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Kava Kava for Anxiolysis and GABA-a Receptor Upregulation


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#1 Raza

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Posted 27 August 2012 - 06:09 PM


The big 'Treating Anxiety Safely and Effectively' thread blacklists Kava Kava as a Gabaergic which should result in counterproductive GABA-a receptor downregulation, but after finding multiple reports (for example, here) of sensitization (rather than the expected desensitization) over long term use I looked into this and beg to differ.

http://www.ncbi.nlm..../pubmed/7701051

Abstract

Regional differences in the modulation of [3H] muscimol binding to GABAA receptor complexes by kavapyrones, compounds of the rhizome of the plant Piper methysticum which possess sedative activity, were demonstrated using membrane fractions obtained from target brain centers of kavapyrone action: hippocampus (HIP), amygdala (AMY) and medulla oblongata (MED), and from brain centers outside the main kavapyrone effects as frontal cortex (FC) and cerebellum (CER). The kava extract enhanced the binding of [3H] muscimol in a concentration-dependent manner with maximal potentiation of 358% over control in HIP followed by AMY and MED (main target brain centers). Minimal stimulation was observed in CER followed by FC. In contrast, apart from CER, the potency of kavapyrones was similar in the brain areas investigated with EC50 values ranging between 200 and 300 microM kavapyrones. Scatchard analysis revealed that the observed effects of kavapyrones were due to an increase in the number of binding sites (Bmax), rather than to a change in affinity. At a kavapyrone concentration of 500 microM the order of enhancement in Bmax was HIP = AMY > MED > FC > CER. When kavapyrones are included together with pentobarbital or HPO the two classes of compounds produced a more than additive, i.e., synergetic effect on [3H] muscimol binding. Our findings suggest that one way kavapyrones might mediate sedative effects in vivo is through effects on GABAA receptor binding.


http://home.caregrou...r_methystic.htm

Sedative and hypnotic effects: Kavalactones increase GABA receptor density in specific areas of rodent brain (especially hippocampus and amygdala) suggesting GABA-a receptor mediation of the sedative effects of kava, although earlier studies did not find GABA or benzodiazepine receptor binding. German EEG studies have confirmed the limbic structures, especially the amygdylar complex, mediate the sedative effects of kava
(Holm E, et al. Arzneimittelforschung 1991 Jul;41(7):673-683.)



So while Kava Kava extracts are well established to be gabaergics, it seems they aren't agonists at the GABA-a receptor so much as that they potentiate their signal through some other mechanism, either resulting in or as a result of increasing GABA-a receptor density.

I shouldn't have to add that this makes it an incredibly promising substance for the treatment of anxiety and insomnia; something that helps immediately and adds up positively over long term use.

The one nut left to crack is the hepatotoxicity issue reported from western use of Kava extracts. Wikipedia says this has only been known to happen from stem and leaf extracts, however, and that root extracts have a long history of safe use.

Thoughts?

Edited by Raza, 27 August 2012 - 06:14 PM.

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#2 Godot

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Posted 27 August 2012 - 07:39 PM

Excellent find! I've enjoyed kava very much on occassion, but due to its fast effects always assumed its action on GABA was a direct agonism.

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#3 Raza

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Posted 28 August 2012 - 09:39 AM

I've also always intuitively imaged receptor up- and down regulation to be a gradual, long term process that you wouldn't really feel... but it's been coming back as a mechanism of action for various very noticeable effects, such as the immediate potentiation of various agonist drugs by NMDA antagonists causing downregulated receptors to regrow, and now perhaps as the MoA for Kava's relaxation. Receptorgenesis might be much quicker than you'd imagine.
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#4 thegron

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Posted 16 September 2012 - 04:48 AM

This is a very interesting find, thank you. I am going to look into this further.

#5 ScienceGuy

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Posted 16 September 2012 - 07:56 PM

The big 'Treating Anxiety Safely and Effectively' thread blacklists Kava Kava as a Gabaergic which should result in counterproductive GABA-a receptor downregulation, but after finding multiple reports (for example, here) of sensitization (rather than the expected desensitization) over long term use I looked into this and beg to differ...

So while Kava Kava extracts are well established to be gabaergics, it seems they aren't agonists at the GABA-a receptor so much as that they potentiate their signal through some other mechanism, either resulting in or as a result of increasing GABA-a receptor density.

I shouldn't have to add that this makes it an incredibly promising substance for the treatment of anxiety and insomnia; something that helps immediately and adds up positively over long term use.

The one nut left to crack is the hepatotoxicity issue reported from western use of Kava extracts. Wikipedia says this has only been known to happen from stem and leaf extracts, however, and that root extracts have a long history of safe use.

Thoughts?


