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How It Works - Kava


DISCLAIMER: This is not intended to be medical advice and is only for informative purposes.

Before starting any new supplement, herb or drug, one should always consult their physician. If taking other medications, one should always give a complete list of their current medications, supplements and drugs to their physician and pharmacist since kava has the potential to interact in a potentially dangerous way with certain medications (such as acetaminophen, alcohol).​

The following is the simplest explanation for how kava works in the brain.
It will show: how does kava work for anxiety, how does kava work for insomnia, how does kava help pain, how does kava help with muscle relaxation, how does kava work in the brain and what kava does to the body to give its effect.

This is by no means exhaustive or complete, and there is conflicting evidence on some points. That being said, here is the most basic explanation including all proposed theories (which all are likely to play some role in kava's mechanism of action).

First, an overview of psychopharmacology.
Neurons are cells (found in our brain, spinal cord, and other nerves that sense pain, cause muscles to move, etc). Neurons do what they do because of chemical signals and electrical signals. There are four main parts to a neuron but for these purposes we will think of them as having two sides. One side receives information and one transmits information. In two neurons (neurons are found in 'chains') there is a gap where neurons communicate with each other. Neurotransmitters from one neuron send out these neurotransmitters to the other neuron which has receptors on the surface. Once they are bind to the surface of the receiving neuron in receptors, they are either dealt with in several ways or something re-uptakes them back to the original cell. Naturally, our bodies re-uptake all sorts of transmitters in order to recycle the neurotransmitters and to make sure there isn't too much action on the destination cell. It's basically a constant cycle of the first cell taking back what it gave to the 2nd cell in varying degrees.

These cells also have channels (normal, non neural cells too) that either allow things in or out of cells based on various things. Some channels pump things out, some accept cells if they meet a certain criteria. For this, we will just look at the channels that allow substances 'in'. These can allow things 'in' based on their electrical charge or if there’s what’s called a ligand (something that binds to a receptor). For our purposes we will look at the first two.

Voltage-gated channels
These are channels that are described above as allowing substance in based on their electrical charge (sodium has a +1 and calcium has a +2 charge). When a receiving neuron gets a substance that has the right charge, the cells will respond.

By inhibiting these sodium and calcium channels, it will make it harder for these neurons to become “excited”. When these channels are blocked as is the case with kava, there would be a relaxing effect and in the case of our mouth and stomach, it will numb those membranes (it also is what controls epilepsy among other things).
Sodium channel blockers are sometimes used as local anesthetics, antiarrhythmic (stopping abnormal rhythms of the heart) meds, and some anticonvulsants (antiepileptic drugs).

By blocking sodium channels, certain anticonvulsants can help reduce the amount of glutamate which is an excitatory neurotransmitter, again showing a possible mechanism of action of kava's calming effects.

These anticonvulsants help to suppress neurons from firing rapidly (which happens during seizures) but also can show why they are used as mood stabilizers.

Anticonvulsants are also commonly used to treat bipolar disorder because many seem to act as mood stabilizers, again showing a possible mechanism of kava's effects. In addition, they also are being used to treat neuropathic pain (eg. diabetic nerve pain, fibromyalgia pain) which many have used kava with great success.

Another interesting note is that it's been hypothesized that the analgesic effect of some antidepressants is due to sodium channel blockade which can help explain [part of] the analgesic effect of kava [http://www.ncbi.nlm.nih.gov/pubmed/17175203]

Calcium channel blockers are commonly used to treat people with high blood pressure (hypertension) but do so less potently than beta-blockers which significantly decrease the heart's responsiveness to various signals from the sympathetic nervous system, therefore making them more "reversible" and having not as much of a "blanket effect" which shows why we aren't all collapsing of low BP.

The vast majority of calcium channels are also responsible for decreasing what's called "E-C Coupling" (which is the process of converting an electrical signal to a mechanical reaction) of the smooth, skeletal and cardiac muscle.
This can explain the effect on the smooth muscle (eg. bowel movements that seem to be stimulated by kava) as well as the skeletal muscle relaxant effect that we see.

