Which specific CYP450 enzymes does Kava inhibit/induce?

[MikeB]

I have heard that Kava inhibits "most" liver enzymes in the CYP450 system.

However, this study seems to suggest that out of CYP1A2, CYP2D6, CYP2E1, and CYP3A4/5, Kava only affected CYP2E1, producing a 40% reduction. The rest seemed to be unaffected.

Can someone cite a source detailing how Kava inhibits "most" liver enzymes, or which other enzymes it interacts with, specifically? This would be tremendously helpful for me as I learn how Kava interacts with other things.

 

[verticity]

I think you answered your own question. That is interesting information.

 

[kavadude]

@MikeB you seem to be going through a lot of kava studies; if you don't mind, I wonder if you could send me a short blurb about ones that stand out to you, when you read them? (I was compiling some studies at http://kavafaq.com/research/ late last year but did not get far before I got sidetracked onto other things)

 

[verticity]

Here are some other studies:

Inhibition of human cytochrome P450 activities by kava extract and kavalactones.
The abstract says "Whole kava extract.... 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%) ... CYP2A6, 2C8, and 2E1 activities were unaffected." which completely contradicts the other study.

http://www.sciencedirect.com/science/article/pii/S094471130470330X
This study says "the kava extract and the three kava lactones were found to be potent inhibitors of CYPs 1A2, 2C9, 2C19, 2E1, and 3A4", so a broad spectrum effect, including 2E1.

So, it seems like "more research is needed".

 

[avahZ]

I dug into this stuff awhile back and came to one conclusion. Like many things we ingest, those enzymes break down MANY things on first past system (another words once you digest a medication, food, etc. the blood passes through the liver first and alot of it is broken down by those enzymes). Kava is just another natural substance being broken down like many others. The problems show up when you are over taxing those enzymes and this has caused some people to have higher liver panels. And there appears to be some people who can not have kava because for some genetic reason kava really beats down their enzymes (is it only two day, high FKs, etc I dont know). This is one reason you can not have grape fruit when you are taking blood pressure and other medications, but they dont try to outlaw grapefruit now do they...

After starting kava, I would recommend EVERY kava drinker have a liver panel done to be sure you are not in that minority. That being said, you can beat that liver down also if you take alot of medications that use the same enzyme pathways, drink alot booze, drink booze with kava, or even my own vice of mixing coffee and kava. Until further studies or other solid evidence, I do have a liver panel done when I get my physical and so far so good.

 

[verticity]

... my own vice of mixing coffee and kava.....

That is indeed a wicked vice.

I guess of the three studies above, I would put the most credence in the original one cited by @MikeB since that one involved human subjects (who were alive!), although the number of subjects was relatively small. The studies I cited just measured the effect of kava on cytochrome P450 in a test tube, which could be quite misleading, compared to its effect in a whole functioning liver.

Since the number of subjects in the human study was only 12, it could well have missed a minority population with an abnormal reaction.

 

[MikeB]

@kavadude - All of the studies that stood out to me were the ones I've posted here, so you can look at my post history. These ones were significant, as well as the one that gauges the strength of kava's mechanism of action as an MAO-B inhibitor.

In general, my belief at this stage is that while kava is certainly natural and appears to have numerous benefits over other anxiolytic treatments, particularly benzodiazepenes, that it does still need to be evaluated pharmaceutically when gauging how it interacts with other substances, whether synthetic or herbal. That goes double if it leads to broad-spectrum liver enzyme inhibition, which means it would literally interact with almost every medication on the market.

I am starting to suspect that most "drug interaction checkers" online do not accurately reflect the real interactions that kava has with other medications.

It would be good to get more anecdotal reporting on whether kava interacts with other medications that people take - not necessarily just psychotropic drugs, but things that people might be on for completely different reasons, like for blood pressure or cholesterol, or for someone who's on an anti-psychotic, etc. That might give us valuable data on what liver enzymes it really inhibits.

 

[sɥɐʞɐs]

I think it's commonly understood around here, and hopefully by most of the general population, that online 'drug interaction checkers' are no where near definitive, especially in the case of rare herbs, entheogens and non FDA approved substances.

Likewise, there is very little definitive research on kava and all it's possible intricacies compared to more well known and widely used substances. This forum does collect anecdotal evidence and the more people start signing up, the bigger pool of stories we'll hear. There's definitely people that sign up from time to time and describe their experience with kava + whatever...or come on here complaining about certain kava effects, only to eventually admit they were also taking Seroquel or something. We'd need a huge number of reports, to start finding patterns, but as of yet, the kava community is one of the smallest, kava drinkers that join the forum are even fewer, and one's who join to talk about a possible kava interaction they experienced are even fewer yet.

The definitive answers you seek are simply unavailable. So we stick with what little research is documented and the VAST amount of anecdotal evidence that shows kava to be one of the safest drugs to ever be regularly consumed. At the same time, we share our own experiences here to see if anything can be learned from it. Little kava lab rats, or as I like to say; Papua New Guinea Pigs.

 

[kavadude]

The simple fact is that kava-consuming countries do not have a long history of pharmaceutical medicine, nor have there been large trials of the sort that typically suss these things out. Thus pretty much any "interactions" are anecdotal. There is enough research to say that kava should not be taken with any kind of known seriously hepatotoxic substance (alcohol, paracetamol), but beyond that, again, largely anecdotal.

 

[Steve Mariotti]

I wish I had the time to get my liver tested, then drink kava mixed with vodka during the day every day for a full week, then get my liver tested again.

It'd be worth a week of misery to get some numbers.

