What's new

Kava Fact of the Day The pharmacokinetic distribution aspects of kavain, and how research routinely uses concentrations unattainable in vivo.

The Kap'n

The Groggy Kaptain (40g)
KavaForums Founder
Kava Fact of the day: Kavalactone Concentration in the brain, the pharmacokinetic distribution aspects of kavain, and how research routinely uses concentrations unattainable in vivo.

Today we’re going to address why tissue distribution of kavalactones is such a big deal in kava research, and kava effects. We’ll explore why older research papers we read today may not reflect real-world effects that we see with kava.

Let’s start with the term “Pharmacokinetics”. This is the word that describes the process in which compounds enter the body, move about the body, change within the body, and leave the body [1]. Pharmacokinetics in regards to kavalactones have been studied for many years, however we normally see specific kavalactones targeted for this type of research. Kavain was chosen for the majority of the research seeing as kavain is the most selected and sought after kavalactone, and also exists in larger quantities in most cultivars [2]. Kavain also happens to be the kavalactone studied when looking at the GABA-A receptor [3].

Pharmacokinetics includes absorption, distribution, metabolism and excretion. We’ll be addressing the distribution phase, specifically to the brain. Distribution describes how much of a substance is spread around the body, and varies considerably based on the properties of the substance and the individual consuming it. The goal of this phase is to achieve “effective drug concentration”. This is the effective concentration of the compound at its targeted receptor site. In order to exert its effects, a medication must reach this effective drug concentration [4]. The driving force behind drugs that are active at the central nervous system boils down to the amount of time and concentration of the compound that can be present in a specific brain site. This process is governed by many chemical processes including plasma pharmacokinetics, protein binding, passive and active transport across the blood-brain-barrier, bulk flow, and active and passive exchanges between cells internally and externally [5]. We won't go into detail about these processes as their functions can become extremely complex, and far too complex for the scope of this article.
The kinetics of kavain have been studied in humans to an extent. Researchers in 2003 administered a 800mg dose of kavain with serum markers showing between 10-40ng/ml (that’s nanograms per milliliters of serum fluid). All forms of kavain metabolites began to appear after only .25 hours reaching peak after 30 more minutes at .75 hours [6]. It’s worth noting here that there may be an entourage effect when kavalactones are present together that may alter their absorption and distribution times [7]. This is great, however it doesn’t speak correlatively to research we see with brain function like at GABA-A receptors.

Isn’t it just the classic scenario when we discover a new quality of kava to be told “Let’s hold on now, are we sure we can even reach these concentrations in the body?”. If you haven’t seen that yet, let me be the first to say it:

Let’s hold on now, are we sure we can even reach these concentrations in the body?

This is the key question to a vast majority of kava research in the past. Researchers used a concentration of 300 µM to understand kavain’s functional characteristics and molecular mechanisms at GABA-A subunits [3]. This concentration level of 300 µM works out to 69 µg/ml in the brain. Researchers also used concentrations of 100 µM and 500 µM when researching kavain’s binding abilities to GABA [8]. When looking at the disposition of radioactive kavain given to rats at the dosage of 100mg/kg (much greater than average kavalactone consumption), we see a brain tissue distribution of 38.8ng. This corresponds to .03% of the total kavain dose making it to the brain [9]. With this in mind we can begin to understand that many of these novel effects require kavalactone concentrations in areas of the body that simply are not attainable. It’s important to keep in mind that scenarios that play out in the petri dish in the lab can be extremely different than those found in a living organism. This rule applies to instances of using extremely high concentrations in the context of activity AND toxicity.

Essentially what this means is likely a good bit of the research we’ve seen in the past and the conclusions they arrived at were based on applying amounts of kavalactones to cells that were FAR outside natural distribution and tissue concentrations levels, and hence would not occur in the standard kava drinker ever.


