What is Kava
Traditional kava is a drink prepared from the roots of Piper Methysticum, a plant native to islands in the South Pacific, where it is used for its natural relaxing and social enhancing qualities. Kava has historically been used by South Pacific Islanders as a safe, natural alternative to drugs and alcohol, because it can bring about significant mood boosting, cognitive enhancing and anxiety relieving effects. This allows users to loosen up and connect easier during social interaction. However, the main draw to kava is that it provides these effects without any of the drunkenness that can impair fine motor skills and is completely non addictive. Connoisseurs describe the experience as a calm, enhanced state of natural sobriety. Kava also provides a vast array of additional therapeutic effects that have been well documented over generations. And its total lack of side effects is believed to come primarily from its unique chemical properties, which gives it the ability to naturally enhance the activity of the body’s main pleasure chemicals dopamine, serotonin, and GABA. This is why kava has been revered as one of the most sacred and prized natural substances in all of the South Pacific for over 3000 years. It is a foundational pillar of the social fabric of these cultures and is used in for almost every occasion imaginable including social gatherings, spiritual ceremonies, weddings, and funerals. 1,2,3,4,5
How Traditional Kava Works
The therapeutic effects of kava are due to a combination of the main active ingredients in the plant, (known as kavalactones), not to any single substance or compound. There are a total of 18 different kavalactones and many other supportive constituents present in the plant.6 It is the presence of all of these compounds combined that gives traditional kava its vast array of therapeutic effects on the body and mind. Because of its natural chemical composition, kava is able to illicit all of these effects without driving the body out of balance and leading to toxicity, dependence and withdrawal symptoms. There is a large body of scientific literature available on kava and its many mechanisms of action in the body. In fact, kava has been more thoroughly studied than almost any herb in the world.
Kava’s Most Promising Applications for our Modern World
When Kava is consumed in its true traditional form it can provide an incredibly vast array of benefits. Some of these effects have been observed by indigenous peoples for thousands of years and others have only been recently discovered through scientific analysis. Many of these effects address some of the most fundamental issues that many of us are facing today in our modern world. These include:
-
Stress relief and relaxation
-
Deeper more restorative sleep
-
Boosting mood and sociability
-
Reducing the cravings for drugs and alcohol
-
Enhancing mental focus and creativity
-
The breakdown of bad tissues and cells
-
Increased fat burning
-
Helping to fight pain and inflammation
-
A Potential Alternative to micro dosing: Processing past trauma via mild psychedelic properties
Stress Relief and Relaxation
There is no doubt that kava has become most famous for its anxiety and stress relieving properties. Kava tends to be seen as a completely safe and effective anxiety-reducing alternative to anti-anxiety benzodiazepine drugs without the addiction factor. In fact, kava has been well studied in direct comparison with Benzodiazepines. One study in particular introduced kava at 50mg (WS 1490 extract) after the participants’ Benzodiazepine dosage was reduced by 50%, and kava later replaced the benzodiazepines with 300mg of WS 1490 extract daily. This substitution was extremely effective. Kava appeared to deliver comparable results that were on par with the benzodiazepines used to treat anxiety. As assessed by animal studies using injections, the anti-anxiety effects of kava and its kavalactones can be very rapid and occur as soon as it hits the brain.
These anxiolytic effects have been shown to primarily come from kava’s ability to significantly increase GABA (Gamma amino butyric acid) activity in the brain through its wide array of kavalactones and other active constituents. GABA is the body’s main chemical for shutting down excitability and inducing relaxation. Certain kavalactones bind to a specific site in the brain called the GABA(A) receptor, which is a key target for most anti-anxiety drugs and is known as one of the master regulators of stress and sleep in the body. 7, 8, 9, 10, 11, 12, 13, 14
Deeper More Restorative Sleep
Because of kava’s powerful effects of the GABA system in the body, it has also become well known as one of the most effective sleep supporting agents found in all of nature. Kava’s profound effects on enhancing sleep have been documented by Anthropologists in the south pacific for decades. These effects have also been consistently demonstrated in scientific studies over the years as well.
In many ways, getting adequate sleep is the most important thing that you can do to build and maintain a healthy body and mind. Sleep is the foundation of how the body repairs itself and maintains all of its functions. An enormous amount of physiological recovery goes on during the eight hours of sleep we are supposed to be getting each night. Sleeping reduces the demands placed on your organs and bodily systems, giving your body the opportunity to repair damage, more efficiently filter and remove waste, and recoup some energy. Sleep is also the time when our bodies process stress and trauma by clearing out stress hormones (such as cortisol and adrenaline) and inflammatory compounds (cytokines and prostaglandins) that we have accumulated throughout the day. It is the main mode through which our bodies reset themselves, so by optimizing the quality of your sleep you can stifle the foothold that all your built up stress has over you. This allows you to not only get a leg up on circumstances in your life that are overwhelming you, but it also helps build physical and mental resilience and prevent stress from affecting you as much in the future.
Boosting Mood And Sociability
Kava has historically been used by South Pacific Islanders as a safe, natural alternative to alcohol, because it can bring about significant mood boosting effects, which can substantially enhance social interaction. However, it typically does this without making the person feel drunk in any way, or impairing their fine motor skills. This ability of kava to enhance mood and sociability is believed to come primarily from its effects on dopamine, which is the body’s main pleasure chemical.
