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Kava Fact of the Day B_Max & Upregulation of GABA Receptors?

The Kap'n

The Groggy Kaptain (40g)
KavaForums Founder
Upregulation of GABA Receptors?

Edit: 09/08/2021
This information has been refuted.

I asked one of the world leading kava researchers, Dr. Matthias Schmidt about this specific question, and this was his response:

"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."



Today we’re going to look at one curious study regarding kava’s action at GABA in binding sites in different regions of rat brain. This study from 1994 comes prior to more timely studies which focus on kava and GABA, however it focuses on receptor density as well. We’re going to specifically look at a term known as B_max and how kavalactones affected this number.

What is B_max?
B_max is a parameter that is the measure of the binding of a drug and the number of receptors present in the sample. In short, it’s the maximum density of receptors [1]. This value tells us the physical number of binding sites, and in this case we’ll be seeing how kava may show an ability to increase this number.

What is “downregulation”?
Something you may have heard, especially if you’ve read any literature relating to drug addiction, is a term called “downregulation”. One function of drug tolerance is the desensitisation of receptors after repeated exposure to drugs which bind to them. A mechanism of this has been found to be the reduction in the number of binding sites that drugs can physically bind to [2].

What is “upregulation”?
Just as it looks, upregulation is the opposite action of downregulation. Upregulation refers to the increase in the number of receptor sites on a cell surface by which the orthosteric ligand (natural binding chemical) can attach [3].

So what was found in this kava study related to GABA-A receptor density?
Researchers applied two different concentrations of kavalactone extracts (full spectrum) at the dosage levels of 100um and 500um to see how these dosages affected different brain areas. It was seen that kavalactones influenced the receptor site densities in a dose dependent manner. In the following table you can see the numbers on the right under B_Max increase steadily. This number represents the quantity of receptors in the sample. Concentrations of GABA receptors in the cortical amygdala were seen to rise over 300% with various increases seen in all brain areas tested [4].

What does this mean to the average kava drinker?
Well, since this is one of the only studies referring to this phenomena, we can’t exactly say for sure. The dosages in this study, also, are much higher than what we can achieve when casually drinking kava. With this in mind and concerning the numbers in the above table, it seems that even lower dosages would cause this increase in receptor density to some degree. This finding could lend evidence to the physiological effect that kava can provide over time as kavalactones build up in the body. An increase in the number of GABA receptor sites will allow endogenous (naturally occurring) GABA to exert a larger inhibitory effect overall. Studies have remarked that this could be a main mechanism of action for kava [5], and this could possibly speak towards kava’s anxiolytic ability beyond that of its initial actions.

Summary:
Full-spectrum kava extracts were shown in rat brain to increase GABA binding sites relative to the dose that was given. This is directly opposite of what we see in addiction studies of receptors. Normally you see, with repeated administration of the chemical in question, a downregulation of receptor sites due to overactivation. When downregulation of receptors occurs, we see tolerance and withdrawal once the chemical in question is stopped. With kavalactones we see the opposite. In all areas of the brain studied a marked increase in GABA receptor density was observed. This may speak to kava’s long term ability to quell anxiety, and might possibly even lend a little evidence towards increasing effects over time.

[1] Dong, Chengyan, Zhaofei Liu, and Fan Wang. 2015. “Radioligand Saturation Binding for Quantitative Analysis of Ligand-Receptor Interactions.” Biophysics Reports 1: 148–55. https://doi.org/10.1007/s41048-016-0016-5

[2] Miller, L. G., S. Woolverton, D. J. Greenblatt, F. Lopez, R. B. Roy, and R. I. Shader. 1989. “Chronic Benzodiazepine Administration. IV. Rapid Development of Tolerance and Receptor Downregulation Associated with Alprazolam Administration.” Biochemical Pharmacology 38 (21): 3773–77. https://doi.org/10.1016/0006-2952(89)90584-4