[1] Lanao, J. M., and M. A. Fraile. 2005. “Drug Tissue Distribution: Study Methods and Therapeutic Implications.” Current Pharmaceutical Design 11 (29): 3829–45. https://doi.org/10.2174/138161205774580679.

[2] Lebot, Vincent, and Patricia Siméoni. 2004. “Is the Quality of Kava (Piper Methysticum Forst. F.) Responsible for Different Geographical Patterns?” Ethnobotany Research and Applications. https://scholarspace.manoa.hawaii.edu/handle/10125/135.

[3] Chua, Han Chow, Emilie T. H. Christensen, Kirsten Hoestgaard-Jensen, Leonny Y. Hartiadi, Iqbal Ramzan, Anders A. Jensen, Nathan L. Absalom, and Mary Chebib. 2016. “Kavain, the Major Constituent of the Anxiolytic Kava Extract, Potentiates GABAA Receptors: Functional Characteristics and Molecular Mechanism.” PloS One 11 (6): e0157700. https://doi.org/10.1371/journal.pone.0157700.

[4] Grogan, Sean, and Charles V. Preuss. 2021. “Pharmacokinetics.” In StatPearls. Treasure Island (FL): StatPearls Publishing. https://www.ncbi.nlm.nih.gov/pubmed/32491676.

[5] Westerhout, Joost, Meindert Danhof, and Elizabeth C. M. De Lange. 2011. “Preclinical Prediction of Human Brain Target Site Concentrations: Considerations in Extrapolating to the Clinical Setting.” Journal of Pharmaceutical Sciences 100 (9): 3577–93. https://doi.org/10.1002/jps.22604.

[6] Tarbah, F., H. Mahler, B. Kardel, W. Weinmann, D. Hafner, and Th Daldrup. 2003. “Kinetics of Kavain and Its Metabolites after Oral Application.” Journal of Chromatography B 789 (1): 115–30. https://doi.org/10.1016/S1570-0232(03)00046-1.

[7] Price, J. (2021, December 1). The entourage effect of kavalactones. by Jimmy Price. Retrieved December 15, 2021, from https://kavafacts.substack.com/p/the-entourage-effect-of-kavalactones

[8] Jussofie, A., A. Schmiz, and C. Hiemke. 1994. “Kavapyrone Enriched Extract from Piper Methysticum as Modulator of the GABA Binding Site in Different Regions of Rat Brain.” Psychopharmacology 116 (4): 469–74. https://doi.org/10.1007/BF02247480.

[9] Mathews, James M., Amy S. Etheridge, John L. Valentine, Sherry R. Black, Donna P. Coleman, Purvi Patel, James So, and Leo T. Burka. 2005. “Pharmacokinetics and Disposition of the Kavalactone Kawain: Interaction with Kava Extract and Kavalactones in Vivo and in Vitro.” Drug Metabolism and Disposition: The Biological Fate of Chemicals 33 (10): 1555–63. https://doi.org/10.1124/dmd.105.004317.

 

Alia

'Awa Grower/Collector
Kava Fact of the day: Kavalactone Concentration in the brain, the pharmacokinetic distribution aspects of kavain, and how research routinely uses concentrations unattainable in vivo.

Today we’re going to address why tissue distribution of kavalactones is such a big deal in kava research, and kava effects. We’ll explore why older research papers we read today may not reflect real-world effects that we see with kava.

Let’s start with the term “Pharmacokinetics”. This is the word that describes the process in which compounds enter the body, move about the body, change within the body, and leave the body [1]. Pharmacokinetics in regards to kavalactones have been studied for many years, however we normally see specific kavalactones targeted for this type of research. Kavain was chosen for the majority of the research seeing as kavain is the most selected and sought after kavalactone, and also exists in larger quantities in most cultivars [2]. Kavain also happens to be the kavalactone studied when looking at the GABA-A receptor [3].