Several kavalactones have been shown in studies to be very strong inhibitors of an enzyme in the body called MAO-B (monoamine oxidase-B). This enzyme is responsible for breaking down dopamine and other neurotransmitters, so inhibiting its activity leads to much higher dopamine levels in the nervous system. One study in particular showed that Kava injected into rats at 20, 120, and 220mg/kg of bodyweight caused extracellular dopamine in the brain to increase by up to 150% compared to a control group. This massive influx in dopamine levels persisted for up to 8 hours after administration.15,16, 17,18
Kava has also been thoroughly looked at as a possible therapeutic agent for depression and other mood disorders. One randomized placebo controlled trial looked at 60 adult participants over a 3 week period of time and found that Kava produced significant antidepressant activity compared to placebo.
Non-addictive
One of the most valuable and amazing aspects of kava is that it is able to provide all of these amazing effects on mood and relaxation without being physiologically addictive at all. This has always been well known in the islands, but has also been shown consistently in published studies. Unlike other substances that affect the dopamine pathway, drinking kava is not habit forming and you will not build up a tolerance to the effects of drinking kava, which would cause you to need to drink more each time. In fact, the exact opposite has been shown. The beneficial effects of a drink of kava can be felt even more when it is drank on subsequent occasions, bringing about cumulative effectiveness over time. This is because of the distinctive way that kava affects the brain. It is able to naturally prop up dopamine levels without depleting or down regulating its function. This is another miraculous byproduct of complex plant intelligence.
Reducing Cravings For Drugs And Alcohol
Kava has been shown to be an excellent anti craving agent for those suffering from drug addiction and dependency. This is due to the fact that kavalactones bind to the same receptors in the brain as many of these substances, except kava modulates them in a way that doesn’t create tolerance and dependency. In fact, it is well known by long term kava users that it can produce what is called a “reverse tolerance” effect. This refers to instances where the more an individual uses kava overtime, the less of it they actually need to receive the same effects. The exact mechanisms and reasons for why this occurs are not yet completely understood. However it has been hypothesized that consistent kava use might actually increase ones natural GABA activity overtime by increasing the number of functional GABA receptors in the brain. This would mean that it could possibly assist in permanent rehabilitation of this system that may be impaired in many anxiety and mood disorders or damaged by long term substance abuse.19, 20, 21, 22
Kava And Substance Abuse
The topic of kava is actually extremely relevant right now more than ever due to the fact that millions are reaching for alcohol and other illicit substances during the elevated stress and trauma in our world. Kava is really the only 100% natural, legal, and totally non addictive alternative to alcohol that can really deliver effects that are truly comparable. Kava is also known as a significant neuroprotective and tissue protective agent that has been shown to significantly reduce cytokine storm activity in virtually all tissues in the body.
Enhancing Mental Focus And Creativity
One of kava’s most amazing yet least publicized effects its cognitive enhancing properties. These effects have not yet become extremely well known because they only carry over through the extraction process used in traditional prep and are completely killed by the process of solvent extraction, which is what 99 percent of “kava-like” extracts on the market are made by using. So if you’re not getting real kava, you really won’t be getting these cognitive boosting effects at all. However, within groups of people who are using real kava today, it is becoming extremely popular as a powerful nootropic for studying, working or to enhance creativity. Many scientific studies have demonstrated positive effects on cognitive function. This primarily occurs through the previously mentioned effects that kava has on dopamine, the brain’s main pleasure chemical that also plays a central role in mental focus, motivation, and memory recall. However, because of the relaxing effects that it also has through activating both GABA and serotonin, kava brings about a state of calm focus and mental clarity. This can be much different than the more jittery potentially anxious focus that comes from using stimulants and many other nootropics. This calm focus is generally referred to as an Alpha state, which is known to be the optimal state of mind for accessing maximum creativity and one’s ability learn new information.23, 24
Protecting The Body From Stress Or Toxin Induced Damage
Maybe one of the best and most accurate ways to describe kava’s effects on the human body as a whole is that it is one of nature’s most profound and complete protective substances. In the world of science we refer to it as an extremely powerful neuro and tissue protective agent. This simply means that it is not only able to calm the nervous system and reduce the acute symptoms of stress, but it has also demonstrated the ability to protect the brain and body from the downstream damaging effects that stress, trauma and toxicity have on the entire system. Kava has been shown to illicit these protective effects through a vast array of different mechanisms that extend far past its natural benzodiazepine like action. In fact, in the ethnobotanical community kava is beginning to be commonly referred to as “the great protector” due to the fact that it just might be the most complete neuro and tissue protective substance that we know of in nature. This actually makes a lot of sense because kava plants play a protective role in the natural ecology. Therefore, through adaptation they naturally develop a full spectrum of protective chemical compounds that act as a kind of “biochemical shield” or buffering system against all forms of stress. Because the kava plant is a complete biological organism, this array protective compounds addresses every step of damage mitigation that resides in biology. And since humans are biological organisms that are part of the same ecosystem, these protective compounds are compatible with our bodies as well. Therefore when humans consume the kava plant, it transfers that adaptability to us. This boosts our resilience and generates a similar buffer against stress in our bodies, which reduces the amount of downstream damage that can occur from all environmental stressors.