There are different classes of muscle relaxants, one of which is called "Neuromuscular blockers" which block the transmission of a nerve impulse at the motor end plate (the junction of the nerve to the muscle) as well as "Spasmolytics" which either reduce the level of excitation or enhance the inhibition of the signal.

Usually, a muscle contraction involves a nerve signal at this place which then causes a large influx of calcium ions which causes the neuron to release acetylcholine which then stimulates a contraction. If calcium is blocked from rushing into the neuron, then a muscle contraction can be blocked.

Dr. Mathias Schmidt has actually recently brought this up in a recent conversation about the diuretic effect of kava: Diuretic effects [...] maybe related to the spasmolytic effects?

GABA is a prominent neurotransmitter that basically is the major transmitter that inhibits activity between neurons, thereby calming them down which results in sedation, loss of “muscle tone” (the unconscious contraction that our muscles are in even under normal circumstances), etc. There are two main subtypes of GABA that have different effects (GABA-a and GABA-b). Some examples of things (ligands) that bind to GABA receptors are benzodiazepines, alcohol, valerian, barbituates and some muscle relaxants like carisoprodol (Soma). These ligands can either “turn on” or “turn off” the receptor.

GABA-a is what benzodiazepines mainly target and is more targeted towards calming the brain whereas GABA-b is more of a muscle relaxant although both of them have that property. Kava seems to modulate the GABA system, possibly through creating more GABA receptors (and thus, allowing more ligands places to bind and have an effect) or to decrease the amount of effort that it takes for ligands to bind to GABA receptors. Our bodies naturally create substances that bind to GABA receptors.

Norepinephrine (INN)
Norepinephrine, is basically adrenaline, it is required for attention, fight-or-flight situations, mood, arousal etc. When your body releases this, there’s always some left over that isn’t reabsorbed (re-uptake) so it’s just in between the two cells (and is normally re-uptaken) but if the re-uptake is blocked, those cells are “floating” in between the cells and free to bind to the receptors and exert an effect.

MAOIs and MAOs
"MAO"- MonoAmine Oxidase, of which there are two subtypes (A and B), are enzymes that break down some neurotransmitters, specifically "monoamines".
These monoamines are neurotransmitters that contain one amino group in their chemical structure and are very small molecules derived from amino acids (thus why they contain an amino group in their molecule).

When MAOs are inhibited (eg. an MAO-I), this causes a decrease in the amount of these neurotransmitters that can be broken down. In essence, this causes an increase in the amount of dopamine, serotonin, norepinephrine, epinephrine, and phenethylamine (amongst others).
Both subtypes (A and B) break down dopamine equally. The sub-type B breaks down phenethylamine (which is a substance that causes the release of dopamine) whereas subtype A doesn't.

This means more dopamine (and norepinephrine too I think) is in effect present in the brain if subtype B is inhibited.

Older (irreversible) MAOIs are what you might have heard about having pretty significant dietary concerns and significant side effect profiles.
Kava is a very weak, and reversible MAOI.

See below for some further information on this.

Some Further Explanations on The Above Information:

Regarding MAOI and Kava:
From "Inhibition of platelet MAO-B by kava pyrone-enriched extract from Piper methysticum Forster (kava-kava)":
"Kava-kava extract was found to be a reversible inhibitor of MAO-B in intact platelets (IC50 24 microM) and disrupted platelet homogenates (IC50 1.2 microM). Structural differences of kava pyrones resulted in a different potency of MAO-B inhibition. The order of potency was desmethoxyyangonin > (+/-)-methysticin > yangonin > (+/-)-dihydromethysticin > (+/-)- dihydrokavain > (+/-)-kavain. The two most potent kava pyrones, desmethoxyyangonin and (+/-)-methysticin displayed a competetive inhibition pattern with mean Ki 0.28 microM and 1.14 microM respectively. The inhibition of MAO-B by kava pyrone-enriched extracts might be an important mechanism for their psychotropic activity."

