Combinations - Kava-kava As Potentiating Agent Due To Inhibition of CYP450 Enzymes?

[Bajeda]

I just uploaded some articles that make reference to the inhibiting activity of some kavalactones on particular enzymes in the CYP450 system, including CYP3A4.

Here they are:

Effects of herbal components on cDNA-expressed cytochrome P450 enzyme catalytic activity

Composition and biological activity of traditional and commercial kava extracts

Potential for interaction of kava and St. John's wort with drugs


Here is an excerpt from the study linked to in the bottom hyperlink.

The inhibition of CYP450 enzymes by whole kava extract (containing 100 μM total kavalactones) and individual kavalactones was also investigated in human liver microsomes (Mathews et al., 2002). The extract caused 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. The activities of CYP2C9, 2C19, 2D6 and 3A4 were measured with kavain, DMY, methysticin and DHM, each at 10 μM. While kavain did not inhibit these enzymes, there was significant inhibition of CYP2C9 by DMY (42%), methysticin (58%) and DHM (69%); of 2C19 by DHM (76%); of 2D6 by methysticin (44%); of 3A4 by DMY (40%), methysticin (27%) and DHM (54%). Unger et al. (2002) tested several ethyl acetate extracts of kava for inhibitory effects of CYP3A4. They observed a 70–80% inhibition of the enzyme by the different fractions with kavain, DHK, methysticin, DHM and DHY being the main inhibitory principles.

These data collectively indicate that kava has a high potential for causing herb–drug interactions through inhibition of CYP450 enzymes responsible for the majority of the metabolism of pharmaceutical agents used currently. Co-ingestion of kava with prescription medications or over-the-counter products, including other herbal remedies that are metabolized with one or more of these enzymes, might result in elevated and potentially toxic concentrations of the co-administered agents or their metabolites (Anke and Ramzan, 2004). Some common pharmaceutical agents that are metabolized by these enzymes include, for 1A2: amitryptyline, caffeine, diazepam, warfarin; 2C9: aspirin, phenytoin, tolbutamide, warfarin; 2C19: amitryptyline, diazepam, imipramine, propranolol; 2D6: fluoxetine, haloperidol, morphine, many β-blockers; 3A4: amitryptyline, many calcium channel blockers, midazolam, several antifungal agents. In the earlier report (Almeida and Grimsley, 1996), a possible interaction of kava with alprazolam to produce a semicomatose state may also in part have been pharmacokinetic in nature with kava inhibiting CYP enzymes and hence increasing plasma alprazolam concentrations to toxic levels.

Now, I'm not sure about all the drugs that are affected by inhibition of CYP450 - I need to look that up - but from the pharmacological evidence it appears Kava may be able to potentiate a number of substances from the kavalactone's inhibition of metabolism through some of these enzymes.

The medical evidence already warns of mixing benzodiazepines and piper methysticum. I thought it was only due to Kava being somewhat of a CNS depressant, but didn't realize the CYP450 inhibition played a part. Alprazolam and Kava are particularly potent when combined, and can be dangerous if one doesn't watch the dose as the kavalactones have enough inhibitory effect to prevent metabolism of the substance, raising its toxicity.

It seems there is a chance for Kava to potentiate opiates quite a bit as well, though this would also be riskier as Kava has sedative effects.


Does anyone have experience with using Kava to potentiate other substances, rather than just complement with its own effects? Even accidentally, if you have had an experience where you found another substance to be potentiated when used in conjunction with Kava I'd like to hear about it.

And also, does anyone know what the main substances are that utilize CYP450 assisted metabolism?

Any other thoughts?

Reputation Comments on this post:

excellent! The research followed by your intepretation is very helpful

[rxbandit]

Very nice research. My concern would be the heavy load placed on the kidney having to process both kava and say an opiate at the same time. I am aware that kava is pretty rough on the kidney by itself. could kidney failure be a possible risk with heavy dosing?

I'm interested to know more.

[Bajeda]

Kava doesn't seem to be too difficult a substance for the body to handle, government scaremongering about supposed heptatoxicity aside.

My main concern for many combinations would be toxicity of the other substance increasing because of the inhibition from kavalactones. Another issue to think about is the effects of the Kava itself. Grapefruit juice is one thing, but it doesn't produce psychoactive effects of its own!

[psyche]

Someone could try mixing with the cannabis, since they mention the 2C9 variant... slower metabolism for THC. It'd be very precious to have a substance that, in addition to enhancing greatly, also attenuates a high. Too bad SWIM has recently run into troubles with customs, they took away his kava, now he thinks they're watching his address.