[3] Edited by Dr. Esam El-Fakahany and Becky Merkey, & MEd. (n.d.). 16. Receptor Regulation. Principles of Pharmacology Study Guide. https://open.lib.umn.edu/pharmacology/chapter/receptor-regulation/

[4] 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

[5] The Mechanism and Rationale for the Avoidance of Taking Benzodiazepines Along with Kava (Piper methysticum) and/or Valerian (Valeriana officinalis) Supplements. EBM Consult. https://www.ebmconsult.com/articles...valerian-valeriana-officinalis-cns-depression
 
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KavaTasteGood

Kava Curious
Quite sad that this information has been refuted. It would have been a rather convenient way to explain this reverse tolerance or sensitization, and the non-addictive anxiolytic effect of kava. Hope research will clarify this to us soon, this is captivating :)
 

Pzk

Kava Enthusiast
"increasing effects over time" .... really?

To me, kava hit me the first time I used it. I used a lot the first year I found kava... my record was 300gr of good kava (2x wash) one day.

What I can say since then, also after a long break, and now using it again, is, that there is no increasing effect over time for me. Perhaps the second day in a row is often a bit more intense, perhaps even the third day. But after that, I often feel almost no effect. Just a bit dizzy, or even a bit ill. But no (nice) effects. I always need breaks to feel kava in a way that is pleasing.

But sometimes kava doesn't have a pleasing effect even after a break. Kava is mysterious...
 

KavaTasteGood

Kava Curious
Yeah for me neither, and it's been around a month that I started this lovely root. Actually, I felt increasing effects because of bettering my extraction "workflow" and that's it. I shared a dose of my preparation for a collegue, and he told me that he felt it straightaway and that he didn't take everything because it was too intense for him. Same for another mate that felt nothing because he dosed just 10g, but perfectly when he took the indicated 30-35g.

I felt also that there is some "tolerance" if I indulge two time in a day. The second time is just less intense and satisfactory. But it may be entirely explained by the "set and setting" of looking forward to the evening resting time after a hardworking day, something that I don't have when I started when I wake up in the morning and redo at night. This is actually cool and self limitating.
 

sensei

Newbie
Upregulation of GABA Receptors?

Edit: 09/08/2021
This information has been refuted.

I asked one of the world leading kava researchers, Dr. Matthias Schmidt about this specific question, and this was his response:

"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."

Today we’re going to look at one curious study regarding kava’s action at GABA in binding sites in different regions of rat brain. This study from 1994 comes prior to more timely studies which focus on kava and GABA, however it focuses on receptor density as well. We’re going to specifically look at a term known as B_max and how kavalactones affected this number.

What is B_max?
B_max is a parameter that is the measure of the binding of a drug and the number of receptors present in the sample. In short, it’s the maximum density of receptors [1]. This value tells us the physical number of binding sites, and in this case we’ll be seeing how kava may show an ability to increase this number.

What is “downregulation”?
Something you may have heard, especially if you’ve read any literature relating to drug addiction, is a term called “downregulation”. One function of drug tolerance is the desensitisation of receptors after repeated exposure to drugs which bind to them. A mechanism of this has been found to be the reduction in the number of binding sites that drugs can physically bind to [2].

What is “upregulation”?
Just as it looks, upregulation is the opposite action of downregulation. Upregulation refers to the increase in the number of receptor sites on a cell surface by which the orthosteric ligand (natural binding chemical) can attach [3].

So what was found in this kava study related to GABA-A receptor density?
Researchers applied two different concentrations of kavalactone extracts (full spectrum) at the dosage levels of 100um and 500um to see how these dosages affected different brain areas. It was seen that kavalactones influenced the receptor site densities in a dose dependent manner. In the following table you can see the numbers on the right under B_Max increase steadily. This number represents the quantity of receptors in the sample. Concentrations of GABA receptors in the cortical amygdala were seen to rise over 300% with various increases seen in all brain areas tested [4].

