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Mechanism of Action - Kava

The Kap'n

The Kap'n

The Groggy Kaptain (40g)
KavaForums Founder
Maria Daniel said:
Does Kava upregulate GABAa at all? and Is Kava a GABAa agonist or an Allosteric Modulator?
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I asked this exact question about GABA-A upregulation to Dr. Schmidt of Herbresearch.de. Here is his response verbatim:

My email:

Hello Dr. Schmidt! I hope you're doing well.

I have a question for you regarding the possible upregulation of GABA receptors in the presence of crude kava extracts.

Over the time I've been slowly introducing our audience base to the finer scientific details of kava I've noticed a specific area that gathers more attention than others.

It seems that people gravitate towards the idea that kava can cause an increase in GABA-A receptor site density. I believe this may be relevant to users seeking relief of the extended portion of BZP withdrawal.

Being that I've only found this in one paper I have to think it may be something more of a fluke or aberration in results, thus I wanted to see if you knew anything more regarding this, or if this was indeed just a one off result that hasn't been replicated. I personally haven't found any more evidence that backs up the idea that kava directly influences GABA-A receptor site densities (B_Max).

Thank you, and I hope you have a great weekend!

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.
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This is his response:

Good evening!



The paper was published in 1994. This was a time when GABA receptor interactions were “en vogue”, and any herbal effect was explained by this mechanism. When this generally did not work out, the GABA hype was slowly forgotten. I am afraid it is no different with kava, especially as receptor interactions are usually demonstrated in vitro, and then you cannot really draw conclusions on what’s happening in the human organism. Ultimately we do not really know the exact mechanism of action, but that’s also true for many chemically defined drugs. In contrast, the effect can be demonstrated and reproduced in animal experiments, so we know exactly that it works, we just do not known what biochemistry is in the play.



Kind regards



Mathias
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In regards to GABA-A Binding:

The following source found little to no binding affinity.

Davies, L. P., C. A. Drew, P. Duffield, G. A. Johnston, and D. D. Jamieson. 1992. “Kava Pyrones and Resin: Studies on GABAA, GABAB and Benzodiazepine Binding Sites in Rodent Brain.” Pharmacology & Toxicology 71 (2): 120–26. https://sci-hub.se/10.1111/j.1600-0773.1992.tb00530.x

This paper shows some binding affinity, however we're now likely thinking this is due to kavain's preference target of specific subunits of the GABA-A receptor and its general preference for allosteric sites on the GABA-A receptor complex.

Dinh, L. D., U. Simmen, K. B. Bueter, B. Bueter, K. Lundstrom, and W. Schaffner. 2001. “Interaction of Various Piper Methysticum Cultivars with CNS Receptors in Vitro.” Planta Medica 67 (4): 306–11. https://doi.org/10.1055/s-2001-14334.
 
Maria Daniel

Maria Daniel

Kava Curious
Hmmm. Not the answer I was hoping for yet the mystery of it all makes kava all the more intriguing. Let me also ask, what have you gathered as far as interactions, contraindications, and potentiations of kava with other GABAergics (l.theanine, phenibut, benzodiazepines, etc)
 
The Kap'n

The Kap'n

The Groggy Kaptain (40g)
KavaForums Founder
Maria Daniel said:
Hmmm. Not the answer I was hoping for yet the mystery of it all makes kava all the more intriguing. Let me also ask, what have you gathered as far as interactions, contraindications, and potentiations of kava with other GABAergics (l.theanine, phenibut, benzodiazepines, etc)
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Pharmacodynamic interactions only. It seems kava deepens and lengthens the sedative nature of any GABAergic substance. This would make sense if constituents such as kavain are working as general allosteric modulators, causing the channel of the GABA-A receptor to remain open longer, or for more frequently when in the presence of endogenous ligands, as well as allosteric modulators such as BZP drugs.

Shinomiya, Kazuaki, Toshio Inoue, Yoshiaki Utsu, Shin Tokunaga, Takayoshi Masuoka, Asae Ohmori, and Chiaki Kamei. 2005. “Effects of Kava-Kava Extract on the Sleep-Wake Cycle in Sleep-Disturbed Rats.” Psychopharmacology 180 (3): 564–69. https://sci-hub.se/10.1007/s00213-005-2196-4

Tsutsui, Ryuki, Kazuaki Shinomiya, Yasuhiro Takeda, Yoshihito Obara, Yoshihisa Kitamura, and Chiaki Kamei. 2009. “Hypnotic and Sleep Quality–Enhancing Properties of Kavain in Sleep-Disturbed Rats.” Journal of Pharmacological Sciences advpub: 0910300293–0910300293. https://sci-hub.se/10.1254/jphs.09167FP
 
Maria Daniel

Maria Daniel

Kava Curious
Kapmcrunk said:
Pharmacodynamic interactions only. It seems kava deepens and lengthens the sedative nature of any GABAergic substance. This would make sense if constituents such as kavain are working as general allosteric modulators, causing the channel of the GABA-A receptor to remain open longer, or for more frequently when in the presence of endogenous ligands, as well as allosteric modulators such as BZP drugs.

Shinomiya, Kazuaki, Toshio Inoue, Yoshiaki Utsu, Shin Tokunaga, Takayoshi Masuoka, Asae Ohmori, and Chiaki Kamei. 2005. “Effects of Kava-Kava Extract on the Sleep-Wake Cycle in Sleep-Disturbed Rats.” Psychopharmacology 180 (3): 564–69. https://sci-hub.se/10.1007/s00213-005-2196-4

Tsutsui, Ryuki, Kazuaki Shinomiya, Yasuhiro Takeda, Yoshihito Obara, Yoshihisa Kitamura, and Chiaki Kamei. 2009. “Hypnotic and Sleep Quality–Enhancing Properties of Kavain in Sleep-Disturbed Rats.” Journal of Pharmacological Sciences advpub: 0910300293–0910300293. https://sci-hub.se/10.1254/jphs.09167FP
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so in that, it may be correct to call kava a "potentiator" for other GABAergics?
 
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