 

[MikeB]

@sɥɐʞɐs:

There's definitely people that sign up from time to time and describe their experience with kava + whatever...or come on here complaining about certain kava effects, only to eventually admit they were also taking Seroquel or something.
​

Has that actually happened, specifically with Seroquel? That would be a really useful data point. We have very good data on how Seroquel is metabolized in vivo, so if it interacts with Kava, that could produce some useful hypotheses to check into regarding Kava's "true" CYP450 enzyme inhibition.

I'm also very interested in this because it's extremely important to the image of Kava that we try to avoid the following from happening:

Someone who happens to be on propranolol for hypertension ends up hearing about Kava. They try it for the first time. Kava inhibits both enzymes metabolizing the propranolol, leading to serum levels increasing to dangerous levels. The person becomes dangerously hypotensive and passes out and ends up in the hospital. Perhaps they make a full recovery, but it doesn't matter: case report of "kava-induced" hypotensive shock. The special interests come out and here comes the media shitstorm.

The funny thing is the reaction I described above isn't really that far-fetched, because that's exactly what happens if you drink *alcohol* while on propranolol. But there are lots of special interest groups that don't like kava very much... possibly some of whom sell alcohol.

The key thing is that people on propranolol know not to drink alcohol because that's on the label. So the best thing we could do is to be up front: "Kava may be a broad-spectrum liver enzyme inhibitor that may interact with a very wide range of medications. It's been consumed traditionally for thousands of years as a monotherapy -- that's it. It has obviously not been used in conjunction with anything like modern pharmaceuticals, and if you do that you are venturing into new territory. So check with your doctor before taking kava."

 

[MikeB]

And for god's sakes, someone needs to get the data about kava on these online drug interaction checkers changed! I mean hell, does it interact with birth control? I guess not, or some terrible incident would have probably happened already. But sheesh!! I should send some emails, maybe...

 

[MikeB]

OK, well since I have the fire to organize here, I do think it'd be good to start a mega-thread of some sort in which we just anecdotally talk about what legal, medicinal things Kava does and does not interact well with.

I know this forum has a policy of avoiding discussing Kava along with other drugs, which I agree is a good idea. But it would still be good to get some data on medications prescribed legally, or "minor" legal psychoactives that anyone can prescribe over the counter.

On my end, for instance, here are my personal reactions to taking Kava while having previously taken the following things. None of these medications were things I was abusing, these were all taken in conjunction with a doctor:

• Propranolol - BAD. Jesus Christ, I never should have done this, it ruined an entire day for me.
  
• Adderall - NOT GOOD. Potentiates the Adderall a bit. Kind of makes everything extra-"heady" in a certain sense.
  
• Clonazepam - MIXED. Can make you more sedated, so be careful.
• St. John's Wort - OKAY. Didn't seem to have any negative interaction that I could tell.

I also can personally attest to the following legal psychoactives that I always consumed in moderation:

• Alcohol - BAD. Don't do it. Unless you like vomiting. A lot.
  
• Caffeine - GOOD. They seem to synergize decently well, actually.
• Nicotine - OKAY. I have mixed kava with a cigar and didn't notice anything, but I'm also a very infrequent smoker.

I'm curious to see what other people have experienced regarding the following

• SSRI's - ???? they're all metabolized differently, so which ones have people tolerated kava well on?
• SNRI's - ???? same as above
• Things like bipolar meds, anti-psychotics, etc?
• Caffeine?
• Nicotine?

Would this be helpful? If so, where should I post this?

 

[sɥɐʞɐs]

@MikeB, if I recall correctly, the Seroquel guy was telling us he had elevated limited enzymes and he was certain it was 100% kavas fault, despite every other daily drinker getting checked and having perfect blood work. When prompted to divulge any other meds he might be on, one of them was Seroquel, but he still insisted kava was to blame.

Obviously it's the combination of the 2 that created his problem, if not also a personal biology issue, Seroquel on it's own has well documented liver warnings, kava on the other hand seems to not be a problem, in most cases.
Unless, of course, you mix it with something that already does.

 

[verticity]

In my case I have been using kava with the SNRI Effexor and the antipsychotic Risperdal (at a very low dose of 1 mg/day) with no obvious problems for some time. In my case, caffeine: BAD if too much caffeine.

Propranolol is not something to fuck with. It's one of those things where an overdose of it by itself can kill you. It would be unwise to mix it with anything not doctor-approved.

 

[verticity]

Would this be helpful? If so, where should I post this?

You could post it right here, or start a thread called "Anecdotal drug interactions of kava" or something.

 

[MikeB]

Thanks to both of you for those data points.

@verticity: the main problem is that I think primary care physicians are going to not think kava interacts with *anything* if all of the drug interaction checkers say it doesn't interact with anything. Doctors don't dig up pubmed studies about CYP450 interactions from scratch every time they prescribe stuff. They look up contraindications and that's mostly it.

 

[Steve Mariotti]

I've been taking duloxetine (Cymbalta) for over ten years and introduced kava a year and a half ago as a bi-weekly drinker, and I've seen nothing to indicate a negative interaction. Regular blood tests indicate everything is totally cool.

 

[verticity]

Thanks to both of you for those data points.

@verticity: the main problem is that I think primary care physicians are going to not think kava interacts with *anything* if all of the drug interaction checkers say it doesn't interact with anything. Doctors don't dig up pubmed studies about CYP450 interactions from scratch every time they prescribe stuff. They look up contraindications and that's mostly it.

That is a problem for sure. But I think compiling a list of peoples' reports of interactions here is nonetheless a good idea. Doctors won't read it, but it will be available for folks to educate themselves.

 

[MikeB]

Is it possible to split this into a new thread? Who is the moderator, @kavadude?