What does this mean to the average kava drinker?
Well, since this is one of the only studies referring to this phenomena, we can’t exactly say for sure. The dosages in this study, also, are much higher than what we can achieve when casually drinking kava. With this in mind and concerning the numbers in the above table, it seems that even lower dosages would cause this increase in receptor density to some degree. This finding could lend evidence to the physiological effect that kava can provide over time as kavalactones build up in the body. An increase in the number of GABA receptor sites will allow endogenous (naturally occurring) GABA to exert a larger inhibitory effect overall. Studies have remarked that this could be a main mechanism of action for kava [5], and this could possibly speak towards kava’s anxiolytic ability beyond that of its initial actions.

Summary:
Full-spectrum kava extracts were shown in rat brain to increase GABA binding sites relative to the dose that was given. This is directly opposite of what we see in addiction studies of receptors. Normally you see, with repeated administration of the chemical in question, a downregulation of receptor sites due to overactivation. When downregulation of receptors occurs, we see tolerance and withdrawal once the chemical in question is stopped. With kavalactones we see the opposite. In all areas of the brain studied a marked increase in GABA receptor density was observed. This may speak to kava’s long term ability to quell anxiety, and might possibly even lend a little evidence towards increasing effects over time.

[1] Dong, Chengyan, Zhaofei Liu, and Fan Wang. 2015. “Radioligand Saturation Binding for Quantitative Analysis of Ligand-Receptor Interactions.” Biophysics Reports 1: 148–55. https://doi.org/10.1007/s41048-016-0016-5

[2] Miller, L. G., S. Woolverton, D. J. Greenblatt, F. Lopez, R. B. Roy, and R. I. Shader. 1989. “Chronic Benzodiazepine Administration. IV. Rapid Development of Tolerance and Receptor Downregulation Associated with Alprazolam Administration.” Biochemical Pharmacology 38 (21): 3773–77. https://doi.org/10.1016/0006-2952(89)90584-4

[3] Edited by Dr. Esam El-Fakahany and Becky Merkey, & MEd. (n.d.). 16. Receptor Regulation. Principles of Pharmacology Study Guide. https://open.lib.umn.edu/pharmacology/chapter/receptor-regulation/

[4] 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

[5] The Mechanism and Rationale for the Avoidance of Taking Benzodiazepines Along with Kava (Piper methysticum) and/or Valerian (Valeriana officinalis) Supplements. EBM Consult. https://www.ebmconsult.com/articles...valerian-valeriana-officinalis-cns-depression
I don't see any evidence of the study being refuted other than the opinion of one scientist, regardless of whether he's considered an expert or not.

Where is the study where the evidence presented in 1994 has been refuted?

None of the linked studies to do that.
 

sensei

Newbie
Furthermore, another pseudo-gabaergic gabapentin which has previously been stated to not affect Gaba receptors actually increases expression of α4β2δ extra synaptic Gaba receptors that are responsible for tonic inhibition.

Kavain potentiates the exact same extra synaptic Gaba a receptors.


It's interesting that both kava and gabapentin are calcium channel blockers along with having gabaergic properties.

Gabapentin increases expression of δ subunit-containing GABAA receptors
 
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The Kap'n

The Groggy Kaptain (40g)
KavaForums Founder
Furthermore, another pseudo-gabaergic gabapentin which has previously been stated to not affect Gaba receptors actually increases expression of α4β2δ extra synaptic Gaba receptors that are responsible for tonic inhibition.

Kavain potentiates the exact same extra synaptic Gaba a receptors.


It's interesting that both kava and gabapentin are calcium channel blockers along with having gabaergic properties.

Gabapentin increases expression of δ subunit-containing GABAA receptors
Concentration. Chua et al eventually uses 300µM to elicit these currents, and that just seems a tad on the....incredibly high side for any organ exposure? If were were speaking in nM, maybe, but µM, I just have to point in the opposite direction. I absolutely agree about the Gabapentin, in fact I would go as far as to say it even feels similar in some very distinct ways. So I'm not saying you're wrong there at all, just that we haven't exactly cracked it just yet.

