Acknowledgement goes our to infraredez post on Kava Forums about how kava works on the brain. "Here is his original post"
Below is what he had to say in his findings.
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.
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, 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." [[http://www.ncbi.nlm.nih.gov/pubmed/9832350]
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") [http://www.scbt.com/datasheet-204875-rasagiline.html]
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." [http://www.progressivepsychiatry.com/PDF/0711PT202650LAK.pdf] [http://www.ncbi.nlm.nih.gov/pubmed/11769822]
Studies showing both activities: Agonist [http://www.cabdirect.org/abstracts/20093001788.html;jsessionid=4BFA12C6F3DFA4260FF18AB17C0E133A]
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) I can't remember much about that part.
Here are some of the bookmarks I found regarding this (in no particular order) [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC58680/] [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2796570/] [http://www.ncbi.nlm.nih.gov/pubmed/14746512] [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2667282/] [http://www.ncbi.nlm.nih.gov/pubmed/18184321] [http://www.ncbi.nlm.nih.gov/pubmed/17880927] [http://www.ncbi.nlm.nih.gov/pubmed/18184321] [http://www.jbc.org/content/280/10/8951.long] [http://www.ncbi.nlm.nih.gov/pubmed/15829256] [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3394094/] [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2634932/]