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Kava Fact of the Day TRPA1, Nociceptors, and Kava's skin effects.

The Kap'n

The Groggy Kaptain (40g)
KavaForums Founder
TRPA1 & Kava's Skin Effects


Today’s fact of the day will be diving into a topic known as TRP channels. TRP stands for “transient receptor potential”. These channels allow the influx of calcium into the cell and play an intricate role in the sensing of pain, irritation, hot and cold sensation, inflammation, mucous secretion, coughing and sneezing. They are part of a receptor family known as “nociceptors”. We’re going to be focusing on one of these receptors, TRPA1. The TRPA1 receptor is a target of the mediators that promote inflammatory pain in the nervous system [1]. Cinnamic acid and its derivatives were seen to act as an agonist at this TRPA1 nociceptor.

What is a nociceptor?
A nociceptor is a sensory receptor that is activated by noxious stimuli that damage or threaten the body’s integrity [2]. Nociceptive pain arises from tissues damaged in a physical, or chemical way. These receptors activate at certain temperatures, and certain pressures to trigger a response [3]. In short they’re pain receptors. They are a means of neural feedback to the body. A common reference to this is when dealing with pain relieving compounds. They are known as antinociceptives, and block pain.

What is TRPA1?
TRPA1 is defined as the thermoreceptive (temperature sensitive) transient receptor potential ankyrin. These sit at the ends of nociceptive nerve fibers. It’s calcium permeable and allows calcium ions into the cell. Ankyrins may seem difficult to grasp, but an easy way to remember its location is by looking at the greek word from which it is derived, ankyra, which translates to “anchor”. Ankyrins anchor ion channels among other transport mechanisms to the plasma membrane of the cell [4]. When this receptor is activated it tells the neuron to fire an action potential which is then processed as a pain or sensory signal by the body.

What is a TRPA1 agonist?
Any TRPA1 agonist is a chemical that binds to the receptor, and stimulates a biological response. Agonists cause action, where antagonists cause inaction, and block the action of the agonist [1]. Agonists in regards to the topic of today’s post will be those chemicals that activate this TRPA1 receptor. TRP channel agonists include common food items such as olive oil, horseradish, hot peppers and cinnamon. Cinnamic acid is a known TRPA1 agonist and will be the focus here.

What is cinnamic acid?
Cinnamic acid is an organic compound classified as an unsaturated carboxylic acid. It occurs in a number of plants naturally. This compound is mostly obtained from the oil extract of cinnamon [5]. Cinnamic acid and derivatives are not spoken about much in research papers with kava, however they have been identified as constituents of kava by means of chemical separation as cinnamic bornyl ester, and 3,4-methylenedioxy cinnamic acid [6,7]. These chemicals are important because they have been found to activate the TRPA1 receptor in a dose dependent manner [8].

What does this have to do with kava?
The hypothesis I’m making here is that a constituent of kava, cinnamic acids and derivatives, not the kavalactones, may be involved with feeling cold, the itch, and possibly even dermopathy in regards to kava consumption. It was seen that extracts of kava (aqueous and solvent based) promote proinflammatory responses from mast cells where individual kavalactones did not [9]. This study also noticed calcium influx that could not be explained by kavalactones. This was left open ended as the study was unable to uncover what part of aqueous extracts caused this proinflammatory response in mast cells. Coincidentally, the influx of Ca+ is exactly how the TRP channels operate [10]. More research is needed, but here I postulate that the influx of calcium in mast cells can possibly be explained by cinnamic acid and derivatives attaching to and activating TRPA1. It was found that by blocking TRPA1, they could prevent the degranulation of mast cells and thus reduce allergic skin effects [11]. This would explain the itch and dermatologic reactions such as dermopathy, as well as the cold feeling when TRPA1 is activated in areas outside that of the mast cell.

Summary:
We’ve routinely seen, and personally experienced, the itch and skin effects associated with drinking kava. It’s still up in the air as to what exactly causes these issues, but today I theorize that it’s NOT the kavalactones themselves, but a lesser known part of kava known as cinnamic acid. Cinnamic acid is known to attach to and activate receptors known as “nociceptors” or pain/temperature receptors. These receptors are found on mast cells (cells involved with release of histamines) as well as in many other areas of the body. When these are activated it causes influx of calcium into the mast cell as well as activating these receptors. This may speak to the negative skin reaction such as itch and kava skin as well as may be tied to the cold feeling many kava drinkers report. More research in this area is needed to confirm my hypothesis, however this gives us one more avenue to search in regards to the skin effects with kava.