GABA-A Upregulation though, I just don't think is going on. Above and beyond what Dr. Schmidt says. We don't see any type of withdrawal effects from kava, and upreg of GABAR is going to involve some type of weird cessation effect, right? At least that's what I would think.
 

sensei

Newbie
Concentration. Chua et al eventually uses 300µM to elicit these currents, and that just seems a tad on the....incredibly high side for any organ exposure? If were were speaking in nM, maybe, but µM, I just have to point in the opposite direction. I absolutely agree about the Gabapentin, in fact I would go as far as to say it even feels similar in some very distinct ways. So I'm not saying you're wrong there at all, just that we haven't exactly cracked it just yet.

GABA-A Upregulation though, I just don't think is going on. Above and beyond what Dr. Schmidt says. We don't see any type of withdrawal effects from kava, and upreg of GABAR is going to involve some type of weird cessation effect, right? At least that's what I would think.
Firstly, I believe that some currents were elicited at 100 υM.

Respectfully, there's about 150 mL of cerebro spinal fluid. And remember that's all we have to make 300 micromolar because the receptors are on the outside of the cells. They're exposed to the cerebrospinal fluid. We don't have to get kavain and kavalactones through the cell membrane if we even could.

The molecular weight of kavain is 230 g. One micro mole would be 230 micrograms in a liter. 300 micromolar would be 69 mg in a liter. 300 micromolar in the brain's cerebrospinal fluid would be 10 mg.

The blood-brain barrier absolutely loves lipophilic substances. That's why the brain has one of the highest concentrations of methamphetamine when people ingest methamphetamine out of all the body's organs. In fact, it's third behind the lungs and the liver. 10% of the dose ends up in the brain.


Now if we go by those pharmacokinetics, we only need 100 mg of kavain to get 10 mg into the brain.

Even If we decide that we're going to include blood as part of what we need to make 300 micromolar Kavain, that's only another 150 ml. So now we're at 20 mg of kavain or 200 mg of an ingested dose.

The bottom line is that 1,000 mg of kavalactones, Even at the minimum accepted Bioavailability of 70% (most scientists thinks it's 90 but some say it's lower as 70) means that 700 mg of kavalactones are absorbed providing 70 mg to the brain

This is the equivalent of 900 micromolar.

One shell will do that. As will 500 mg of 70% kavalactones three times a day.

Now take into account that we know kavain and other Kavalactones have half lives that are at least 9 hours, perhaps longer. Many people use kava multiple times a day.

Now. Read my next sentence.

One thing we don't know is how long kavain and other Kavalactones bind the receptor. Lsd binds to the receptor for 24 hours or longer even though it's undetectable in blood or urine after an hour or two. Who's to say that kavalactones don't do the same thing?

It doesn't take very long to look up these things and do the math and then find citations for concentrations or percentages of administered lipophilic substances that end up crossing the blood brain barrier.

Math doesn't lie

And you know science!
 
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The Kap'n

The Groggy Kaptain (40g)
KavaForums Founder
Firstly, I believe that some currents were elicited at 100 υM.

Respectfully, there's about 150 mL of cerebro spinal fluid. And remember that's all we have to make 300 micromolar because the receptors are on the outside of the cells. They're exposed to the cerebrospinal fluid. We don't have to get kavain and kavalactones through the cell membrane if we even could.

The molecular weight of kavain is 230 g. One micro mole would be 230 micrograms in a liter. 300 micromolar would be 69 mg in a liter. 300 micromolar in the brain's cerebrospinal fluid would be 10 mg.

The blood-brain barrier absolutely loves lipophilic substances. That's why the brain has one of the highest concentrations of methamphetamine when people ingest methamphetamine out of all the body's organs. In fact, it's third behind the lungs and the liver. 10% of the dose ends up in the brain.


Now if we go by those pharmacokinetics, we only need 100 mg of kavain to get 10 mg into the brain.

Even If we decide that we're going to include blood as part of what we need to make 300 micromolar Kavain, that's only another 150 ml. So now we're at 20 mg of kavain or 200 mg of an ingested dose.

