Kava Fact of the Day Kava, Caffeine, and CYP1A2

[The Kap'n]

(Icey, Public domain, via Wikimedia Commons)​

Recently we covered CYP450 enzymes and how kava may inhibit the activity at some of these areas. Today we’re going to focus specifically on the enzyme CYP1A2, and how inhibiting it effects caffeine metabolism.

We’ve seen quite a number of kava drinkers over the years remark about how their morning coffee began to be somewhat more of a stimulating experience. Some kava drinkers find this extra boost a side benefit of drinking kava. Other people experiencing this marked increase in stimulation may find it overpowering.

Caffeine metabolism occurs primarily in the liver, with a half-life of 5 hours, and requires about 8-10 hours to clear entirely. First pass metabolism accounts for 75-80% of caffeine’s metabolism in the body. The enzyme responsible for this is CYP1A2 [1].

Kava has been shown in its different forms to inhibit the enzyme CYP1A2 to varying degrees. In 2005 a study was carried out on kava drinking volunteers. They had the subjects stop drinking kava for 30 days, and measured the metabolic rate of caffeine both prior to and after the break. The caffeine metabolism ratio was shown to increase by 200% after 30 days. This indicated, when consuming kava on a regular basis, that some users can see what feels like DOUBLE the amount of caffeine they’ve ingested. This study also suggested these values return back to normal once kava drinking is stopped [2].

So, kava lovers, if you’ve been drinking your morning coffee and are seeing a definite increase in the stimulatory properties, this could be the culprit as to why.


[1] Institute of Medicine (US) Committee on Military Nutrition Research. Caffeine for the Sustainment of Mental Task Performance: Formulations for Military Operations. Washington (DC): National Academies Press (US); 2001. 2, Pharmacology of Caffeine. Available from: https://www.ncbi.nlm.nih.gov/books/NBK223808/

[2] Cabalion, P., Barguil, Y., Duhet, D., Mandeau, A., Warter, S., Russmann, S., Tarbah, F., & Daldrup, T. (2005). Kava in modern therapeutic uses: To a better evaluation of the benefit/risk relation: researches in New Caledonia and in Futuna. Revista de Fitoterapia, 5(special issue), 53–70.

 

[AvaCat]

Thats neat i must be different in though i can still drink a cup or shot of espresso and fall asleep haha.

 

[The Kap'n]

Thats neat i must be different in though i can still drink a cup or shot of espresso and fall asleep haha.

Totally normal

CYP1A2 is a highly variable enzyme and can be expressed in varying concentrations. This means the kava/coffee combo may be benign to one person while way be overstimulating to the next.

"There is approximately 40% variability in liver expression of the CYP1A2 gene and 60% variability in caffeine metabolism"

Thorn, Caroline F et al. “PharmGKB summary: very important pharmacogene information for CYP1A2.” Pharmacogenetics and genomics vol. 22,1 (2012): 73-7

PharmGKB summary: very important pharmacogene information for CYP1A2 - PMC

www.ncbi.nlm.nih.gov

 

[Orz[EST]]

I almost knew it! I posted something like 'coffee is not a potentiator of kava, it seems to be the other way around'.

Now I know it and thanks.

 

[Aceofwands9]

This helps explain why i gave up drinking rockstar energy drinks when i started drinking kava and went back to just coffee. I just felt overstimulated and that i didn't need them anymore.

 

[Alia]

View attachment 11795
(Icey, Public domain, via Wikimedia Commons)​

Recently we covered CYP450 enzymes and how kava may inhibit the activity at some of these areas. Today we’re going to focus specifically on the enzyme CYP1A2, and how inhibiting it effects caffeine metabolism.

We’ve seen quite a number of kava drinkers over the years remark about how their morning coffee began to be somewhat more of a stimulating experience. Some kava drinkers find this extra boost a side benefit of drinking kava. Other people experiencing this marked increase in stimulation may find it overpowering.

Caffeine metabolism occurs primarily in the liver, with a half-life of 5 hours, and requires about 8-10 hours to clear entirely. First pass metabolism accounts for 75-80% of caffeine’s metabolism in the body. The enzyme responsible for this is CYP1A2 [1].

Kava has been shown in its different forms to inhibit the enzyme CYP1A2 to varying degrees. In 2005 a study was carried out on kava drinking volunteers. They had the subjects stop drinking kava for 30 days, and measured the metabolic rate of caffeine both prior to and after the break. The caffeine metabolism ratio was shown to increase by 200% after 30 days. This indicated, when consuming kava on a regular basis, that some users can see what feels like DOUBLE the amount of caffeine they’ve ingested. This study also suggested these values return back to normal once kava drinking is stopped [2].

So, kava lovers, if you’ve been drinking your morning coffee and are seeing a definite increase in the stimulatory properties, this could be the culprit as to why.