[1] Mihara, Satoru, and Takayuki Shibamoto. 2015. “The Role of Flavor and Fragrance Chemicals in TRPA1 (transient Receptor Potential Cation Channel, Member A1) Activity Associated with Allergies.” Allergy, Asthma, and Clinical Immunology: Official Journal of the Canadian Society of Allergy and Clinical Immunology 11 (1): 11.
(https://doi.org/10.1186/s13223-015-0074-0)

[2] Messlinger, K. 1997. “[What is a nociceptor?].” Der Anaesthesist 46 (2): 142–53.
(https://doi.org/10.1007/s001010050384) (In German)

[3] Talavera, Karel, Justyna B. Startek, Julio Alvarez-Collazo, Brett Boonen, Yeranddy A. Alpizar, Alicia Sanchez, Robbe Naert, and Bernd Nilius. 2020. “Mammalian Transient Receptor Potential TRPA1 Channels: From Structure to Disease.” Physiological Reviews 100 (2): 725–803.
(https://doi.org/10.1152/physrev.00005.2019)

[4] Wikimedia Foundation. (2021, February 2). Ankyrin. Wikipedia.
(https://en.wikipedia.org/wiki/Ankyrin)

[5] Wikimedia Foundation. (2021, March 21). Cinnamic acid. Wikipedia.
(https://en.wikipedia.org/wiki/Cinnamic_acid)

[6] Xuan, Tran Dang, Masakazu Fukuta, Ao Chang Wei, Abdelnaser Abdelghany Elzaawely, Tran Dang Khanh, and Shinkichi Tawata. 2008. “Efficacy of Extracting Solvents to Chemical Components of Kava (Piper Methysticum) Roots.” Journal of Natural Medicines 62 (2): 188–94.
(https://doi.org/10.1007/s11418-007-0203-2)

[7] Wu, Di, Muraleedharan G. Nair, and David L. DeWitt. 2002. “Novel Compounds from Piper Methysticum Forst (Kava Kava) Roots and Their Effect on Cyclooxygenase Enzyme.” Journal of Agricultural and Food Chemistry 50 (4): 701–5.
(https://doi.org/10.1021/jf010963x)

[8] Sadofsky, Laura R., Andrew N. Boa, Sarah A. Maher, Mark A. Birrell, Maria G. Belvisi, and Alyn H. Morice. 2011. “TRPA1 Is Activated by Direct Addition of Cysteine Residues to the N-Hydroxysuccinyl Esters of Acrylic and Cinnamic Acids.” Pharmacological Research: The Official Journal of the Italian Pharmacological Society 63 (1): 30–36.
(https://doi.org/10.1016/j.phrs.2010.11.004)

[9] Shimoda, Lori M. N., Christy Park, Alexander J. Stokes, Henry Halenani Gomes, and Helen Turner. 2012. “Pacific Island ’Awa (Kava) Extracts, but Not Isolated Kavalactones, Promote Proinflammatory Responses in Model Mast Cells.” Phytotherapy Research: PTR 26 (12): 1934–41.
(https://doi.org/10.1002/ptr.4652)

[10] Freichel, Marc, Julia Almering, and Volodymyr Tsvilovskyy. 2012. “The Role of TRP Proteins in Mast Cells.” Frontiers in Immunology 3 (June): 150.
(https://doi.org/10.3389/fimmu.2012.00150)

[11] Kang, Jun, Yong Ding, Baizhan Li, Hong Liu, Xu Yang, and Mingqing Chen. 2017. “TRPA1 Mediated Aggravation of Allergic Contact Dermatitis Induced by DINP and Regulated by NF-κB Activation.” Scientific Reports 7 (February): 43586.
(https://doi.org/10.1038/srep43586)
 

Alia

'Awa Grower/Collector
TRPA1 & Kava's Skin Effects


Today’s fact of the day will be diving into a topic known as TRP channels. TRP stands for “transient receptor potential”. These channels allow the influx of calcium into the cell and play an intricate role in the sensing of pain, irritation, hot and cold sensation, inflammation, mucous secretion, coughing and sneezing. They are part of a receptor family known as “nociceptors”. We’re going to be focusing on one of these receptors, TRPA1. The TRPA1 receptor is a target of the mediators that promote inflammatory pain in the nervous system [1]. Cinnamic acid and its derivatives were seen to act as an agonist at this TRPA1 nociceptor.