The bottom line is that 1,000 mg of kavalactones, Even at the minimum accepted Bioavailability of 70% (most scientists thinks it's 90 but some say it's lower as 70) means that 700 mg of kavalactones are absorbed providing 70 mg to the brain

This is the equivalent of 900 micromolar.

One shell will do that. As will 500 mg of 70% kavalactones three times a day.

Now take into account that we know kavain and other Kavalactones have half lives that are at least 9 hours, perhaps longer. Many people use kava multiple times a day.

Now. Read my next sentence.

One thing we don't know is how long kavain and other Kavalactones bind the receptor. Lsd binds to the receptor for 24 hours or longer even though it's undetectable in blood or urine after an hour or two. Who's to say that kavalactones don't do the same thing?

It doesn't take very long to look up these things and do the math and then find citations for concentrations or percentages of administered lipophilic substances that end up crossing the blood brain barrier.

Math doesn't lie

And you know science!
Why should we go by the pharmacokinetics of methamphetamine?

and I do mean that respectfully, because I really like the questions you’re uncovering. I apologize if I came across as overly assertive. Defending kava for so many years has hardened that part of my behavior.
 
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sensei

Newbie
Why should we go by the pharmacokinetics of methamphetamine?

and I do mean that respectfully, because I really like the questions you’re uncovering. I apologize if I came across as overly assertive. Defending kava for so many years has hardened that part of my behavior.
Because lipophilic substances are lipophilic substances.

But I will do the math for an actual organ distribution study in mice of kavain.

Mice were given an injection of 7 mg per kilogram. Since a mouse is 025 kg, that's equivalent to 175 micrograms total kavain.

The concentration of kavain was 64.7 nanograms per milligram of wet brain tissue. Since a mouse has a 1,000 mg brain, that's equivalent to 64 micrograms of kavain in the brain.

A little math shows that that's approximately 30% of the intravenous dose of kavain administered to the mouse.

Now obviously IV administration is 100% bioavailable, however, all we have to do is multiply 30%* .7 and we get 21%. Based on 70% oral bioavailability and assuming humans and mice have the same organ distribution which is extremely reasonable because we do frequently have that.

Obviously I was a little bit conservative with my earlier assessment of 10% concentration of the oral dose in the brain.

Please feel free to check my math.
 
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sensei

Newbie
Why should we go by the pharmacokinetics of methamphetamine?

and I do mean that respectfully, because I really like the questions you’re uncovering. I apologize if I came across as overly assertive. Defending kava for so many years has hardened that part of my behavior.
Nothing to apologize about.

For the record, I'm a huge proponent of kava. I believe that individual kavalactones may hold promise for specific things in the same way that in the aggregate they do things that they don't do individually.

Personally, I believe If the upregulation extends across all Gaba a subtypes it will be the best GABAA receptor normalizing/healing compound ever.

Used in concert with gabapentin. I think it could heal a lot of people from gabaergic dysfunction caused by alcohol, phenibut, benzodiazepine abuse.

REGARDING THE EXTREMELY MINUTE NUMBER OF PEOPLE THAT CLAIM KAVA WITHDRAWAL:

I HAVE A FEELING THEY WERE CONSUMING EXTREMELY LARGE AMOUNTS (AND/OR OTHER SUBSTANCES THEY DID NOT ADMIT TO) AND THE MONOAMINE OXIDASE INHIBITION AS WELL AS NOREPINEPHRINE REUPTAKE INHIBITION IS WHAT CAUSED THE WITHDRAWALS NOT ANYTHING GABBAERGIC.

Caps are for emphasis not for shouting I'm not being mean
 

The Kap'n

The Groggy Kaptain (40g)
KavaForums Founder
Honestly I think we're mostly on the same page. I've been eyeing this one spot for a while, and the gabapentin correlation struck me by physically consuming it. Took me by surprise.

It would be really valuable to have studies directly measuring kavain in human cerebrospinal fluid to confirm these projections.
 
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