This was done in vitro (in a test tube or anywhere outside of a living organism), and the MAO-B inhibition was shown to be reversible which is much safer than irreversible MAOIs. Now, it's important to see how strongly kava acted as an MAOI...

To do this, it's very important that we take into account the "affinity" of the ligand. Affinity is a word that is used to describe how strongly a ligand binds to a particular receptor protein and is measured in terms of IC50 which is the "concentration of ligand at which half of the receptor binding sites are occupied" [Source]
Now, lower IC50 values will translate to higher affinity. In this case, it means more inhibition of MAOI-B.

"Kava-kava extract was found to be a reversible inhibitor of MAO-B in intact platelets (IC50 24 microM) and disrupted platelet homogenates (IC50 1.2 microM)"

Remember that the lower the number, the "stronger" the effect of MAO-B inhibition.

Take a prescription MAOI-B, for example, Rasagiline (Azilect) which shows an IC50 of 4.4 nanoM in humans (where "M" is "Molar")

We have the IC50 value of kava (taking the lower of the two, just for illustration purposes) as 1.2 microM which translates to 1200 nanoM.

We can see the drastic difference with Rasagiline being extremely more potent in its antagonism/inhibition of MAOI-B and showing that while kavalactones possibly have some affinity for MAOI-B, it is not nearly close to the potency seen in prescription MAOIs.

Kava and "NMDA"
"Kava also interferes with norepinephrine reuptake and has a high binding affinity with -aminobutyric acid (GABA) and N-methyl-D-aspartate (NMDA) receptors."

Studies showing both activities:


The top citation only shows an affinity, not the role of the ligand. Again, conflicting evidence (like GABA), but I'd venture to guess that kava's interaction with NMDA is something worth researching. I would think it would act as an antagonist, that's just my guess.
"Reverse Tolerance" (sensitization)

As far as what [might] cause the reverse tolerance that some people experience with Kava...

If kava's MOA is indeed through the modulation of GABA-a receptors, specifically through positive allosteric modulators at receptor sites causing upregulation (although not exclusively) than it would seem logical to assume that repeated administration will cause an increasing intensity of effect (at least in the GABAergic sense) wherein due to upregulation, there is an increase in the amount of GABA receptors on the cellular surface and therefore, the active ligands in kavalactones are able to bind to (and therefore exert their effect) to a greater degree.

During downregulation (tolerance) of μ-opioid agonists [for example], part of the physioslogical change involves receptor phosphorylation due to G protein-coupled cellular kinases which significantly impedes that receptor's signaling and effectively causes less effective binding of the associated ligands. Then, there is of course the downregulation of actual receptor sites which both lead to tolerance, dependence and a decrease in "effect".
It's possible that some similar mechanism is also responsible, albeit in a different way since we're talking about the reverse of the above example.

There is also a lot of research that shows that proteins (Delta FosB and RGS9-2, a regulator of G protein signaling) are involved with tolerance and addiction. This protein Delta FosB, has been theorized to activate genes that increase the person's sensitivity to a given drug. Delta FosB slowly accumulates in the body and remains active far longer than CREB (a protein involved with transcription). This then causes a hypersensitivity and is a leading area of research in drug addiction. There has even been some evidence that FosB can cause actual structural changes in the brain (nucleus accumbens I think) although I can't remember much about that part.

Here are some of the bookmarks I found regarding this (in no particular order)

All that being said, we still don't know why kava does this :cool:
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Kava Enthusiast
The inhibition of dopamine breakdown, is equal among MAOI a inhibitors and MAOI b inhibitors

also kava is a dopamine reuptake inhibitor


The inhibition of dopamine breakdown, is equal among MAOI a inhibitors and MAOI b inhibitors

also kava is a dopamine reuptake inhibitor
You're absolutely right, both subtypes break down dopamine equally. What I was meaning to say was that sub-type b breaks down phenethylamine (which releases dopamine) whereas A doesn't, meaning more dopamine (and norepinephrine too I think) is in effect present in the brain if B is inhibited. That is vague though, thanks for that.