Many studies have shown that kavalactones exhibit actions very similar to common antiepileptic drugs that protect the brain from seizure induced damage. In other words, kavalactones seem to help calm down the inflammatory storm that ensues after a significant injury or insult to the brain. Since this inflammation is the primary cause of most of the damage that occurs to the brain tissue post injury, reducing it is thought to significantly help prevent much of the damage from occurring altogether. This protective effect is thought to occur through increased GABA signaling, but also through blocking what are called voltage gated calcium (Ca) channels. The blocking of these channels lowers toxic excitability in the brain as well and prevents the formation of something called hydroxyl free radicals, which are a byproduct of this over excitation that can cause the significant damage to the cells. Activation of these channels is also the primary mechanism by which many environmental stressors such as electromagnetic frequencies (EMFs) can induce cellular damage as well. This suggests that kava could possibly be an important tool for protecting the brain cells from potential damage caused by harmful EMFs. Kavalactones are also known to be activators of an adaptive pathway called Nrf2 (Nuclear factor erythroid 2–related factor 2), which upregulates the body’s own antioxidant and detoxification systems (such as the Glutathione system) that further reduce inflammation and help protect it from damage caused by environmental toxins. All of these effects have also given kava a lot of attention as a possible agent to assist in neurorehabilitation.
One study showed that Kavalactones were able to slow the progression of Alzheimer’s disease by protecting the neurons against beta amyloid plaque induced neurotoxicity through this Nrf2 activation. Two kavalactones, dihydromethysticin and methysticin, have also demonstrated protective effects against ischemia (stroke induced damage) similar in potency to the pharmaceutical Memantine, with the former requiring 150% of the dose and the latter 50% of the dose of Memantine. This was also seen with whole Kava extract, and was attributed to those two components as other Kavalactones showed no protective effects.25, 26, 27, 28, 29, 30, 31, 32, 33
Helping To Fight Pain And Inflammation
In recent years, kava has also started gaining attention for its effects on pain and systemic inflammation. In addition to the anti-inflammatory effects previously mentioned, Studies have shown that kava has action very similar to over the counter NSAIDS (Non-steroidal anti-inflammatories) like aspirin, ibuprofen, and acetaminophen, which all act as what are called COX (cyclooxygenase) inhibitors. kava has been shown to inhibit both COX1 and COX2 which in turn reduces the production of prostaglandins, chemicals that promote inflammation, pain, and fever.34, 35
The Breakdown Of Bad Tissues And Cells
Perhaps one of the most exciting areas of research currently being done on kava is looking at its potential application in the field of cancer and metabolic conditions. The interest of the scientific community was originally peaked back in 2000 when an epidemiological study showed a close inverse relationship between cancer incidence and kava consumption in a large number of different islands in the south pacific. The data indicated that the more kava was consumed by a population, the lower the cancer incidence for that population. This correlation was totally consistent across all 8 countries studied. Since then, the body of accumulating scientific data on kava’s potential application for cancer treatment and prevention has grown immensely.
There are now a large number of studies that demonstrate multiple mechanisms of the anti-mutagenic action of certain types of kava. One kavalactone in particular called Yangonin was shown to activate a pathway called AMPK that significantly increases cellular autophagy, a bodily process that involves breaking down and recycling old damaged cells (including cancerous cells) and their components into usable energy as fuel. This occurred partly through the suppression of a pathway called mTOR (Mammalian Target of Rapamycin), which is one of the primary pathways that drives cancer growth. Other compounds in kava known as flavokawains have been shown in numerous studies to be directly toxic to cancer cells, stimulating what is called apoptosis (cell death) in these cells. These effects have been scientifically demonstrated in a vast array of different forms of cancer including breast, bone, brain, gastric, oral, synovial, thyroid, lung, prostate, bladder, ovarian, melanoma and leukemia. More research needs to be done so this topic can be fully explored but so far the data is very promising.36-57
Increased Fat Burning
Another thing that is important to note is that this AMPK pathway that kava so powerfully activates is also the body’s primary fat burning pathway that shifts its metabolism into this “recycle” mode, where it breaks down stored body fat and old damaged tissue to convert them into usable energy as fuel when little food is present. This pathway is usually activated when a person is fasting, intermittent fasting or is eating very little food. This way the body will survive by making fuel out of its own tissues and stored body fat. So by activating this pathway it appears that kava is actually able to help mimic the effects of fasting and calorie restriction, thus stimulating the body to burn fat as fuel and helping to clear out unwanted tissues. This is one reason why kava is now gaining popularity as a profound keto adaptive agent that can help someone get into ketosis while attempting a ketogenic diet and further enhance the diet once they are adapted. The use of both coffee and MCT oil have both become extremely popular in recent years for their ability to jump start fat burning as well. However, the team at TRU KAVA has discovered that there is an incredibly synergistic effect between coffee, kava oil, and MCT oil that when combined drastically amplifies the effects of all three and seems to take fat burning to a whole new level.