Pharmacokinetics includes absorption, distribution, metabolism and excretion. We’ll be addressing the distribution phase, specifically to the brain. Distribution describes how much of a substance is spread around the body, and varies considerably based on the properties of the substance and the individual consuming it. The goal of this phase is to achieve “effective drug concentration”. This is the effective concentration of the compound at its targeted receptor site. In order to exert its effects, a medication must reach this effective drug concentration [4]. The driving force behind drugs that are active at the central nervous system boils down to the amount of time and concentration of the compound that can be present in a specific brain site. This process is governed by many chemical processes including plasma pharmacokinetics, protein binding, passive and active transport across the blood-brain-barrier, bulk flow, and active and passive exchanges between cells internally and externally [5]. We won't go into detail about these processes as their functions can become extremely complex, and far too complex for the scope of this article.
The kinetics of kavain have been studied in humans to an extent. Researchers in 2003 administered a 800mg dose of kavain with serum markers showing between 10-40ng/ml (that’s nanograms per milliliters of serum fluid). All forms of kavain metabolites began to appear after only .25 hours reaching peak after 30 more minutes at .75 hours [6]. It’s worth noting here that there may be an entourage effect when kavalactones are present together that may alter their absorption and distribution times [7]. This is great, however it doesn’t speak correlatively to research we see with brain function like at GABA-A receptors.

Isn’t it just the classic scenario when we discover a new quality of kava to be told “Let’s hold on now, are we sure we can even reach these concentrations in the body?”. If you haven’t seen that yet, let me be the first to say it:

Let’s hold on now, are we sure we can even reach these concentrations in the body?

This is the key question to a vast majority of kava research in the past. Researchers used a concentration of 300 µM to understand kavain’s functional characteristics and molecular mechanisms at GABA-A subunits [3]. This concentration level of 300 µM works out to 69 µg/ml in the brain. Researchers also used concentrations of 100 µM and 500 µM when researching kavain’s binding abilities to GABA [8]. When looking at the disposition of radioactive kavain given to rats at the dosage of 100mg/kg (much greater than average kavalactone consumption), we see a brain tissue distribution of 38.8ng. This corresponds to .03% of the total kavain dose making it to the brain [9]. With this in mind we can begin to understand that many of these novel effects require kavalactone concentrations in areas of the body that simply are not attainable. It’s important to keep in mind that scenarios that play out in the petri dish in the lab can be extremely different than those found in a living organism. This rule applies to instances of using extremely high concentrations in the context of activity AND toxicity.

Essentially what this means is likely a good bit of the research we’ve seen in the past and the conclusions they arrived at were based on applying amounts of kavalactones to cells that were FAR outside natural distribution and tissue concentrations levels, and hence would not occur in the standard kava drinker ever.


[1] Lanao, J. M., and M. A. Fraile. 2005. “Drug Tissue Distribution: Study Methods and Therapeutic Implications.” Current Pharmaceutical Design 11 (29): 3829–45. https://doi.org/10.2174/138161205774580679.

[2] Lebot, Vincent, and Patricia Siméoni. 2004. “Is the Quality of Kava (Piper Methysticum Forst. F.) Responsible for Different Geographical Patterns?” Ethnobotany Research and Applications. https://scholarspace.manoa.hawaii.edu/handle/10125/135.

[3] Chua, Han Chow, Emilie T. H. Christensen, Kirsten Hoestgaard-Jensen, Leonny Y. Hartiadi, Iqbal Ramzan, Anders A. Jensen, Nathan L. Absalom, and Mary Chebib. 2016. “Kavain, the Major Constituent of the Anxiolytic Kava Extract, Potentiates GABAA Receptors: Functional Characteristics and Molecular Mechanism.” PloS One 11 (6): e0157700. https://doi.org/10.1371/journal.pone.0157700.

[4] Grogan, Sean, and Charles V. Preuss. 2021. “Pharmacokinetics.” In StatPearls. Treasure Island (FL): StatPearls Publishing. https://www.ncbi.nlm.nih.gov/pubmed/32491676.