Where did you see that kava inhibited re-uptake of dopamine? That would be interesting.


Kava Enthusiast
"The biochemical mechanism of kava's anxiolytic activity has been postulated to occur through enhanced ligand binding to GABA type A receptors, blockage of violated-gated sodium channels and calcium ion channels, norepinephrine and dopamine reuptake inhibition, and reversible inhibition of monoamine oxidase (MAO) B [see [39] for a review]. To note, the binding of kava extracts to several neurotransmitters such as GABAA1, dopamine D2 and the opiates (μ and δ), were demonstrated in vitro and in the rat brain [40,41]."


so we also have gaba a, d2 (which helps social interaction) and the some opiates going on,

so many different effects on the brain, theres really a lot going on


Wow, that's quite the systematic review- good find.

The statement, "The biochemical mechanism of kava's anxiolytic activity has been postulated to occur through... dopamine reuptake inhibition..." cites an article that I don't have full access to, but there is nothing in the abstract even mentioning dopamine, however it does mention GABA, norepinephrine, sodium and calcium ion channels. [http://www.ncbi.nlm.nih.gov/pubmed/12383029]

That makes me wonder if the basis for that dopamine claim is this (which is later cited by the systematic review as the basis for the delta and mu opioid claims): http://www.ncbi.nlm.nih.gov/pubmed/12494336.

For this study, the extracts used were: "Methanolic leaf and root extracts of the Hawaiian kava". We know about the strength of strong solvents like this in regards to these soluble solutes vs the normal solvent we use (H2O) so that's worth keeping mind when reading the following.
"Leaf extracts also inhibited binding to dopamine D2, opioid (mu and delta) and histamine (H1 and H2) receptors more potently than the corresponding root extracts with IC50 values ranging from 1 to 100 micrograms/ml vs. > or = 100 micrograms/l, respectively."
[1000 milliliters to a liter]

It looks like the binding of ligands to D2, mu and delta opioid receptors were in an antagonistic manner, rather than acting as an agonist. That being said, they were using leaf extracts which were had significantly higher inhibitory effects than the root extracts (which looked clinically negligible, and that's with a strong solvent extraction too). Those IC50 values are very significantly different (~1000 times less potent), and without the Ki values, it'd be really hard for me to say that there is any clinically significant pharmacological action caused by any of those ligands (which aren't defined).

To make it simpler, it's similar to the hypothesis that kava exerts effects through the endocannabinoid system (ie. Yangonin). While Yangonin does have an affinity for the CB1 receptor, we don't know what effect the ligand has (agonist, antagonist, etc). Also, and more importantly, the affinity is in the micromolar range vs. the nanomolar range which is more common for actual cannibinoids (ie. THC).
THC has an Ki of 10nM for CB1. By comparison, the Ki of Yangonin is 0.72 μM.

Keep in mind there are 1000 micromoles (μM) to 1 nanomole (nM).
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Kava Enthusiast
do you think the antagonization of opiods is why having a lot of kava makes you want to have less kava?


Nope, like I was saying in that post, the effects seem to only be present in a clinically significant way in the leaves, and even then, only in a strong solvent extraction.

I think it's due to interaction with NMDA, which would also go a long way in explaining its anticraving effects, anti-addictive traits, lack of tolerance, etc.

NMDA, among other things, is theorized to be a central part of the pharmacological mechanism behind tolerance, dependence and craving. For instance, it's been shown scientifically and anecdotally than concurrent administration of potent NMDA antagonists and opioids can decrease the tolerance the individual experiences.