Kava Oil: The Newest Way to Enhance Your Coffee and Your Fast Through Increased Fat Burning
Kava in and of itself is an excellent tool to use during fasting, intermittent fasting, and keto adaptation because of its ability to suppress appetite, lower cortisol and accelerate fat burning and autophagy. This makes it a phenomenal adjunct to coffee during fasting or intermittent fasting for several reasons. By lowering the cortisol spike that some get from drinking coffee you are also lowering the blood glucose spike that goes along with it. And by cranking up fat burning you are able to use body fat for fuel more quickly and stave off appetite for much longer. It also of course adds an extra mood and nootropic (mental clarity) kick to your coffee, while taking away the jitters that some get while drinking it. So it turns out that kava is a fantastic tool to take the overall effects of coffee and MCT to the next level, but also a great tool for those who like coffee but normally get side effects from it. And of course it’s a great alternative for those who don’t do well with coffee no matter what.
A Potential Alternative to micro-dosing: Processing past trauma via mild psychedelic properties
Today there is a massive trend exploding around the world involving both the use of high dose psychedelics (for clinical use) and micro doses of psychedelics to address many mental illnesses and improve many aspects of cognitive function such as creativity and introspective thinking. However, there are many potential legal and side effect related issues that individuals seeking these experiences with classic psychedelics may face. One far less publicized aspect of kava is that it actually contains mild psychedelic properties that are only present in the traditional drink form. But unlike other classic psychedelic compounds (such as psilocybin mushrooms, LSD, DMT, Ayahauasca and Cannabis), kava has much more subtle psychedelic properties that don’t affect a person’s ability to function in everyday circumstances. This means that kava can provide these subtle psychedelic properties while allowing the person to maintain complete sobriety, which means it can be tolerated by most people and can be taken on a regular basis (daily perhaps) without side effects. Also, unlike any of these other compounds, with kava there is no possibility for bad trips or traumatic experiences to occur. This is also the case with micro dosing classic psychedelics (like psilocybin, LSD etc.). However, all classic psychedelics (even in microdoses) are still illegal in most places around the world with the exception of limited clinical applications and studies that are popping up in a few select places. Classic psychedelics are also known to induce tolerance in people who take them consecutively, leading to a loss of effectiveness overtime. This means many people have to cycle off of them regularly to continue getting effects. Kava, on the other hand, maintains its full effectiveness with regular use and is completely legal and can deliver many of the same benefits as micro dosing. For all these reasons kava is becoming a great highly accessible alternative to micro dosing that can easily be made available to the masses without any liability or safety issues.
The natives of the South Pacific have always said that kava has a gradual transformative effect on a person’s psyche with long term use, allowing the user to become more introspective and empathetic overtime. They believe that this subtle cumulative effect on the mind that occurs after prolonged regular use can be even more transformative for some people than more powerful short lived classic psychedelic experiences. This is because the effects are so subtle and gradual that it allows for a slow transition into new perspectives and thought patterns that are easier for individuals to gradually integrate into their everyday lives. Kava lowers the emotional stress system in the brain that is overactive and easily triggered in those who have past or current unresolved traumas in their lives. This can allow these individuals to regularly reflect on these experiences from a place of complete emotional safety, which allows them to gradually create new positive associations with these experiences. This forms new neurological structures (in the form of brain connections) that reinforce those positive reflections and associations. These new brain connections supersede and replace the old ones that reinforce the trauma stress response.
It is important to understand that we as humans can’t change the past, but we can change how we relate to the past. And Psychedelic plant medicines like kava allow us to do that. Kava might be an even better option than classic psychedelics for many people who have many traumatic past experiences and thought patterns that are best processed slowly over an extended period of time. There are many who simply can’t or won’t tolerate the more aggressive psychedelics and kava gives these individuals another option. For these reasons many researchers and scientists around the world believe that kava will have huge implications for conditions like PTSD, Anxiety, and Depression going into the future.
The Significance of Kava to our Modern World in the Time of COVID-19
No matter what personal or philosophical beliefs you hold, there is no question that the circumstances surrounding COVID-19 are truly unprecedented, and the current state of the entire world far surpasses what most of us thought could ever be possible. There is more fear, chaos and collective uncertainty than the vast majority of us have ever experienced in our entire lifetimes. There is mass economic destruction occurring all over the world. Millions are losing their jobs. Many are still locked in their homes, cut off from human contact and interaction. Many still can’t go to restaurants, bars, parties or family gatherings. Most of our individual freedoms and luxuries have been stripped away from us at the drop of a hat. Our lack of work, personal freedoms, connection to one another and positive perspectives on it all have all begun to separate many of us from a key fundamental aspect of ourselves that makes us most human, our sense of purpose.
The social sciences and modern clinical psychology have clearly demonstrated that there is nothing more fundamental to an individual’s (or a culture’s) ability to achieve deep fulfillment, happiness and success than having a true sense of purpose. Individuals who lack a sense of purpose have an exponentially higher proclivity towards substance abuse, crime, mental illness, disease, suicide and death by all causes. Having a sense of purpose is what gives us meaning in this life. And without it we begin to collapse as humans.
This makes it abundantly clear that the long term psychological ramifications of this world wide crisis could very well far exceed that of any potential effect that one temporary virus may have on us collectively on this planet. Already in the U.S. alone, alcohol and drug abuse rates are drastically increasing, when they were already at epidemic levels previous to COVID. And unfortunately, mental illness and suicide rates are projected to be at record highs within the coming months to years. We are most likely only at the beginning of what can only be described as an unimaginable amount of collective trauma that we as humans are all taking on together.