[1] Institute of Medicine (US) Committee on Military Nutrition Research. Caffeine for the Sustainment of Mental Task Performance: Formulations for Military Operations. Washington (DC): National Academies Press (US); 2001. 2, Pharmacology of Caffeine. Available from: https://www.ncbi.nlm.nih.gov/books/NBK223808/

[2] Cabalion, P., Barguil, Y., Duhet, D., Mandeau, A., Warter, S., Russmann, S., Tarbah, F., & Daldrup, T. (2005). Kava in modern therapeutic uses: To a better evaluation of the benefit/risk relation: researches in New Caledonia and in Futuna. Revista de Fitoterapia, 5(special issue), 53–70.

This is also interesting- from Dec. 2014. Coffee and Liver Health Clinical Gastroenterol: "Over the past 20 years, an increasing number of epidemiological and experimental studies have demonstrated the positive effects of coffee on chronic liver diseases. Coffee consumption has been inversely associated with the activity of liver enzymes in subjects at risk, including heavy drinkers. Coffee favours an improvement in hepatic steatosis and fibrosis, and a reduction in cirrhosis and the risk of hepatocellular carcinoma."

 

[faldho]

This affects caffeine tolerance right? So if you quit Kava for 30 days you would need twice as much caffeine to feel the same?

 

[Jacob Bula]

This is also interesting- from Dec. 2014. Coffee and Liver Health Clinical Gastroenterol: "Over the past 20 years, an increasing number of epidemiological and experimental studies have demonstrated the positive effects of coffee on chronic liver diseases. Coffee consumption has been inversely associated with the activity of liver enzymes in subjects at risk, including heavy drinkers. Coffee favours an improvement in hepatic steatosis and fibrosis, and a reduction in cirrhosis and the risk of hepatocellular carcinoma."

I believe my coffee habits saved my liver during my 20s.

 

[The Kap'n]

This affects caffeine tolerance right? So if you quit Kava for 30 days you would need twice as much caffeine to feel the same?

Essentially if you were to get accustomed to the feeling of caffeine and kava together, and you suddenly quit kava, the caffeine would appear to have a higher tolerance value as the enzymatic pathway that kava was suppressing is now available to more quickly metabolize caffeine.

 

[spoutti]

Im trying to understand what the theobromine means in the graph up there. I drink lots of mate these days, so im wondering how kava would affect my morning mate.
Im not sure about black teas and kava in the morning as well. Will see when I do get my kava and probably will cut my tea/mate dose in half when I have a morning heady kava.

But would love to have your input @Kapmcrunk about mixing mate and kava

 

[The Kap'n]

Im trying to understand what the theobromine means in the graph up there. I drink lots of mate these days, so im wondering how kava would affect my morning mate.
Im not sure about black teas and kava in the morning as well. Will see when I do get my kava and probably will cut my tea/mate dose in half when I have a morning heady kava.

But would love to have your input @Kapmcrunk about mixing mate and kava

Certainly.

[1]​

Above we can see a more detailed representation of the metabolism of caffeine. To the right we see Caffeine demethylated through the pathways CYP1A2 and lesser CYP2E1 pathway to theobromine. Theobromine is then broken down by xanthine oxidase into 3,7 DMU. We currently don't know kava's effect at xanthine oxidase (XO). There are studies showing that inhibition of XO being common by a variety of dietary flavonoids and chalcones [2]. Kavalactones and flavokavains fall into these categories, so the chance at inhibition at this spot is certainly not zero.

What I believe this to mean is that you'll likely see an effect at beverages high in caffeine, and likely mate as well due to it's caffeine level. Theobromine in mate may end up sticking around longer if kavalactones and FKs do indeed inhibit XO, but more research is needed in this area, as there are no studies that directly address XO inhibition with kava or constituents of kava.

What this means to you?

You may find a bit more stimulatory properties out of your mate depending on your personal physiology. The word is still out on whether kava inhibits that process of further breakdown of theobromine.



[1] Nehlig, Astrid. 2018. “Interindividual Differences in Caffeine Metabolism and Factors Driving Caffeine Consumption.” Pharmacological Reviews 70 (2): 384–411. https://doi.org/10.1124/pr.117.014407.

[2] Nagao, A., M. Seki, and H. Kobayashi. 1999. “Inhibition of Xanthine Oxidase by Flavonoids.” Bioscience, Biotechnology, and Biochemistry 63 (10): 1787–90. https://doi.org/10.1271/bbb.63.1787.

 

[The Kap'n]

This affects caffeine tolerance right? So if you quit Kava for 30 days you would need twice as much caffeine to feel the same?

Hey, sorry for such a late response. I was going through the thread again and saw your question.

Possibly. You would be back to whatever your body's normal rate of metabolization of caffeine would be naturally after you flush kava out of your system. If you noticed caffeine twice as effective with kava in the mix, then you'll notice it being less effective without kavalactones circulating.

