Kavalactone Concentrations

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

In this article 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 begin with the term “pharmacokinetics,” which refers to the process by which compounds enter the body, circulate throughout it, undergo changes within it, and ultimately exit the body [1]. While pharmacokinetics of kavalactones have been extensively researched over the years, these studies typically focus on specific kavalactones. Kavain, being the most commonly sought-after kavalactone and existing in larger quantities in most cultivars, has been the subject of the majority of this research [2]. Additionally, kavain is the kavalactone studied when examining the GABA-A receptor [3].

Pharmacokinetics encompasses absorption, distribution, metabolism, and excretion. In this discussion, we will focus on the distribution phase, particularly as it pertains 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 concentrationâ€. 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 will not delve into the intricacies of these processes as they can be highly complex and go well beyond 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 is worth noting that the presence of multiple kavalactones together may have an entourage effect, which could potentially 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 a classic scenario to be met with skepticism when a new quality of kava is discovered, and be told, “Hold on now, are we even certain that we can attain these concentrations in the human 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]. Considering this, it becomes clear that many of these novel effects may require kavalactone concentrations in parts of the body that are not realistically attainable. It is crucial to keep in mind that situations that occur in a laboratory petri dish may differ greatly from those in a living organism. This applies to instances of using excessively high concentrations in both the context of activity and toxicity.

Essentially, this implies that much of the research we have seen in the past, and the conclusions drawn from it, were based on applying levels of kavalactones to cells that were significantly beyond natural distribution and tissue concentration levels. As a result, these levels would not be found in the average kava drinker.

Sources:

[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.