What is a nociceptor?
A nociceptor is a sensory receptor that is activated by noxious stimuli that damage or threaten the body’s integrity [2]. Nociceptive pain arises from tissues damaged in a physical, or chemical way. These receptors activate at certain temperatures, and certain pressures to trigger a response [3]. In short they’re pain receptors. They are a means of neural feedback to the body. A common reference to this is when dealing with pain relieving compounds. They are known as antinociceptives, and block pain.

What is TRPA1?
TRPA1 is defined as the thermoreceptive (temperature sensitive) transient receptor potential ankyrin. These sit at the ends of nociceptive nerve fibers. It’s calcium permeable and allows calcium ions into the cell. Ankyrins may seem difficult to grasp, but an easy way to remember its location is by looking at the greek word from which it is derived, ankyra, which translates to “anchor”. Ankyrins anchor ion channels among other transport mechanisms to the plasma membrane of the cell [4]. When this receptor is activated it tells the neuron to fire an action potential which is then processed as a pain or sensory signal by the body.

What is a TRPA1 agonist?
Any TRPA1 agonist is a chemical that binds to the receptor, and stimulates a biological response. Agonists cause action, where antagonists cause inaction, and block the action of the agonist [1]. Agonists in regards to the topic of today’s post will be those chemicals that activate this TRPA1 receptor. TRP channel agonists include common food items such as olive oil, horseradish, hot peppers and cinnamon. Cinnamic acid is a known TRPA1 agonist and will be the focus here.

What is cinnamic acid?
Cinnamic acid is an organic compound classified as an unsaturated carboxylic acid. It occurs in a number of plants naturally. This compound is mostly obtained from the oil extract of cinnamon [5]. Cinnamic acid and derivatives are not spoken about much in research papers with kava, however they have been identified as constituents of kava by means of chemical separation as cinnamic bornyl ester, and 3,4-methylenedioxy cinnamic acid [6,7]. These chemicals are important because they have been found to activate the TRPA1 receptor in a dose dependent manner [8].

What does this have to do with kava?
The hypothesis I’m making here is that a constituent of kava, cinnamic acids and derivatives, not the kavalactones, may be involved with feeling cold, the itch, and possibly even dermopathy in regards to kava consumption. It was seen that extracts of kava (aqueous and solvent based) promote proinflammatory responses from mast cells where individual kavalactones did not [9]. This study also noticed calcium influx that could not be explained by kavalactones. This was left open ended as the study was unable to uncover what part of aqueous extracts caused this proinflammatory response in mast cells. Coincidentally, the influx of Ca+ is exactly how the TRP channels operate [10]. More research is needed, but here I postulate that the influx of calcium in mast cells can possibly be explained by cinnamic acid and derivatives attaching to and activating TRPA1. It was found that by blocking TRPA1, they could prevent the degranulation of mast cells and thus reduce allergic skin effects [11]. This would explain the itch and dermatologic reactions such as dermopathy, as well as the cold feeling when TRPA1 is activated in areas outside that of the mast cell.

Summary:
We’ve routinely seen, and personally experienced, the itch and skin effects associated with drinking kava. It’s still up in the air as to what exactly causes these issues, but today I theorize that it’s NOT the kavalactones themselves, but a lesser known part of kava known as cinnamic acid. Cinnamic acid is known to attach to and activate receptors known as “nociceptors” or pain/temperature receptors. These receptors are found on mast cells (cells involved with release of histamines) as well as in many other areas of the body. When these are activated it causes influx of calcium into the mast cell as well as activating these receptors. This may speak to the negative skin reaction such as itch and kava skin as well as may be tied to the cold feeling many kava drinkers report. More research in this area is needed to confirm my hypothesis, however this gives us one more avenue to search in regards to the skin effects with kava.