So although taking action to strengthen our immune systems and protecting our physical bodies from this pathogen is crucial, it is perhaps even more important that we work to align ourselves with personal perspectives, values and aspirations that reconnect us with a genuine sense of purpose in our lives. The meaning that we find in purpose is the crucial ingredient that allows us to identify the silver lining in any challenging or traumatic situation, which is what gives us the strength and insight to move forward and overcome extremely challenging circumstances.
So it’s extremely important in our current world for us to allocate as many resources and tools that we can find that will allow us to sharpen our bodies and minds in order to cultivate and claim a deeper sense of wisdom and perspective that inherently resides within each of us as individuals. I believe that psychedelic tools like kava that can be practically embraced and easily tolerated by entire cultures can be some of the most powerful medicinal agents that we have on this planet for not only acting as an alternative to drugs and alcohol to safely help combat short term physical and mental distress, but to also open up our minds and help us to obtain perspective outside of our immediate pain. And that perspective has the ability to turn tremendous pain into tremendous purpose in our lives. Soft subtle psychedelic medicines like kava create an opportunity, which can be made accessible to almost anyone, to safely search deep within ourselves and begin to truly understand the immense value of our health, families, personal freedoms, functioning economies, and natural environments that comprise this beautiful garden of a planet that we call home. Collective shifts in perspective like this can even give us the insight we need to more effectively begin addressing many of the even more serious epidemics that we as humans are facing in our world today such as chronic disease, environmental pollution and economic unsustainability.
Perhaps the most important thing that we can learn during the time of COVID and the current state of our world is that any large scale solution to any large collective issue starts with the physical, psychological, and emotional health of each individual. But all action within individuals really actually all begins with mindset. Throughout history we have learned that many of the highest collective values and mentalities of almost every culture that we know of have been heavily influenced by the psychoactive substances that they upheld most within their societies. According to countless anthropological accounts, many indigenous cultures that fully embraced plant psychedelics and saw them as sacred often ended up having minimal to almost no mental health issues within their populations. Many of these same anthropologists believed this was largely due to the perspective that these plant medicines had instilled within the individuals that made up the societies. We must understand that it is healthy individuals make health societies. And plant medicines like kava are profound tools that can possibly have world changing applications by helping us to take control of our minds, physical health and eventually our circumstances which can empower us with the means to reach our full human potential.
References
1. Kava: an overview. J Ethnopharmacol. 1992 Aug;37(1):13-45.Singh YN1.
2. Kava-kava and anxiety: growing knowledge about the efficacy and safety. Life Sci. 2002 Apr 19;70(22):2581-97.Bilia AR1, Gallon S, Vincieri FF.
3. Kava hepatotoxicity solution: A six-point plan for new kava standardization. 2011 Jan 15;18(2-3):96-103. doi: 10.1016/j.phymed.2010.10.002. Epub 2010 Nov 26.Teschke R1, Sarris J, Lebot V.
4. Safety review of kava (Piper methysticum) by the Natural Standard Research Collaboration. Expert Opin Drug Saf. 2005 Jul;4(4):779-94.Ulbricht C1, Basch E, Boon H, Ernst E, Hammerness P, Sollars D, Tsourounis C, Woods J, Bent S.
5. Extracts and kavalactones of Piper methysticum G. Forst (kava-kava) inhibit P-glycoprotein in vitro. Drug Metab Dispos. 2005 Nov;33(11):1580-3. Epub 2005 Jul 28. Weiss J1, Sauer A, Frank A, Unger M.
6. Kava extract for treating anxiety. Cochrane Database Syst Rev. 2003;(1):CD003383. Pittler MH1, Ernst E.
7. Kava-kava extract in anxiety disorders: an outpatient observational study. Adv Ther. 1998 Jul-Aug;15(4):261-9. Scherer J1.
8. Efficacy of kava-kava in the treatment of non-psychotic anxiety, following pretreatment with benzodiazepines. Psychopharmacology (Berl). 2001 Sep;157(3):277-83. Malsch U1, Kieser M.
9. Kava-Kava extract LI 150 is as effective as Opipramol and Buspirone in Generalised Anxiety Disorder--an 8-week randomized, double-blind multi-centre clinical trial in 129 out-patients. 2003;10 Suppl 4:38-49. Boerner RJ1, Sommer H, Berger W, Kuhn U, Schmidt U, Mannel M.
10. Extracts of kava (Piper methysticum) induce acute anxiolytic-like behavioral changes in mice. Psychopharmacology (Berl). 2003 Oct;170(1):33-41. Epub 2003 Jul 4. Garrett KM1, Basmadjian G, Khan IA, Schaneberg BT, Seale TW.
11. Kavain, the Major Constituent of the Anxiolytic Kava Extract, Potentiates GABAA Receptors: Functional Characteristics and Molecular Mechanism. PLoS One. 2016 Jun 22;11(6):e0157700. doi: 10.1371/journal.pone.0157700. eCollection 2016. Chua HC1, Christensen ET1,2, Hoestgaard-Jensen K2, Hartiadi LY1, Ramzan I1, Jensen AA2, Absalom NL1, Chebib M1.
