Does coffee make you anxious? The role of COMT & caffeine metabolism
For those who know me, they know I am a total coffee fiend. It is one thing I am not prepared to give up. Which makes it somewhat ironic that I also have slow COMT and am heterozygous on CYP1A2 — the gene that metabolises caffeine.
Looking back, my stint as a barista — coffee on tap, all day, right in the middle of perimenopause — was a recipe for oestrogen clearance disaster.
These days, I never drink my coffee naked. I add a collagen powder and sometimes MCT powder, which I find takes the edge off the caffeine hit. No coffee after 12 (ideally 10am). And if I forget and think an afternoon coffee is a good idea, it’s L-theanine to the rescue.
So what's actually going on?
When you drink coffee, caffeine works primarily by blocking adenosine receptors — the ones involved in making you feel sleepy. By taking the brakes off, caffeine increases alertness and can enhance dopamine and adrenaline activity. That's the buzz, the focus, the "let's go" feeling most of us are chasing. [1]
But here's where genetics comes in.
Two genes play a key role in how your body handles caffeine:
CYP1A2 — the gene that codes for the enzyme responsible for metabolising and clearing caffeine from your body. Fast metabolisers clear it quickly. Slow metabolisers? The caffeine hangs around much longer than it should. [1,2]
COMT — the gene that codes for the enzyme responsible for breaking down catecholamines: dopamine, adrenaline, and noradrenaline. If your COMT is running slowly, these can take longer to break down. [3]
Put slow COMT and slow CYP1A2 together, add a strong coffee, and you’ve got a bit of a pressure cooker situation. Caffeine stays in your system longer than it should, and the adrenaline and dopamine it triggers aren’t clearing the way they need to. Hello anxiety, racing heart, and lying awake at 2am wondering why you thought that afternoon coffee was a good idea.
Worth noting for anyone in perimenopause: COMT is also responsible for metabolising catechol oestrogens — specifically 2-hydroxy and 4-hydroxy oestrogen. [3]
So if you’ve got slow COMT and you’re downing coffee throughout the day, you’re not just dealing with slow adrenaline clearance — all that extra adrenaline is competing for the same enzyme your body uses to clear oestrogen. Not ideal at a time when your body is already working overtime to clear fluctuating oestrogen.
What you can do about it
If this sounds familiar, you don't necessarily have to give up coffee — but you might need to manage it differently.
A few things that help:
Wait 90 minutes — don't reach for coffee the moment you wake up. Cortisol rises naturally in the first 90 minutes after waking — let it do its job first. Caffeine on top of a cortisol spike is a recipe for that wired, anxious feeling before your day has even started.
Not on an empty stomach — and make sure you're well hydrated first. Coffee on an empty, dehydrated stomach hits harder and faster than it needs to.
Time it — depending on your CYP1A2 variant, caffeine has a half-life of anywhere from 4 to 10+ hours. That means a 3pm coffee could still have half its caffeine active in your system anywhere from 7pm to well past midnight. No coffee after 12 is my personal non-negotiable — and now you can see why. [2]
Pair it — adding MCT powder and collagen to your morning coffee can take the edge off the caffeine hit, while giving you a bonus 10g of protein in the morning.
Damage control — if you've overdone it, L-theanine is your best friend. An amino acid found naturally in green tea, it takes the edge off caffeine's stimulating effects without killing the focus. [4]
Know your genes — if you consistently feel anxious, wired, or can't sleep after coffee, there's a good chance your COMT or CYP1A2 (or both) have something to say about it.
The takeaway
Coffee isn't the enemy — but your genes might be changing the rules around how much, when, and how you drink it.
If you've always written yourself off as "just sensitive to caffeine," it might be worth looking a little deeper. Understanding your genetics can completely change how you manage your daily coffee habit. Without having to give it up entirely.
Which for me is very much non-negotiable!
References
1. Kapellou, A., King, A., Graham, C. A. M., Pilic, L., & Mavrommatis, Y. (2023). Genetics of caffeine and brain-related outcomes — a systematic review of observational studies and randomized trials. Nutrition Reviews, 81(12), 1571–1598. https://doi.org/10.1093/nutrit/nuad029
2. Grzegorzewski, J., Bartsch, F., Köller, A., & König, M. (2022). Pharmacokinetics of caffeine: A systematic analysis of reported data for application in metabolic phenotyping and liver function testing. Frontiers in Pharmacology, 12, 752826. https://doi.org/10.3389/fphar.2021.752826
3. Andrade, P., Santamarina, A. B., de Freitas, J. A., Marum, A. B. R. F., & Pessoa, A. F. M. (2025). Personalized nutrition and precision medicine in perimenopausal women: A minireview of genetic polymorphisms COMT, FUT2, and MTHFR. Clinics, 80, 100549. https://doi.org/10.1016/j.clinsp.2024.100549
4. Hidese, S., Ogawa, S., Ota, M., Ishida, I., Yasukawa, Z., Ozeki, M., & Kunugi, H. (2019). Effects of L-theanine administration on stress-related symptoms and cognitive functions in healthy adults: A randomized controlled trial. Nutrients, 11(10), 2362. https://doi.org/10.3390/nu11102362