[1] Mihara, Satoru, and Takayuki Shibamoto. 2015. “The Role of Flavor and Fragrance Chemicals in TRPA1 (transient Receptor Potential Cation Channel, Member A1) Activity Associated with Allergies.” Allergy, Asthma, and Clinical Immunology: Official Journal of the Canadian Society of Allergy and Clinical Immunology 11 (1): 11.
(https://doi.org/10.1186/s13223-015-0074-0)

[2] Messlinger, K. 1997. “[What is a nociceptor?].” Der Anaesthesist 46 (2): 142–53.
(https://doi.org/10.1007/s001010050384) (In German)

[3] Talavera, Karel, Justyna B. Startek, Julio Alvarez-Collazo, Brett Boonen, Yeranddy A. Alpizar, Alicia Sanchez, Robbe Naert, and Bernd Nilius. 2020. “Mammalian Transient Receptor Potential TRPA1 Channels: From Structure to Disease.” Physiological Reviews 100 (2): 725–803.
(https://doi.org/10.1152/physrev.00005.2019)

[4] Wikimedia Foundation. (2021, February 2). Ankyrin. Wikipedia.
(https://en.wikipedia.org/wiki/Ankyrin)

[5] Wikimedia Foundation. (2021, March 21). Cinnamic acid. Wikipedia.
(https://en.wikipedia.org/wiki/Cinnamic_acid)

[6] Xuan, Tran Dang, Masakazu Fukuta, Ao Chang Wei, Abdelnaser Abdelghany Elzaawely, Tran Dang Khanh, and Shinkichi Tawata. 2008. “Efficacy of Extracting Solvents to Chemical Components of Kava (Piper Methysticum) Roots.” Journal of Natural Medicines 62 (2): 188–94.
(https://doi.org/10.1007/s11418-007-0203-2)

[7] Wu, Di, Muraleedharan G. Nair, and David L. DeWitt. 2002. “Novel Compounds from Piper Methysticum Forst (Kava Kava) Roots and Their Effect on Cyclooxygenase Enzyme.” Journal of Agricultural and Food Chemistry 50 (4): 701–5.
(https://doi.org/10.1021/jf010963x)

[8] Sadofsky, Laura R., Andrew N. Boa, Sarah A. Maher, Mark A. Birrell, Maria G. Belvisi, and Alyn H. Morice. 2011. “TRPA1 Is Activated by Direct Addition of Cysteine Residues to the N-Hydroxysuccinyl Esters of Acrylic and Cinnamic Acids.” Pharmacological Research: The Official Journal of the Italian Pharmacological Society 63 (1): 30–36.
(https://doi.org/10.1016/j.phrs.2010.11.004)

[9] Shimoda, Lori M. N., Christy Park, Alexander J. Stokes, Henry Halenani Gomes, and Helen Turner. 2012. “Pacific Island ’Awa (Kava) Extracts, but Not Isolated Kavalactones, Promote Proinflammatory Responses in Model Mast Cells.” Phytotherapy Research: PTR 26 (12): 1934–41.
(https://doi.org/10.1002/ptr.4652)

[10] Freichel, Marc, Julia Almering, and Volodymyr Tsvilovskyy. 2012. “The Role of TRP Proteins in Mast Cells.” Frontiers in Immunology 3 (June): 150.
(https://doi.org/10.3389/fimmu.2012.00150)

[11] Kang, Jun, Yong Ding, Baizhan Li, Hong Liu, Xu Yang, and Mingqing Chen. 2017. “TRPA1 Mediated Aggravation of Allergic Contact Dermatitis Induced by DINP and Regulated by NF-κB Activation.” Scientific Reports 7 (February): 43586.
(https://doi.org/10.1038/srep43586)
Truly one of the best yet, written, Fact of the Day.
 

The Kap'n

The Groggy Kaptain (40g)
KavaForums Founder
Truly one of the best yet, written, Fact of the Day.
Thank you! This one took quite a while of researching.

Source #9 is what gave me my ammunition to go about looking for some other cause and it's interesting that TRP channels conveniently explain their mystery influx of Ca+ into mast cells. I can cautiously say that preparing kava in the traditional sense along with hibiscus mucilage seems to increase this effect. As source #9 found an even further increase in Ca+ exchange when hibiscus was used.
 

Alia

'Awa Grower/Collector
Thank you! This one took quite a while of researching.