12. GABA-modulating phytomedicines for anxiety: A systematic review of preclinical and clinical evidence. Phytother Res. 2018 Jan;32(1):3-18. doi: 10.1002/ptr.5940. Epub 2017 Nov 23. Savage K1,2, Firth J3,4, Stough C2, Sarris J1,4.
13. Kava in the treatment of generalized anxiety disorder: a double-blind, randomized, placebo-controlled study. J Clin Psychopharmacol. 2013 Oct;33(5):643-8. doi: 10.1097/JCP.0b013e318291be67. Sarris J1, Stough C, Bousman CA, Wahid ZT, Murray G, Teschke R, Savage KM, Dowell A, Ng C, Schweitzer I.
14.The Kava Anxiety Depression Spectrum Study (KADSS): a randomized, placebo-controlled crossover trial using an aqueous extract of Piper methysticum. Psychopharmacology (Berl). 2009 Aug;205(3):399-407. doi: 10.1007/s00213-009-1549-9. Epub 2009 May 9. Sarris J1, Kavanagh DJ, Byrne G, Bone KM, Adams J, Deed G
15. Inhibition of platelet MAO-B by kava pyrone-enriched extract from Piper methysticum Forster (kava-kava). 1998 Sep;31(5):187-92. Uebelhack R1, Franke L, Schewe HJ.
16. Reversible and irreversible small molecule inhibitors of monoamine oxidase B (MAO-B) investigated by biophysical techniques. Bioorg Med Chem. 2015 Feb 15;23(4):770-8. doi: 10.1016/j.bmc.2014.12.063. Epub 2015 Jan 3.Rojas RJ1, Edmondson DE2, Almos T3, Scott R3, Massari ME3.
17. Effect of kava extract and individual kavapyrones on neurotransmitter levels in the nucleus accumbens of rats. Prog Neuropsychopharmacol Biol Psychiatry. 1998 Oct;22(7):1105-20. Baum SS1, Hill R, Rommelspacher H.
18. Kava as an anticraving agent: preliminary data. Pac Health Dialog. 2001 Sep;8(2):335-9. Steiner GG1.
19. Kavain, the Major Constituent of the Anxiolytic Kava Extract, Potentiates GABAA Receptors: Functional Characteristics and Molecular Mechanism. PLoS One. 2016 Jun 22;11(6):e0157700. doi: 10.1371/journal.pone.0157700. eCollection 2016. Chua HC1, Christensen ET1,2, Hoestgaard-Jensen K2, Hartiadi LY1, Ramzan I1, Jensen AA2, Absalom NL1, Chebib M1.
20. Effect of kava extract and individual kavapyrones on neurotransmitter levels in the nucleus accumbens of rats. Prog Neuropsychopharmacol Biol Psychiatry. 1998 Oct;22(7):1105-20. Baum SS1, Hill R, Rommelspacher H.
21. Kavapyrone enriched extract from Piper methysticum as modulator of the GABA binding site in different regions of rat brain. Psychopharmacology (Berl). 1994 Dec;116(4):469-74. Jussofie A1, Schmiz A, Hiemke C.
22. Enhanced cognitive performance and cheerful mood by standardized extracts of Piper methysticum (Kava-kava). Hum Psychopharmacol. 2004 Jun;19(4):243-50. Thompson R1, Ruch W, Hasenöhrl RU.
23. Effects of oxazepam and an extract of kava roots (Piper methysticum) on event-related potentials in a word recognition task. 1993;27(1):46-53. Münte TF1, Heinze HJ, Matzke M, Steitz J.
24. Kava pyrones exert effects on neuronal transmission and transmembraneous cation currents similar to established mood stabilizers--a review. Prog Neuropsychopharmacol Biol Psychiatry. 2001 Nov;25(8):1555-70. Grunze H1, Langosch J, Schirrmacher K, Bingmann D, Von Wegerer J, Walden J.
25. Kavain, the Major Constituent of the Anxiolytic Kava Extract, Potentiates GABAA Receptors: Functional Characteristics and Molecular Mechanism. PLoS One. 2016 Jun 22;11(6):e0157700. doi: 10.1371/journal.pone.0157700. eCollection 2016. Chua HC1, Christensen ET1,2, Hoestgaard-Jensen K2, Hartiadi LY1, Ramzan I1, Jensen AA2, Absalom NL1, Chebib M1.
26. Kava pyrones exert effects on neuronal transmission and transmembraneous cation currents similar to established mood stabilizers--a review. Prog Neuropsychopharmacol Biol Psychiatry. 2001 Nov;25(8):1555-70. Grunze H1, Langosch J, Schirrmacher K, Bingmann D, Von Wegerer J, Walden J.
27. Electromagnetic fields act via activation of voltage-gated calcium channels to produce beneficial or adverse effects. J Cell Mol Med. 2013 Aug;17(8):958-65. doi: 10.1111/jcmm.12088. Epub 2013 Jun 26.Pall ML1.
28. Electromagnetic fields act via activation of voltage-gated calcium channels to produce beneficial or adverse effects. J Cell Mol Med. 2013 Aug;17(8):958-65. doi: 10.1111/jcmm.12088. Epub 2013 Jun 26.Pall ML1.