[rxbandit]

I found this on the topic

"
Clouatre Consulting Group, 1223 Wilshire Blvd. 761, Santa Monica, CA 90403-5400, USA. dallasclouatre@mac.com
Before 1998, extracts of kava kava, Piper methysticum, were considered to be very safe alternatives to anxiolytic drugs and to possibly exert a wide range of other benefits. Major reviews published through the end of 2002 continued to confirm kava's safety and efficacy. Nevertheless, by January 2003 kava extracts had been banned in the entire European Union and Canada, and were subject to cautions and advisories by the US FDA as a result of 11 cases of hepatic failure leading to liver transplants, including four deaths. A total of 78 cases of hepatotoxicity reputedly linked to kava ingestion are available for review from various databases. Of these adverse events, four probably are linked to kavalactones taken alone and another 23 are potentially linked to kava intake, but also involve the concomitant ingestion of other compounds with potential hepatotoxicity. Three possible mechanisms for kavalactone hepatotoxicity are known: inhibition of cytochrome P450, reduction in liver glutathione content and, more remotely, inhibition of cyclooxygenase enzyme activity. The direct toxicity of kava extracts is quite small under any analysis, yet the potential for drug interactions and/or the potentiation of the toxicity of other compounds is large. Presently, kava toxicity appears to be "idiosyncratic." The risk-to-benefit ratio of kava extracts, nevertheless, remains good in comparison with that of other drugs used to treat anxiety.
PMID: 15068826 [PubMed - indexed for MEDLINE]"

http://www.ncbi.nlm.nih.gov/entrez/q..._uids=15068826

It does not look incredibly safe to mix with other drugs, caution should be taken, at least thats what i gather from this article.

[Bajeda]

Originally Posted by rxbandit

I found this on the topic

"
Clouatre Consulting Group, 1223 Wilshire Blvd. 761, Santa Monica, CA 90403-5400, USA. dallasclouatre@mac.com
Before 1998, extracts of kava kava, Piper methysticum, were considered to be very safe alternatives to anxiolytic drugs and to possibly exert a wide range of other benefits. Major reviews published through the end of 2002 continued to confirm kava's safety and efficacy. Nevertheless, by January 2003 kava extracts had been banned in the entire European Union and Canada, and were subject to cautions and advisories by the US FDA as a result of 11 cases of hepatic failure leading to liver transplants, including four deaths. A total of 78 cases of hepatotoxicity reputedly linked to kava ingestion are available for review from various databases. Of these adverse events, four probably are linked to kavalactones taken alone and another 23 are potentially linked to kava intake, but also involve the concomitant ingestion of other compounds with potential hepatotoxicity. Three possible mechanisms for kavalactone hepatotoxicity are known: inhibition of cytochrome P450, reduction in liver glutathione content and, more remotely, inhibition of cyclooxygenase enzyme activity. The direct toxicity of kava extracts is quite small under any analysis, yet the potential for drug interactions and/or the potentiation of the toxicity of other compounds is large. Presently, kava toxicity appears to be "idiosyncratic." The risk-to-benefit ratio of kava extracts, nevertheless, remains good in comparison with that of other drugs used to treat anxiety.
PMID: 15068826 [PubMed - indexed for MEDLINE]"

http://www.ncbi.nlm.nih.gov/entrez/q..._uids=15068826

It does not look incredibly safe to mix with other drugs, caution should be taken, at least thats what i gather from this article.

Argh! The hepatoxicity monster rears its head again!

Kava-Kava DOES NOT Cause Liver Damage

Kava-Kava and Alcohol


And some files....

Kavalactones Fail to Inhibit Alcohol Dehydrogenase 'In Vitro'

Safety of Ethanolic Kava Extract: Results of a Study of Chronic Toxicity in Rats


There was another fairly comprehensive study on the issue that was too big to upload before that I must have misplaced. Will look for it, though it had the same conclusion as the rest, the liver toxicity scare is overdone and baseless.


Here is another theory on the matter -----> http://the.honoluluadvertiser.com/ar.../ln/ln03a.html

And finally, the Executive Summary of a Phytopharm Consulting investigation contracted by "Center for Development of Enterprise" (CDE), a joint EU-ACP institution. It found that only four of the 76 supposed cases of hepatoxicity were even related to Kava intake, and even then, with a huge amount of other studies and thousands upon thousands of incidences of use without any problems, the entire shennanigans are BS and it recommends any and all EU kava bans are lifted.


Now, I realize you may not know much about Kava, but pleaaaaase, leave the liver issue alone. There is so much data to refute it and basically any scientist who studies the hepatoxicity issue directly can't find any evidence for it, but you get a bunch of idiots who keep mentioning it in their studies for god knows what reason. Thank you.

Originally Posted by psyche

Someone could try mixing with the cannabis, since they mention the 2C9 variant... slower metabolism for THC. It'd be very precious to have a substance that, in addition to enhancing greatly, also attenuates a high. Too bad SWIM has recently run into troubles with customs, they took away his kava, now he thinks they're watching his address.