NMDA and Opioids

NMDA and Ethanol

NMDA and Nicotine

NMDA and Dopamine

In addition, there are plenty of anecdotal reports that show concurrent use of NMDA antagonists can actually effectively eliminate the development of tolerance to stimulants (eg. amphetamines).
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Ah, I guess I might be right.

"Kava also interferes with norepinephrine reuptake and has a high binding affinity with -aminobutyric acid (GABA) and N-methyl-D-aspartate (NMDA) receptors."

Kava and NMDA


The top citation only shows an affinity, not the role of the ligand. Again, conflicting evidence (like GABA), but I'd venture to guess that kava's interaction with NMDA is something worth researching. I would think it would act as an antagonist, but then again, who knows.


EDIT: The post below is a response to a post by a member who has since left the forums and his post is no longer visible, though the questions he asked still are (questions listed by number, responses by me in bullet points)

1. "By inhibiting these sodium and calcium channels, it will make it harder for these neurons to become “excited”" - is there any way someone could elaborate on this, why is it sodium and calcium that excite the neurons?
  • Those channels are normally closed (due to a negative charge across the membrane), but when they respond to Na (+1 charge) and Ca (+2) electrical current they depolarize and cause the rise of the action potential. For neurons, action potential is what basically causes the neuron to "fire". Also, it's worth noting that Na and Ca don't inherently affect all cells or even neurons.

2. In regards to creating more GABA receptors, I have received previous information something like heroin can increase the number of pain receptors (and that is why those coming off it hurt inside their bones, because they have created new receptors that didn't exist before)... is this true?
  • Actually, it's the reverse. Tolerance is due in part to the down-regulation in proteins on the membrane surface which translates to less of a given receptor. Normally, we have endogenous ligands binding to these receptors and this decrease is part of (I think) what causes the resulting pain in withdrawal. I also think that the sensitization of pronociceptive receptors and the desensitization of antinociceptive receptors have an effect on this too.

3. You also mention decreasing the amount of effort of ligands to bond to receptors. What could be some possible reasons that a ligand would be more or less inclined to bond to a receptor?
  • This has to do with affinity (represented in Ki) which are influenced by several mechanisms (some being: Van Der Waals forces and electrostatic interactions, among others). This is a pretty complex idea which incorporates the ideas of the dissociation constant.

4. You mention these organisms work because of chemical and electrical signals. Do you think an electrical charge could have an effect?
  • See #1. One could argue with some degree of accuracy that almost everything is due to electricity (resulting from subatomic particles P+ and e-).

5. As the heart is responsible for pumping blood through the system, and we know with conscious intent of our brain we can affect the electromagnetic signals produced, do you think it is a viable postulate that by consciously channeling positive energy towards kava it could increase its effectiveness in our biochemical machinery? That would account for the songs and such that native sing to their kava, as our hearts pumps blood through the system, creating electromagnetic fields that increase absorption rate to the GABA receptors?
  • Well, this is where things get a little pseudo-scientific. I've seen not one study that shows any change in Ki from conscious thoughts or actions to address that specific question. There is no way that I know of for someone to "channel" a positive or negative (charge, in the ionic sense) to any part of any organ. Things can get really philosophical the deeper you go with this (ie. thought experiments) and something that a professor once proposed was the idea that particles behave in probabilistic and observable ways. Atoms are made up of these particles, and atoms make up molecules, which make up compounds, and eventually, organs such as the brain. Therefore, what is the conception of free-will in a scientific (chemical) sense? It was an interesting postulate, but that's kinda beside the point here. The EM radiation that organs give off isn't necessarily as controllable as some make it seem. Consciousness is the totality of neurons communicating through electrical impulses, but to say that one can control that in a pharmacologically significant way is a bit of a stretch.