[5] Westerhout, Joost, Meindert Danhof, and Elizabeth C. M. De Lange. 2011. “Preclinical Prediction of Human Brain Target Site Concentrations: Considerations in Extrapolating to the Clinical Setting.” Journal of Pharmaceutical Sciences 100 (9): 3577–93. https://doi.org/10.1002/jps.22604.

[6] Tarbah, F., H. Mahler, B. Kardel, W. Weinmann, D. Hafner, and Th Daldrup. 2003. “Kinetics of Kavain and Its Metabolites after Oral Application.” Journal of Chromatography B 789 (1): 115–30. https://doi.org/10.1016/S1570-0232(03)00046-1.

[7] Price, J. (2021, December 1). The entourage effect of kavalactones. by Jimmy Price. Retrieved December 15, 2021, from https://kavafacts.substack.com/p/the-entourage-effect-of-kavalactones

[8] Jussofie, A., A. Schmiz, and C. Hiemke. 1994. “Kavapyrone Enriched Extract from Piper Methysticum as Modulator of the GABA Binding Site in Different Regions of Rat Brain.” Psychopharmacology 116 (4): 469–74. https://doi.org/10.1007/BF02247480.

[9] Mathews, James M., Amy S. Etheridge, John L. Valentine, Sherry R. Black, Donna P. Coleman, Purvi Patel, James So, and Leo T. Burka. 2005. “Pharmacokinetics and Disposition of the Kavalactone Kawain: Interaction with Kava Extract and Kavalactones in Vivo and in Vitro.” Drug Metabolism and Disposition: The Biological Fate of Chemicals 33 (10): 1555–63. https://doi.org/10.1124/dmd.105.004317.

I guess a detailed answer (from any given researcher) is-- how does this relate to people?
Thinking back to the cancer-preventative research in kava, that all began annecdotally
with the fact that Pacific Islanders who consume kava beverage regularly have very low
rates of cancer. The actual lab research, going on 11 years now, attempts to break down
which KL or Flavokawains, etc. are involved and how much?
I like to think of something one of those researchers said awhile back (Dr. Amanda Martin)
"It's not necessarily that more is better. What you're looking for is the right amount. And with
kava, an aqueous solution is the right amount".
 

The Kap'n

The Groggy Kaptain (40g)
KavaForums Founder
I guess a detailed answer (from any given researcher) is-- how does this relate to people?
Thinking back to the cancer-preventative research in kava, that all began annecdotally
with the fact that Pacific Islanders who consume kava beverage regularly have very low
rates of cancer. The actual lab research, going on 11 years now, attempts to break down
which KL or Flavokawains, etc. are involved and how much?
I like to think of something one of those researchers said awhile back (Dr. Amanda Martin)
"It's not necessarily that more is better. What you're looking for is the right amount. And with
kava, an aqueous solution is the right amount".
It would make sense that these studies in high concentrations were meant to delve into topics that gave clues as to kavas activity. In fact I would expect it entirely. The issue from my perspective is that today it seems that researchers are continuing to cite these studies as if they were active in aqueous doses (the CYP inhibitory/induction properties for example). The vast majority of the toxicity studies are at dosages unheard of in human consumption. Underscoring this, while it does seem to reduce some of the more hopeful properties we've been talking about, it also almost entirely eliminates the toxicity aspect of kava routinely referenced, at least in my opinion :)
 

Alia

'Awa Grower/Collector
It would make sense that these studies in high concentrations were meant to delve into topics that gave clues as to kavas activity. In fact I would expect it entirely. The issue from my perspective is that today it seems that researchers are continuing to cite these studies as if they were active in aqueous doses (the CYP inhibitory/induction properties for example). The vast majority of the toxicity studies are at dosages unheard of in human consumption. Underscoring this, while it does seem to reduce some of the more hopeful properties we've been talking about, it also almost entirely eliminates the toxicity aspect of kava routinely referenced, at least in my opinion :)
Agree completely!
 
Top