Source #9 is what gave me my ammunition to go about looking for some other cause and it's interesting that TRP channels conveniently explain their mystery influx of Ca+ into mast cells. I can cautiously say that preparing kava in the traditional sense along with hibiscus mucilage seems to increase this effect. As source #9 found an even further increase in Ca+ exchange when hibiscus was used.
We are fortunate to have Dr. Helen Turner at Chaminade University as well as JD Baker . Helen studied some deep, complex calcium channeling research while getting her PhD. , or so I understand. Both are very interested in kava in general and Hawaiian 'awa specifically.
 

Rami MeloMelo

Berkeley, CA
Kava Vendor
Lebot has been harping for a while - and @Alia - that there's more to kava than the lactones/lipid soluble compounds. Glad to see the research coming out. Very well written JP! The relationship between Ca, Mast, and the TRPA1/Cinnamic acid seems like it would definitely need more study, but a very reasonable relationship to make. TRPA1 is also associated with healing signal pathways (https://immunology.sciencemag.org/content/5/50/eaba5683), and I can see how this can be a beneficial relationship (This was a welcome side-effect that allowed drinkers to exfoliate their skin, a practice long help by Hawaiian drinkers).

This definitely helps explain why some of our drinkers in the Bay always complain about the kava chills, something I can't seem to get the circle here to understand. A lovely side effect if you live in the South Pacific though - blistering hot outside? Drink Kava and cool off.
 

faldho

Kava Curious
Does anyone take anti-histamines regularly? I have been taking Quercetin daily and I'm not really sure how to measure if there's a difference when I'm not taking it. (my skin is fine now as a daily drinker, but there are too many variables involved)
 

Zaphod

Kava Lover
Excellent research! I am still shocked, that with the amount of kava research, that its one true unpleasant "side effect" for many doesn't have a better explanation or mitigation. So I guess the next question is what could a daily user try, for anecdotal research purposes, to test this hypothesis. Maybe a daily anti-histamine for a week or two to see what happens? Is there a way to neutralize Cinnamic acid or filter it out without effecting kavalactone profile?
 

Orz[EST]

Kava Enthusiast
TRPA1 is activated by mustard oil. It is used in animal research as TRPA1 agonist.
Cinnamon leaf oil I once accidentally applied to my skin. The feeling was "oh no, skin will peel off. It was like hot flush. I ran to fridge, opened it, found olive oil and rinsed it with olive oil and toilet paper. The feeling passed. The skin was red. Quite soon, I had no intense stimuation of whatever the receptors were stimulated. It felt hot rather than cold. TRPA1 is considered both mechanioreceptor and biting frost receptor, not that of "cool", which is TRPM8 activated by menthol. Very different. TRPV1 is hot receptor, it is not that brief experience and it is activated by chilli peppers strongly and by vanilline, mildly.

Cinnamon essential oil (active ingredient: cinnamaldehyde), capsicum sp. essential oil (active ingredient: capsaicin) as well as peppermint essential oil (active ingredient: menthol), each one of them is used in certain aromatic ointments. Mileage varies. Some need cooling effect, others need heat, some may need that rush-like action of TRPA1.
 

Orz[EST]

Kava Enthusiast
Quite clearly, olive oil is very mild compared to ceylon cinnamon leaf essential oil (NOTE: USA uses cassia instead of ceylon cinnamon and their main difference is not only taste and price but toxicity -- cassia is toxic in large doses while the same cannot be said about the ceylon cinnamon). I tend to believe that kava is in the ballpark of olive oil rather than cinnamon oil. Heck, I have chewed kava and it is not extremely intense experience except numbness. Attributing causative role of TRPA1 to dermopathy requires stronger evidence because there are much more potent TRPA1 agonists and other mechanisms have been described.

Further reading:
 
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The Kap'n

The Groggy Kaptain (40g)
KavaForums Founder
TRPA1 is activated by mustard oil. It is used in animal research as TRPA1 agonist.
Cinnamon leaf oil I once accidentally applied to my skin. The feeling was "oh no, skin will peel off. It was like hot flush. I ran to fridge, opened it, found olive oil and rinsed it with olive oil and toilet paper. The feeling passed. The skin was red. Quite soon, I had no intense stimuation of whatever the receptors were stimulated. It felt hot rather than cold. TRPA1 is considered both mechanioreceptor and biting frost receptor, not that of "cool", which is TRPM8 activated by menthol. Very different. TRPV1 is hot receptor, it is not that brief experience and it is activated by chilli peppers strongly and by vanilline, mildly.