29. kavalactone derivative inhibits lipopolysaccharide-stimulated iNOS induction and NO production through activation of Nrf2 signaling in BV2 microglial cells. Pharmacol Res. 2013 May;71:34-43. doi: 10.1016/j.phrs.2013.02.002. Epub 2013 Feb 16. Terazawa R1, Akimoto N, Kato T, Itoh T, Fujita Y, Hamada N, Deguchi T, Iinuma M, Noda M, Nozawa Y, Ito M.
30. A novel kavalactone derivative protects against H2O2-induced PC12 cell death via Nrf2/ARE activation. Bioorg Med Chem. 2010 May 1;18(9):3133-9. doi: 10.1016/j.bmc.2010.03.034. Epub 2010 Mar 20. Tanaka A1, Hamada N, Fujita Y, Itoh T, Nozawa Y, Iinuma M, Ito M.
31. Kavalactones protect neural cells against amyloid beta peptide-induced neurotoxicity via extracellular signal-regulated kinase 1/2-dependent nuclear factor erythroid 2-related factor 2 activation. Mol Pharmacol. 2008 Jun;73(6):1785-95. doi: 10.1124/mol.107.042499. Epub 2008 Mar 11. Wruck CJ1, Götz ME, Herdegen T, Varoga D, Brandenburg LO, Pufe T.
32. Extract of kava (Piper methysticum) and its methysticin constituents protect brain tissue against ischemic damage in rodents. Eur J Pharmacol. 1992 May 14;215(2-3):265-9. Backhauss C1, Krieglstein J.
33. Cyclooxygenase enzyme inhibitory compounds with antioxidant activities from Piper methysticum (kava kava) roots. 2002 Jan;9(1):41-7. Wu D1, Yu L, Nair MG, DeWitt DL, Ramsewak RS.
34. Novel compounds from Piper methysticum Forst (Kava Kava) roots and their effect on cyclooxygenase enzyme. J Agric Food Chem. 2002 Feb 13;50(4):701-5. Wu D1, Nair MG, DeWitt DL.
35. The correlation between cancer incidence and kava consumption.Hawaii Med J. 2000 Nov;59(11):420-2. Steiner GG.
36. Anticancer activities of constituents of kava (Piper methysticum) The South Pacific Journal of Natural Science 2005 vol 23:26-29 N. Tabudravu, Marcel Jaspars
37. Kavalactone yangonin induces autophagy and sensitizes bladder cancer cells to flavokawain A and docetaxel via inhibition of the mTOR pathway.J Biomed Res. 2017 Sep 26;31(5):408-418. doi: 10.7555/JBR.31.20160160.Liu Z1, Ha US1, Yu K1, Wu C1, Yokoyama N1, Zi X2.
38. Kavalactone yangonin induces autophagy and sensitizes bladder cancer cells to flavokawain A and docetaxel via inhibition of the mTOR pathway. J Biomed Res. 2017 Sep 26;31(5):408-418. doi: 10.7555/JBR.31.20160160. Liu Z1, Ha US1, Yu K1, Wu C1, Yokoyama N1, Zi X2.
39. The flavokawains: uprising medicinal chalcones.Cancer Cell Int. 2013 Oct 22;13(1):102. doi: 10.1186/1475-2867-13-102. Abu N, Ho WY, Yeap SK, Akhtar MN, Abdullah MP, Omar AR, Alitheen NB1.
40. Flavokawain B induced cytotoxicity in two breast cancer cell lines, MCF-7 and MDA-MB231 and inhibited the metastatic potential of MDA-MB231 via the regulation of several tyrosine kinases In vitro. BMC Complement Altern Med. 2016 Feb 27;16:86. doi: 10.1186/s12906-016-1046-8. Abu N1,2, Akhtar MN3, Yeap SK4, Lim KL5, Ho WY6, Abdullah MP7, Ho CL8, Omar AR9, Ismail J10, Alitheen NB11.
41. In Vivo Anti-Tumor Effects of Flavokawain A in 4T1 Breast Cancer Cell-Challenged Mice. Anticancer Agents Med Chem. 2015;15(7):905-15.Abu N, Mohamed NE, Yeap SK, Lim KL, Akhtar MN, Zulfadli AJ, Kee BB, Abdullah MP, Omar AR, Alitheen NB1.
42. Flavokawain B, a kava chalcone, inhibits growth of human osteosarcoma cells through G2/M cell cycle arrest and apoptosis. Mol Cancer. 2013 Jun 10;12:55. doi: 10.1186/1476-4598-12-55. Ji T1, Lin C, Krill LS, Eskander R, Guo Y, Zi X, Hoang BH.
43. Inhibition of glioma growth by flavokawain B is mediated through endoplasmic reticulum stress induced autophagy. 2018;14(11):2007-2022. doi: 10.1080/15548627.2018.1501133. Epub 2018 Aug 17. Wang J1, Qi Q1, Zhou W1, Feng Z1, Huang B1, Chen A1, Zhang D1, Li W1, Zhang Q1, Jiang Z1, Bjerkvig R2, Prestegarden L2, Thorsen F2,3, Wang X1, Li X1, Wang J1,2.
44. Chalcone flavokawain B induces autophagic-cell death via reactive oxygen species-mediated signaling pathways in human gastric carcinoma and suppresses tumor growth in nude mice. Arch Toxicol. 2017 Oct;91(10):3341-3364. doi: 10.1007/s00204-017-1967-0. Epub 2017 Apr 3. Chang CT1, Hseu YC2,3, Thiyagarajan V4, Lin KY5, Way TD6, Korivi M1, Liao JW7, Yang HL8.