You mean mixing the two together and ingesting the cannabis orally as well as the Kava?

Otherwise, cannabis and Kava are thought to be quite synergistic in combination, though I think this is mostly due to Kava's own effects, particularly the euphoric and anxiolytic aspects.

Eating I haven't heard about, at least in conjunction with Kava I mean. Would be an interesting experiment, though its hard to gauge whether the Kava's psychoactive effects produce the stronger sensations or its cyp450 inhibition has anything to do with increased potency...

[psyche]

AFAIk, there aren't any cases where hepatotoxic effects could be accounted purely for kava. It was an erowid review of the scientific literature that said so. Most of them seem to be from pills rather than pure root. One review found 34 cases of liver toxicity, of which 32 were from supplemental pills. There are some hepatotoxic compounds in the other parts of the plant piper methysticum, and they might've been used by accident.
The bottom line is still, you don't have to worry about your liver if you don't way overdo it and don't combine with heavy alcohol etc just to be sure. The German world has been using the plant as a medicine from the late 1800s.

Edit: Well, what the heck, here's the review http://www.erowid.org/plants/kava/kava_article1.shtml
I found it quite good and thorough.

You mean mixing the two together and ingesting the cannabis orally as well as the Kava?

Otherwise, cannabis and Kava are thought to be quite synergistic in combination, though I think this is mostly due to Kava's own effects, particularly the euphoric and anxiolytic aspects.

Eating I haven't heard about, at least in conjunction with Kava I mean. Would be an interesting experiment, though its hard to gauge whether the Kava's psychoactive effects produce the stronger sensations or its cyp450 inhibition has anything to do with increased potency...

I meant eating kava and smoking cannabis.
You're right, kava shares a lot with cannabis, though SWIM has never had a chance to try it. It would be very hard to judge wether the potentiation occurs by subjective means. SWIM has long wanted to try kava along with cannabis since both of them seem like perfect drugs for combinations, effectwise that is. Especially kava would be interesting to try in small doses to mellow out a strong trip and possible anxiety/bad trip.

[Paracelsus]

Originally Posted by Bajeda

The inhibition of CYP450 enzymes by whole kava extract (containing 100 μM total kavalactones) and individual kavalactones was also investigated in human liver microsomes (Mathews et al., 2002). The extract caused 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. The activities of CYP2C9, 2C19, 2D6 and 3A4 were measured with kavain, DMY, methysticin and DHM, each at 10 μM. While kavain did not inhibit these enzymes, there was significant inhibition of CYP2C9 by DMY (42%), methysticin (58%) and DHM (69%); of 2C19 by DHM (76%); of 2D6 by methysticin (44%); of 3A4 by DMY (40%), methysticin (27%) and DHM (54%). Unger et al. (2002) tested several ethyl acetate extracts of kava for inhibitory effects of CYP3A4. They observed a 70–80% inhibition of the enzyme by the different fractions with kavain, DHK, methysticin, DHM and DHY being the main inhibitory principles.

This data suggests quite a potential for interactions, of all sorts (from not clinically significant to potentiating to fatal). Still, this is theory. All available studies are in vitro (this basically means "in a jar", not in a living organism).

My Saunders Nursing Drug Handbook (2003) states the following on kava:

INTERACTIONS
DRUG: Alcohol, benzodiazepine may increase risk of drowsiness.
HERBAL: Chamomile, golden-seal, melatonin, St. John’s wort, ginseng, valerian may increase risk of excessive drowsiness.
FOOD: None significant.
LAB VALUES: May increase liver function tests.

So most people (including physicians) are probably unaware of the potential for interactions with kava and just know about avoiding combining it with other CNS depressants.

Studies in humans need to be carried out. If (in humans) kava in recreational/therapeutic quantities would have such a pronounced effect on the cytochrome P450 enzymes (significant (>50%) inhibition of 1A2, 2C9, 2C19, 2D6, 3A4 and 4A9/11), I believe that at least some interactions (besides drowsiness) would be known to the medical community. But we have only a few in vitro studies (which all suggest great potential for interactions), but no actual known interactions with kava (except increasing drowsiness), although it was widely used, both recreationally and for anxiety. I personally tend to believe that such studies (in humans) will probably never be carried out, mainly because kava supplements have become rare/banned in most places, thanks to the hepatotoxicity campaign.

Don’t get me wrong, I’m not saying that this potential for interactions isn’t relevant in humans, but we simply do not have enough evidence to draw any conclusions (besides being fucking careful).