Cinnamon essential oil (active ingredient: cinnamaldehyde), capsicum sp. essential oil (active ingredient: capsaicin) as well as peppermint essential oil (active ingredient: menthol), each one of them is used in certain aromatic ointments. Mileage varies. Some need cooling effect, others need heat, some may need that rush-like action of TRPA1.
I don't know where you're from, but I seriously appreciate the effort you put in your posts here.

I was reading through some research about mast cells and bradykinins and one study quoted skin inflammatory effects at the nanomolar level with simple application to skin with some of these agonists. Quite wild.
 

Orz[EST]

Kava Enthusiast
Hmm, this would explain co-irritant role in attention to the more predictable (and supposedly mild) direct mechanism:

 

Orz[EST]

Kava Enthusiast
I don't know where you're from, but I seriously appreciate the effort you put in your posts here.

I was reading through some research about mast cells and bradykinins and one study quoted skin inflammatory effects at the nanomolar level with simple application to skin with some of these agonists. Quite wild.
I appreciate your posts very much too. Northeastern Europe but neither northern nor eastern.
 

The Kap'n

The Groggy Kaptain (40g)
KavaForums Founder
Hmm, this would explain co-irritant role in attention to the more predictable (and supposedly mild) direct mechanism:

Thank you! Added to my list to read :)
 

LUNE1

Newbie
Thank you for documenting this. I definitely think there are ways we can support the Kava in our body. So many herbs are taken in formulas vs solo. Kava seems to be a more solo drug traditionally, but we can support it with other plants I think
 

Orz[EST]

Kava Enthusiast
IDK if it has anything to do with kava but topical application of the strong TRPV1 agonist capsaicin depletes several neurotransmitters such as substance P, CGRP and nerve growth factor. #references

There are some studies with newborn rats and injection into surface of the brain but this is too far from real life use to make any reasonable attempt to explain everyday usage of hot peppers.

Newborn rats immersed into strong capsaicin solution lost ability to feel pain permanently. Won't search ref because it is too far from normal use.

 
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Kalm with Kava

Kava Vendor
IDK if it has anything to do with kava but topical application of the strong TRPV1 agonist capsaicin depletes several neurotransmitters such as substance P, CGRP and nerve growth factor. #references

There are some studies with newborn rats and injection into surface of the brain but this is too far from real life use to make any reasonable attempt to explain everyday usage of hot peppers.

Newborn rats immersed into strong capsaicin solution lost ability to feel pain permanently. Won't search ref because it is too far from normal use.

While I'm totally ok with eating capsaicin for this experiment, I'm going to have to pass on having it injected into my brain. Apologies to everyone excited for the results.
 

jonaspmd

found kava
There are several topical formulations of capsaicin approved by the FDA for various pain conditions (not sure if OTC or you need a prescription in the US). If anyone is interested is self-experimentation, a proper design for such a trial with n=1 would be to apply said product on one side of your body (left or right, and not upper or lower part of the body, as kava dermopathy seems to have a specific progression pattern). Continue the daily applications for a month (that's how long it takes for a full skin regeneration cycle). And then record what you see (take a photo). Then a washout period, one month no kava, for the same epidermal regeneration cycle reason. Then crossover - repeat the whole one month process again, but switch the sides of the body. If you see a difference between the body sides after the first month, and the same difference but reversed by the end of the third month, then you're onto something.

Word of caution, there is something about capsaicin permanently affecting nociceptors. Don't have time to dig in this deeper, but overall capsaicin prodcuts seem safe, they are for example prescribed for osteoarthritis, which is a chronic condition, so presumably the patients use the products for months. Still, definitely do not overuse them more than what's said in the FDA label (packet insert). As you would expect burning sensation is a side effect, which limits the popularity of these creams, which may be an issue for kava drinkers as well.

The available formulations are cream and patches. Highly suggest cream, unless you prefer to look like this :D
images.jpg
 

Blergs

Kava Curious
Any updates on this to help skin??
I'm going crazy with the skin sides bad, it really sucks and is my only major complaint with kava .
And I'm not having as much kava as I want half the time either . Typically 5-10 heaping tablespoons a day I use
 
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