Some People React to Caffeine, Some Don't. Here's Why

By Josh Bloom — Oct 16, 2023
Some people drink coffee, and the next thing you know, they're trying to climb the Empire State Building. But others feel little or nothing. What's going on?
Image: Wikimedia Commons

We've all dined with people who would rather drink the effluent from the Newark, NJ sewage plant than a cup of regular (caffeinated) coffee in the evening. And, of course, there is no shortage of potential axe murderers who would be only too happy to start chopping if you go near them in the morning before coffee #1.

I don't get it. Coffee does absolutely nothing to bring me out of my usual morning (make that daylong) stupor, nor does it keep me up at night, no matter what time I drink it. How can two such disparate creatures both claim ownership of the human genome?

That's your clue. It's genetic. When individuals have widely different responses to drugs, the reason is typically pharmacogenomics –  how your genes affect your body's response to medications. This effect often shows up as a difference in drug metabolism, which is governed primarily by the liver. The liver is packed full of metabolizing enzymes called CYPs, short for cytochrome P450. The primary function of CYPs is the oxidation of chemicals or drugs, which prepares them for elimination, keeping bioaccumulation from taking place.

Although the particular CYPs that metabolize caffeine and opioids are somewhat different, your genes determine the amount and distribution of CYPs in your liver. This can result in differences in blood levels – sometimes significant – between two people taking the same drug dose or drinking coffee. (This is something that the morons at the CDC either should have known or did know and intentionally ignored when putting together the 2016 Opioid Advice document –a one-size-fits-none tome of garbage that is responsible for both the undertreatment of pain as well as the explosion in fentanyl OD deaths. Rant over.)

The CYP enzyme that metabolizes caffeine is called CYP1A2 (an abbreviation for Cytochrome P450 1A2). Here's the metabolic pathway.

Caffeine undergoes oxidative demethylation at 3 sites. The primary site of metabolism, indicated by the yellow arrow, is the "noon" methyl group, which forms paraxanthine. Less common is the loss of the "4:00" methyl group (red arrow), which forms theobromine, the primary xanthine in chocolate. Rarely the "7:00" methyl group (green arrow) is knocked off, resulting in theophylline, an old asthma drug. (1)

Are you slow or fast?

The response to caffeine (these are generalities) can roughly be divided into two groups (2).

Slow metabolizers:

  • caffeine stays in their system for a longer time
  • heightened alertness
  • increased heart rate
  • increased potential side effects
  • jitteriness
  • anxiety
  • Insomnia

Fast metabolizers:

  • experience the stimulating effects of caffeine more acutely
  • these effects dissipate more rapidly
  • fewer negative side effects of caffeine
  • they may be able to consume higher doses without undesired effects

Aside from decaf (Bonus points! Anyone know how it's made? You may be horrified), there's not much you can do about your caffeinoid (yes, it's a made-up word) lot in life, except maybe blame your parents. They're the ones who gave you this.

Left: A ribbon diagram of CYP1A2, Right: Their 5-year anniversary is coming up. Maybe. Images: Wikipedia, Open Clip Art


(1) An "old wive's tale" - drinking coffee for asthma has some science behind it but not much. The amount of theophylline you'll get from metabolizing coffee is insignificant.

(2) This isn't exactly true. There are also ultra-rapid caffeine metabolizers, but no one cares about them. At least, I don't.

Josh Bloom

Director of Chemical and Pharmaceutical Science

Dr. Josh Bloom, the Director of Chemical and Pharmaceutical Science, comes from the world of drug discovery, where he did research for more than 20 years. He holds a Ph.D. in chemistry.

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