Using kava as a potentiator would probably be quite dangerous. If anyone would want to attempt this, it would be best to use low doses of kava, since low doses would inhibit enough CYP450 enzymes to cause noticeable potentiation (I think), while not causing enough drowsiness to affect the experience very much (I think). Staring at low doses of both kava and second drug and then gradually increasing doses would be required.
Also, one should really do some research on the pharmacokinetics of the drug to be potentiated with kava. Is the substance active by itself or does it get metabolized into an active metabolite with any of the enzymes inhibited by kava? If so, is the prodrug (the drug itself) potentially dangerous/unpleasant/inactive if not broken down (tramadol/DXM/codeine)? Would kava interfere with the metabolism of the active metabolites? Etc.

For example, since kava inhibits most CYP450 enzymes responsible for breaking down opiates, it would probably potentiate opiates active by themselves (morphine, hydromorphone, heroin, etc.), while weakening opiates which have to be metabolized to active compounds (codeine, tramadol). The latter could be dangerous with tramadol, because tramadol itself is responsible for most unpleasant effects of recreational tramadol (including the risk of seizures), while less O-desmethyltramadol (the active metabolite with higher mu-opioid affinity) would be formed. Kava would also significantly potentiate DXM (itself), which would mean a long-lasting psychotic experience with higher risk of adverse effects. Since kava + alprazolam is reported to cause more intense drowsiness, kava should potentiate also many other benzodiazepines (only those also potentiated with grapefruit juice – do a search for ‘Grapefruit juice and benzodiazepines’ by Jatelka), both because of CYP3A inhibition and kava’s sedative effects.

I would say that kava as a potentiator would most likely be much more risky than common potentiators like grapefruit juice or cimetidine, which only inhibit CYP3A. The 'best' class of substances to be potentiated with kava would be opioids active by themselves (most opiates).

Also, if anyone considers trying kava, one should obviously check if there is potential for interaction with any medications/recreational drugs taken recently or planned to take.

Whatever your subjects decide to attempt potentiating with kava, be careful and do your research. If in doubt, it would be way better to ask a noob question here rather than possibly end up dead. Stay safe.

[wOrship]

Originally Posted by psyche

I meant eating kava and smoking cannabis.
You're right, kava shares a lot with cannabis, though SWIM has never had a chance to try it. It would be very hard to judge wether the potentiation occurs by subjective means. SWIM has long wanted to try kava along with cannabis since both of them seem like perfect drugs for combinations, effectwise that is. Especially kava would be interesting to try in small doses to mellow out a strong trip and possible anxiety/bad trip.

Swim would now only smoke cannabis in conjunction with having already taken kava, he would never smoke it otherwise because for him it would definitely induce anxiety and paranoia.

Swim says that smoking cannabis on top of his usual dose of kava mellows out the cannabis stone, taking off the edgy feeling that (in him) leads very quickly to the paranoia, every time.

Swim would agree with what swiy supposes about the combination, the synergy between them is amazing - they do seem almost 'made for each other'. He has experienced amazing levels of euphoria and no anxiety whatsoever.

[Bajeda]

Swim was speculating as to whether potential inhibition of the CYP1A2 enzyme by Kava would have subjective effects due to its prevention of caffeine metabolism. He did some brief research and found that caffeine is readily and almost completely absorbed by the body, and that inhibition of its metabolic breakdown into Paraxanthine, Theobromine, and Theophylline wouldn't have much effect other than to increase the propensity of negative side effects. Given that Kava and coffee is a popular mixture that you don't see many complaints about (swim certainly doesn't complain!), it seems likely that it doesn't inhibit action of the isozyme CYP1A2, or it has limited enough inhibitory action that the subjective effects of the Kava in synergy with that of the caffeine cover up any increase in caffeine side effects from its reduced metabolism.

Doesn't seem like there is any further to go in this direction unless something new is learned about interactions between Kava and CYP1A2 or specifically about interactions between Kava and caffeine.

[Ontherooftops]

Swim's octopus enjoys kava+canna quite a bit, and notices the euphoric effects of both are increased dramatically.

The other night swim gave his octopus a very low dose of some quality kava root, approx 1g, along with 1g of potent kratom resin, along with lots of grass, and became excessively innebriated. Extremely euphoric come up, very pleasant, followed by a strange body load that swim disliked somewhat, but eventually mellowed out again into a calm relaxed feeling.

[Bajeda]

Hoppy the bunny had a little error of judgement recently, as he drank some Kava Java and within a few hours also took 200mg of Tramadol. While the bunny isn't sure about the exact CYP450 inhibiting effects of Kava, it seems that it has enough inhibition to leave you with the nastier effects when you take Tramadol. The bunny felt physically good, but mentally he was a wreck. Tramadol isn't something to mix with other substances really anyways, but this is an extra caution to avoid mixing Tramadol and Kava or even take them within 12 hours of each other in order to avoid unpleasant effects.