paraxanthine in the morning, but not in the afternoon/evening
But in the comments, Tomas B says:
I tried it for a few weeks. it does basically nothing for me even at 200 mgs.
Both Kman’s experience and Tomas’ are common. A survey of 24 Reddit reviews across five posts (1, 2, 3, 4, 5) was 2/3 positive (“this works as well as caffeine, but without the jitters, and lasts shorter”) and 1/3 negative (“this does nothing; this puts me to sleep”). Amazon reviews have similar variability:
If we take this seriously, paraxanthine works only for a subset of the people who caffeine works for. Why might that be?
First, maybe we shouldn’t take it seriously. For every supplement, there will always be people who say it changed their lives and other people who say it’s useless garbage that made them feel even worse. And some paraxanthine users will be caffeine addicts who didn’t realize that their high caffeine tolerance gives them high paraxanthine tolerance, took the dose recommended on the bottle, and don’t understand why they’re suddenly feeling tired and headachey and miserable. But enough people gave enough data that I think there’s actually something going on here.
One possibility is fast 1A2 metabolism. Caffeine converts to paraxanthine slowly enough that even people with fast 1A2 metabolism have one or the other in their body for a few hours. But if they start with paraxanthine, it might get converted all the way to inactive metabolites so quickly that they feel nothing at all.
Another possibility is some genuine difference between the two substances. This would have to be subtle - a look at the molecular structure above suggests they’re pretty similar - but the two may affect slightly different adenosine receptor subtypes, and different people may have slightly more of one subtype or the other.
I tried paraxanthine and it mostly made me sleepy, but sometimes taking the wrong dose of caffeine does this too, so I ascribe no weight to this one either.
What if instead of starting with caffeine, we start with a slightly-tweaked version that’s easier to metabolize quickly?
Methylliberine is a caffeine-like chemical found in coffee beans and related plants. Its metabolism is poorly-studied, but its half-life seems to be about 1.5 hours, after which it may be converted to a chemical called liberine. If There are a few studies suggesting that methylliberine is stimulating in a caffeine-like way, so if liberine isn’t, this would be a caffeine analogue with a 1.5 hour half-life. A few studies also suggest it is safe, which should be our default assumption since it’s present in commonly-eaten foods like coffee, tea, and chocolate, as part of a package with caffeine and other safe-enough-to-eat caffeine-analogues.
Methylliberine is sold under brand names including “Dynamine” and “Roon”:
These companies have marketed it as a special workout supplement, arguing that it takes effect faster than caffeine. But caffeine already takes effect pretty fast, and people correctly observe that methylliberine has no real benefit over caffeine for working out. But are they sleeping on methylliberine as a solution to our take-coffee-at-5-sleep-at-10 problem?
Here we encounter the same problem as with paraxanthine: methylliberine is a caffeine-like stimulant, but it’s not exactly the same as caffeine, and some people think it’s worse. But with paraxanthine, the reviews were about 66-33 positive, and here they’re closer to 50-50 (1, 2, 3, 4, 5, 6, 7). Complaints range from methylliberine being too weak, to being too jitter-inducing, to lacking the sort of “dopamine high” that a good cup of coffee sometimes gives.
Typical positive review (source):
Dynamine is fantastic. It's a quick, reliable en…