6.What do you think plays a bigger role in distributing these chemicals throughout our bodies, water... or blood? Certain cells are water soluble, is there any study indicating if the kavalactones are distributed better in water?
  • Well, blood is partially composed of water (in the plasma) so the two are not separate in that sense. That being said, kavalactones are nonpolar which is due to electronegativity, net-dipole movements and symmetry (or lack thereof). Kavalactones are not water soluble, and therefore they cannot be readily dissolved in water. Regardless, like I said first, since the blood is composed largely of water, it's not really possible to answer that question (because they are one and the same in that way).

7. Why do you think benzodiazepines are so widely distributed, and why does the withdrawal off of a benzo or alcohol create a situation where seizures can occur? What is the mechanism for action to create such an event?
  • Well they are widely distributed in terms of circulation due to the tremendous benefits they offer over barbituates which were the "1st generation" anxiolytics. The withdrawal that can result in seizures is due to the effects these drugs have on GABA.

8. In a more global perspective... would any of you be inclined to be willing to bring this to a reputable institution to perform some laboratory testing?
  • I wish I had that sort of influence :p I myself have nowhere near the amount of resources to conduct any sort of study or even research into this although I hope that those "kava scientists" (the physiological equivalent of Dr. Lebot) will take it up if others don't because I agree that it has a tremendous potential in this regard.

9. I guess the last portion of this is - for some reason, I was under the assumption that it has something to do with the 'shape' of a neuron to help it bind to a particular spot. Perhaps this 'shape' is a combination of polarity and chemistry, but isn't a certain alignment of chemistry akin to a shape? Do the different types of kavalactones have different shapes, which could bond more easily to different receptors?
  • You are right about this. Basically, neurons (and other cells) have transmembrane, peripheral membrane and globular proteins in/on the membrane which is what "receptors" are, just proteins. There is a lot of research in drug design due to structure. The shape of the ligands will be due to a tremendous amount of things (one of which being polarity between bonds due to dipole moments). I'm not quite sure what you mean about "a certain alignment of chemistry akin to a shape". The different kavalactones all have different molecular shapes (and other differing qualities) which is what causes some to bind to certain receptors with different affinities.

Hope that answers some of your questions!
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Kava Enthusiast
This is awesome. It helps explain why many of us find such a wide range of benefits, particularly with regular use.

Krunkie McKrunkface

Kava Connoisseur
This is awesome. It helps explain why many of us find such a wide range of benefits, particularly with regular use.
I suspect that as with micro-nutrients in food there are some subtle but powerful roles being played by the "lesser" kavalactones though it will take time for all this to be understood.

Ricardo Piquant

"the idea that particles behave in probabilistic and observable ways. Atoms are made up of these particles, and atoms make up molecules, which make up compounds, and eventually, organs such as the brain. Therefore, what is the conception of free-will in a scientific (chemical) sense?"

This is quite an interesting concept and worth serious pondering. For me, this brings up questions about subjectivity (which perhaps might be considered to be an illusion from the paradigm quoted above), insofar as I have logically determined for myself that my core self awareness is separate from my body, although is physically enabled by its architecture. I think the "mind" while housed in the body, is a receptor for something originating outside it, and we are currently unable to scientifically measure or identify this. Maybe compete baloney, but I feel to have personally sensed this by way of a shaman long ago. As if, the strict, chemical, unmovable physics that govern the mind's physical manifestation are somehow imprisoning it's desire and ability to be free from those confinements. I'm not sure I can believe these subjective feelings are purely the result of electrical signals and chemicals bouncing around. .. Who knows. .. the great mystery of life. These posts were very interesting reading.


Kava Enthusiast
this is so damn interesting. I intuitively reduced and finally came off lithium (and a swag of benzos) prescribed for bipolar disorder because kava seemed to be having a similar effect for me, and I just kinda felt...directed by the kava to do so. (I don't recommend this for everybody, naturally. Talk to your doc :) ) I now chug one big dose of kava a day (works better than smaller doses throughout the day for me), and while the effects aren't quite as strong as lithium, they are much gentler on my body, and enough to take the extremities out of my symptoms, most of the time. Makes me real mad that we are denied access to this alternative in Australia.