Kava Science Mechanism of kava's lack of withdrawal, some theories.

[yepimonfire]

Most studies hint at the blockage of sodium channels being what causes kava's anti-anxiety properties. To make a very long explanation short, if you make it harder for sodium to enter a neuron, it becomes less easily excited. Benzodiazepines cause withdrawal because any repeated stimulus (including gaba transmission) makes neurons less responsive to that stimulus in order to maintain homeostasis. Sodium channel blockage, unlike gabaergic transmission, is not a stimulus, it simply makes nerve cells less responsive to weaker action potentials. Correct me if I'm wrong but I don't think that the body has any sort of negative feedback loop to overcome sodium channel blockage since it's not an actual stimulus like gaba transmission.

Thoughts?

 

[GussWest]

Preface to say I am a cellular neurobiologist.

What specific publications do you know of that describe kavalactones effects on Na+ channels? I see one paper from 97 on field potentials, suggesting NMDAR as a possible site of action. However, even this paper suggest multiple modalities of action for the kavalactones (which is what I would naturally intuit as well).

I have not had time to dig deeply into the neurobiology and pharmacology of the kavalactones, but intend to as my interest grows. Sincerely appreciate any references you may suggest worth investigation!

A very interesting topic of discussion for me personally!

 

[kavadude]

Hey @GussWest I have been putting together a categorized list of studies at http://kavafaq.com/research . I have yet to add any on mechanism of action though I have read a few in my day, shoot me the links if you read anything interesting

 

[yepimonfire]

http://www.ncbi.nlm.nih.gov/pubmed/12383029

The pharmacological properties of kava are postulated to include blockade of voltage-gated sodium ion channels, enhanced ligand binding to gamma-aminobutyric acid (GABA) type A receptors, diminished excitatory neurotransmitter release due to calcium ion channel blockade, reduced neuronal reuptake of noradrenaline (norepinephrine), reversible inhibition of monoamine oxidase B and suppression of the synthesis of the eicosanoid thromboxane A(2), which antagonises GABA(A) receptor function.

http://www.ncbi.nlm.nih.gov/pubmed/9300426

The action of synthetic kava pyrones, (+)-methysticin and (+/-)-kavain, on voltage-operated Na(+)-channels was studied in whole-cell patch-clamped CA1 hippocampal neurons. In doses of 1-400 microM, both compounds exerted a rapid and reversible inhibition of the peak amplitude of Na(+)-currents.

There's two to get you started. Obviously kavapyrones are pharmacologically complex in their action but I would hazard to guess this is a large part of their sedative properties.

 

[GussWest]

Yep, do you have pdf copies of these full papers? Neither is freely available at Pubmed. PM me for an email address. I'd love to read these. The Singh paper should be a trove of references to the mechanistic pharmacology they gloss over!

All three papers indicate multiple modes of action; which is what I would expect for such a complex pharmacology.
I'd be interested to see if there are labs dissecting all this out at this time.

KD, I will dig deeper into the citations you've collected. Nice work!

 

[verticity]

Yep, do you have pdf copies of these full papers? Neither is freely available at Pubmed. PM me for an email address. I'd love to read these. The Singh paper should be a trove of references to the mechanistic pharmacology they gloss over!

All three papers indicate multiple modes of action; which is what I would expect for such a complex pharmacology.
I'd be interested to see if there are labs dissecting all this out at this time.

KD, I will dig deeper into the citations you've collected. Nice work!

You could ask @Henry I think he has a bunch of full papers

 

[TheKavaSociety]

You could ask @Henry I think he has a bunch of full papers

Yep. Send me a pm

 

[GussWest]

PM sent!

 

[Delicate Drunk]

Yep, do you have pdf copies of these full papers? Neither is freely available at Pubmed. PM me for an email address. I'd love to read these. The Singh paper should be a trove of references to the mechanistic pharmacology they gloss over!

All three papers indicate multiple modes of action; which is what I would expect for such a complex pharmacology.
I'd be interested to see if there are labs dissecting all this out at this time.

KD, I will dig deeper into the citations you've collected. Nice work!

http://sci-hub.io

 

[Zentri]

I'd love an update with your opinions @GussWest once you get around to reading more.

 

[Rick.Sanchez]

Sodium channels aren't much different from anything else in that they're tightly regulated by a wide range of transcriptional, translational, and post translational modifications. Also, the blockade could be caused by some sort of allosteric modulation which would be akin to a receptor agonist. The structure-function biochemistry of kavalactone pharmacology is poorly understood.