Caffeine And Kava

**NOTE AS OF 02/23/2022 - THIS SECTION IS UNDER REVIEW. THE ISSUE SEEN WITH KAVA AND COFFEE MAY, IN FACT BE A PHARMACODYNAMIC INTERACTION INSTEAD OF A KINETIC INTERACTION AT CYP**

We've found people reporting that the mixture of kava and caffeine can cause an increase in the stimulation effects of caffeine when the two are consumed within a reasonable time together. Some members find the combination uncomfortable, while some enjoy the increase in stimulation. However you feel about it, there's always a good scientific explanation regarding why and we would like to share with you what we theorize the culprit to be.

Note: Those kava drinkers that smoke will likely see this effect far less than those that do not.

"Caffeine from coffee or other beverages is absorbed by the stomach and small intestine within 45 minutes of ingestion and then distributed throughout all tissues of the body. Caffeine is metabolized in the liver by the cytochrome P450 oxidase enzyme system (specifically, the CYP1A2 isozyme) into three metabolic dimethylxanthines: paraxanthine, theobromine and theophylline. Paraxanthine increases lipolysis, leading to elevated glycerol and free fatty acid levels in the blood plasma. Theobromine dilates blood vessels and increases urine volume. Theobromine is also the principal alkaloid in cocoa, and therefore chocolate. Theophylline relaxes smooth muscles of the bronchi, and is used to treat asthma. Each of these caffeine metabolites is further metabolized into various methyluric acids and then excreted in the urine."
https://smpdb.ca/view/SMP0000028?highlight[compounds][]=DB00201&highlight[proteins][]=DB00201
Caffeine Metabolism References
Lehninger, A.L. (2005) Lehninger principles of biochemistry (4 th ed.). New York: W.H Freeman.

Salway, J.G. (2004) Metabolism at a glance (3 rded.). Alden, Mass. : Blackwell Pub.

Kava has the ability, similar to grapefruit juice, to suppress certain enzyme pathways in liver. Specifically the enzyme CYP1A2, the liver enzyme responsible for the majority of caffeine's metabolism. What this means is that kava can and does interfere with compounds broken down by the same pathways such as caffeine. Caffeine is prevented from being ""digested"" into its constituent parts, therefore causing a lengthening and strengthening of its effects until it finally is broken down. According to the following study kava may decrease the rate of metabolism by up to 56% which isn't negligible. The effects could even further increase or be altered as you go down the metabolite tree, as kava has inhibition properties at many different commonly seen pathways.

""In the present work the inhibition of P450 enzymes by kava extract and individual kavalactones in human liver microsomes (HLMs) was investigated. Whole kava extract (normalized to 100 microM total kavalactones) caused concentration-dependent decreases in P450 activities, with significant inhibition of the activities of CYP1A2 (56% inhibition), 2C9 (92%), 2C19 (86%), 2D6 (73%), 3A4 (78%), and 4A9/11 (65%) following preincubation for 15 min with HLMs and NADPH; CYP2A6, 2C8, and 2E1 activities were unaffected. The activities of CYP2C9, 2C19, 2D6, and 3A4 were also measured after incubation of HLMs with the major kavalactones kawain (K), desmethoxyyangonin (DMY), methysticin (M), dihydromethysticin (DHM) (each at 10 microM), and NADPH. Whereas K did not inhibit these enzymes, there was significant inhibition of CYP2C9 by DMY (42%), M (58%), and DHM (69%); of 2C19 by DHM (76%); of 2D6 by M (44%); and of 3A4 by DMY (40%), M (27%), and DHM (54%). Consistent with their potency as inhibitors, the two major kavalactones bearing a methylenedioxyphenyl moiety (M and DHM) formed ""455 nm"" metabolic intermediate complexes after incubation with HLMs and NADPH, but K and DMY did not..""
https://www.ncbi.nlm.nih.gov/pubmed/12386118

It means that when we, as kava drinkers, imbibe in coffee and teas and other caffeinated beverages, we may feel a marked increase in the effects of caffeine. We may experience a stronger more persistent stimulation. Those of us sensitive to caffeine will, of course, be even more sensitive and experience the more negative side of the side effect spectrum with caffeine. Increases in anxiety for these people will be especially notable.

So, if your morning cup of coffee has you jittery, and tense, you may know the culprit.

It may seem obvious, but limiting your intake of caffeine will limit the negative or positive increased effects you are getting. Sounds simple, but by switching to a less caffeinated brew, or non-caffeinated beverages you should be able to avoid the negative effects seen by the interaction with kava.