 

[spoutti]

Certainly.

View attachment 12242
[1]​

Above we can see a more detailed representation of the metabolism of caffeine. To the right we see Caffeine demethylated through the pathways CYP1A2 and lesser CYP2E1 pathway to theobromine. Theobromine is then broken down by xanthine oxidase into 3,7 DMU. We currently don't know kava's effect at xanthine oxidase (XO). There are studies showing that inhibition of XO being common by a variety of dietary flavonoids and chalcones [2]. Kavalactones and flavokavains fall into these categories, so the chance at inhibition at this spot is certainly not zero.

What I believe this to mean is that you'll likely see an effect at beverages high in caffeine, and likely mate as well due to it's caffeine level. Theobromine in mate may end up sticking around longer if kavalactones and FKs do indeed inhibit XO, but more research is needed in this area, as there are no studies that directly address XO inhibition with kava or constituents of kava.

What this means to you?

You may find a bit more stimulatory properties out of your mate depending on your personal physiology. The word is still out on whether kava inhibits that process of further breakdown of theobromine.



[1] Nehlig, Astrid. 2018. “Interindividual Differences in Caffeine Metabolism and Factors Driving Caffeine Consumption.” Pharmacological Reviews 70 (2): 384–411. https://doi.org/10.1124/pr.117.014407.

[2] Nagao, A., M. Seki, and H. Kobayashi. 1999. “Inhibition of Xanthine Oxidase by Flavonoids.” Bioscience, Biotechnology, and Biochemistry 63 (10): 1787–90. https://doi.org/10.1271/bbb.63.1787.

Wow, thanks a lot. I didnt know caffein turns (is metabolize the correct verb?) into theobromine. I thought it was a something not found in coffe.

One day or the other I will mix some kava in the morning and mate and see what happens. Thanks for arming me with knowledge

 

[Kava_Root]

I've had some good and bad experiences mixing the two. I once had a couple of tablespoons of a heavy kava that had just arrived in the mail after my morning espresso and I did not have a great time. I was sedated from the kava with the potentiated jitteriness of the caffeine, really bad mix. I have had mornings after heavy sessions the night before that potentiated my morning cup of coffee to an uncomfortable level. However, I visited a kava bar that also served coffee, and several regulars were chasing their shells with it. Different strokes for different folks I guess.

 

[The Kap'n]

Different strokes for different folks I guess.

Exactly, and caffeine metabolization can vary quite considerably between individuals which may explain why some barely notice an effect while others find it unpleasant.

Koonrungsesomboon, Nut, Rapheephorn Khatsri, Penwisa Wongchompoo, and Supanimit Teekachunhatean. 2018. “The Impact of Genetic Polymorphisms on CYP1A2 Activity in Humans: A Systematic Review and Meta-Analysis.” The Pharmacogenomics Journal 18 (6): 760–68. https://doi.org/10.1038/s41397-017-0011-3.

 

[Skinskava]

When I drink kava I dont crave caffeine for 48 hrs after yet if I dont drink kava I have a cup everyday. For some reason kava turns off dependence to most things

 

[The Kap'n]

This is also interesting- from Dec. 2014. Coffee and Liver Health Clinical Gastroenterol: "Over the past 20 years, an increasing number of epidemiological and experimental studies have demonstrated the positive effects of coffee on chronic liver diseases. Coffee consumption has been inversely associated with the activity of liver enzymes in subjects at risk, including heavy drinkers. Coffee favours an improvement in hepatic steatosis and fibrosis, and a reduction in cirrhosis and the risk of hepatocellular carcinoma."

Makes total sense as caffeine being a substrate for CYP1A2 would tie up its activity and reduce its availability. CYP1A2 converts many pre-carcinogenic exogenous compounds into carcinogens as a byproduct of evolution. When this pathway is suppressed there may be a marked reduction in cancer occurrences. G. Steiner briefly points to this in 2000. Really interesting stuff and once you start to dig in, it all coincides and makes sense.

Steiner, G. G. 2000. “The Correlation between Cancer Incidence and Kava Consumption.” Hawaii Medical Journal 59 (11): 420–22. https://pubmed.ncbi.nlm.nih.gov/11149250.

 

[The Kap'n]

When I drink kava I dont crave caffeine for 48 hrs after yet if I dont drink kava I have a cup everyday. For some reason kava turns off dependence to most things

It's like it hits the "mute" button on compulsion.

 

[Valyn]

Yeah I nearly collapsed onto the ground after drinking soda and coffee after a Kava session. I could not stop pacing around the house and thought I'd have to go to the ER.

 

[Orz[EST]]

It's like it hits the "mute" button on compulsion.

I am sure that this is true for alcohol. Not sure about nicotine chewing gum or dip.