45. Flavokawain B induces apoptosis of human oral adenoid cystic cancer ACC-2 cells via up-regulation of Bim and down-regulation of Bcl-2 expression. Can J Physiol Pharmacol. 2011 Dec;89(12):875-83. doi: 10.1139/y11-088. Epub 2011 Nov 24. Zhao X1, Chao YL, Wan QB, Chen XM, Su P, Sun J, Tang Y.
46. The chalcone flavokawain B induces G2/M cell-cycle arrest and apoptosis in human oral carcinoma HSC-3 cells through the intracellular ROS generation and downregulation of the Akt/p38 MAPK signaling pathway. J Agric Food Chem. 2012 Mar 7;60(9):2385-97. doi: 10.1021/jf205053r. Epub 2012 Feb 27. Hseu YC1, Lee MS, Wu CR, Cho HJ, Lin KY, Lai GH, Wang SY, Kuo YH, Kumar KJ, Yang HL.
47. Flavokawain B, a kava chalcone, induces apoptosis in synovial sarcoma cell lines. J Orthop Res. 2012 Jul;30(7):1045-50. doi: 10.1002/jor.22050. Epub 2011 Dec 29. Sakai T1, Eskander RN, Guo Y, Kim KJ, Mefford J, Hopkins J, Bhatia NN, Zi X, Hoang BH.
48. Adenosine 5'-monophosphate-activated protein kinase-dependent mTOR pathway is involved in flavokawain B-induced autophagy in thyroid cancer ce Cancer Sci. 2018 Aug;109(8):2576-2589. doi: 10.1111/cas.13699. Epub 2018 Jul 20. He Q1,2,3, Liu W1,2,3, Sha S1,2,3, Fan S4, Yu Y1,2,3, Chen L1,2,3, Dong M1,2,3.
49. Lung tumorigenesis suppressing effects of a commercial kava extract and its selected compounds in A/J mice. Am J Chin Med. 2011;39(4):727-42. Johnson TE1, Hermanson D, Wang L, Kassie F, Upadhyaya P, O'Sullivan MG, Hecht SS, Lu J, Xing C.
50. Flavokawain B induces apoptosis of non-small cell lung cancer H460 cells via Bax-initiated mitochondrial and JNK pathway. Biotechnol Lett. 2012 Oct;34(10):1781-8. doi: 10.1007/s10529-012-0976-6. Epub 2012 Jun 23.An J1, Gao Y, Wang J, Zhu Q, Ma Y, Wu J, Sun J, Tang Y.
51. Flavokawain B, a kava chalcone, induces apoptosis via up-regulation of death-receptor 5 and Bim expression in androgen receptor negative, hormonal refractory prostate cancer cell lines and reduces tumor growth. Int J Cancer. 2010 Oct 15;127(8):1758-68. doi: 10.1002/ijc.25210. Tang Y1, Li X, Liu Z, Simoneau AR, Xie J, Zi X.
52. Abstract 5678: Kavalactone yangonin induces autophagy, inhibits TSC-mediated translation initiation and acts synergistically with a kava chalcone flavokawain A on growth inhibition in bladder cancer UMUC-3 cells AACR; Cancer Res 2010 Apr vol 70, issue 8 DOI:1158/1538-7445. Zhongbo Liu, Xuesen Li, Anna Simoneau and Xiaolin Zi
53. Effects of the kava chalcone flavokawain A differ in bladder cancer cells with wild-type versus mutant p53. Cancer Prev Res (Phila). 2008 Nov;1(6):439-51. doi: 10.1158/1940-6207.CAPR-08-0165.Tang Y1, Simoneau AR, Xie J, Shahandeh B, Zi X.
54. Kava, a tonic for relieving the irrational development of natural preventive agents. Cancer Prev Res (Phila). 2008 Nov;1(6):409-12. doi: 10.1158/1940-6207.CAPR-08-0172. Agarwal R1, Deep G.
55. Flavokawains B and C, melanogenesis inhibitors, isolated from the root of Piper methysticum and synthesis of analogs. Bioorg Med Chem Lett. 2015 Feb 15;25(4):799-802. doi: 10.1016/j.bmcl.2014.12.082. Epub 2015 Jan 3. Jeong HJ1, Lee CS2, Choi J3, Hong YD2, Shin SS2, Park JS2, Lee JH2, Lee S4, Yoon KD5, Ko J6.
56. The Combination of Flavokawain B and Daunorubicin Induces Apoptosis in Human Myeloid Leukemic Cells by Modifying NF-κB. Anticancer Res. 2018 May;38(5):2771-2778. Lee JJ1, Koh KN2, Park CJ3, Jang S3, Im HJ4, Kim N5.
57. Adenosine 5'-monophosphate-activated protein kinase-dependent mTOR pathway is involved in flavokawain B-induced autophagy in thyroid cancer ce Cancer Sci. 2018 Aug;109(8):2576-2589. doi: 10.1111/cas.13699. Epub 2018 Jul 20. He Q1,2,3, Liu W1,2,3, Sha S1,2,3, Fan S4, Yu Y1,2,3, Chen L1,2,3, Dong M1,2,3.