epistemic status: confident in the overall picture, substantial quantitative uncertainty about the relative potency of caffeine and paraxanthine

tldr: The effects of caffeine consumption last longer than many assume. Paraxanthine is sort of like caffeine that behaves the way many mistakenly believe caffeine behaves.

You've probably heard that caffeine exerts its psychostimulatory effects by blocking adenosine receptors. That matches my understanding, having dug into this. I'd also guess that, insofar as you've thought about the duration of caffeine's effects, you've thought of them as decaying with a ~5 hour half-life. I used to think this, and every effect duration calculator I've seen assumes it (even this fancy one based on a complicated model that includes circadian effects). But this part is probably wrong.

Very little circulating caffeine is directly excreted.^[1] Instead, it's converted (metabolized) into other similar molecules (primary metabolites), which themselves undergo further steps of metabolism (into secondary, tertiary, etc. metabolites) before reaching a form where they're efficiently excreted.

Importantly, the primary metabolites also block adenosine receptors. In particular, more than 80% of circulating caffeine is metabolized into paraxanthine, which has a comparable^[2] binding affinity at adenosine receptors to caffeine itself. Paraxanthine then has its own 3-5 hour half-life as it's metabolized into a handful of other things.

Since paraxanthine is by far the dominant primary metabolite, and its further metabolites are mostly either very short lived or have poor affinity for adenosine receptors, we can fruitfully use a simplified model of Caffeine ⟶ Paraxanthine ⟶ Elimination. The upshot is an effective concentration curve with a broader peak and slower decline -- about twice as long to reach half of peak effective concentration, assuming paraxanthine and caffeine are equipotent -- than that given by the simple elimination model. When I say effective concentration, I mean the concentration of caffeine that would be needed to produce the same effect.

Below is a simulator that models caffeine and paraxanthine metabolism following ingestion of 100mg caffeine or paraxanthine (link to full version). Note that the relative potency of paraxanthine can be adjusted; I am uncertain about how it compares to caffeine within that 4-fold window (see the sec...

Pramath Malik

Pramath Malik