Raza,

Firstly, thank you for this... You have raised an EXCELLENT question regarding precisely what is KAVA KAVA's mechanism of action with regards to GABA RECEPTORS; and as such I have digged deeper into the matter and I have to agree that my perspective is not entirely accurate, and consequently you have caused me to change it. ;)

However, upon review of the existing scientific evidence up to date, I find that I do not in fact entirely agree with you... wherein IMO either neither of us is correct or we both are... UGH? I hear you say? :)

Specifically the problem lies with the fact that whilst those two studies, which do indeed seem to report KAVA KAVA inducing UPREGULATION of the GABA RECEPTORS, specifically via INCREASING RECEPTOR DENSITY, there concomitantly exists just as many (if not more) studies that appear to demonstrate that KAVA KAVA is indeed a GABA RECEPTOR AGONIST.

To complicate matters even further I have found some additional studies that support your perspective. ;)

Consequently, I have concluded that there exists CONFLICTING EVIDENCE and as such we simply cannot say for sure at the present time the full extent of precisely what is and is not KAVA KAVA's mechanism of action with regards to GABA RECEPTORS. Without a doubt more research is need. :)

I have a THEORY as to what is going on but hesitate to mention it since it is pure academic conjecture. ;)

As as result, I humbly admit that I was mistaken in placing KAVA KAVA on the 'DEFINITELY TO BE AVOIDED' LIST within my TREATING ANXIETY SAFELY & EFFECTIVELY thread; wherein I will be moving it to the 'POSSIBLY WHAT IS SAFE & EFFECTIVE TO TAKE' LIST. ;)

For you interest, here are the various conflicting studies, which to facilitate understanding I have grouped into what I deem 'POSITIVE', 'NEGATIVE' and 'NEUTRAL' with regards to reported effects on the GABA PATHWAY:

‘POSITIVE’ STUDIES:

This study reports that KAVALACTONES (A.K.A. KAVAPYRONES) from KAVA KAVA do not influence the GABAA RECEPTOR via interaction with the BENZODIAZEPINE RECEPTOR (N.B. BENZODIAZEPINE RECEPTORS are allosteric modulatory sites on the GABAA RECEPTORS):

Planta Med. 1998 Aug;64(6):504-6.

Influence of genuine kavapyrone enantiomers on the GABA-A binding site.

Boonen G, Häberlein H.

Source
Department of Pharmaceutical Biology, Philipps-University, Marburg, Germany.

Abstract
The influence of kavapyrones from Piper methysticum Forst. on the GABAA receptor was demonstrated using radioreceptor assays. Both the dienolide yangonin and the genuine enolide enantiomers (+)-kavain, (+)-dihydrokavain, (+)-methysticin, and (+)-dihydromethysticin enhanced the specific binding of [3H]bicuculline methochloride ([3H]BMC). The kavapyrones have been investigated at assay concentrations between 100 microM and 10 nM. (+)-Kavain, (+)-methysticin and (+)-dihydromethysticin showed maximal enhancements of 18% to 28% at a concentration of 0.1 microM, whereas a 100-fold concentration of (+)-dihydrokavain revealed a similar modulatory activity of 22%. In the presence of 1 microM yangonin an increase of about 21% of the specific [3H]BMC binding was observed. Desmethoxyyangonin did not alter the binding behavior of the GABAA-receptor. A structure comparison of desmethoxyyangonin and yangonin indicated that the aromatic methoxy group was of particular importance for the modulatory activity. In contrast, the substitution pattern of the aromatic ring did not influence the modulatory activity of the enolides in a decisive manner. A structure comparison of desmethoxyyangonin and (+)-kavain revealed that an angular lactone ring was an important structure requirement. Both the enolides and the dienolides did not inhibit the specific binding of [3H]flunitrazepan. Thus, the influence on the GABAA receptor was not based upon an interaction of these kavapyrones with the benzodiazepine receptor.

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This study (IN VIVO and on HUMANS) found KAVA KAVA to be effective in treating non-psychotic ANXIETY; and reported no instance of WITHDRAWAL SYMPTOMS upon ceasing taking the KAVA KAVA:

Phytother Res. 2004 Apr;18(4):297-300.

Kava treatment in patients with anxiety.

Geier FP, Konstantinowicz T.

Source
Geriatric Hospital Elbroich, Am Falder 6, 40589 Duesseldorf, Germany.

Abstract
In several clinical trials, mainly conducted with a dose of 300 mg kava extract per day, kava has been employed successfully for the treatment of anxiety disorders. The goal of the placebo-controlled double-blind outpatient trial was to obtain more information on the dosage range and efficacy of a kava special extract WS 1490 in patients with non-psychotic anxiety. 50 patients were treated with a daily dose of 3 x 50 mg WS 1490 during a 4-week treatment period followed by a 2-week safety observation phase. In the active treatment group, the total score of the Hamilton anxiety scale (primary efficacy variable), showed a therapeutically relevant reduction in anxiety versus placebo (more than 4 points). In the secondary variables studied, HAMA 'somatic and psychic anxiety' subscales, the Erlangen anxiety, tension and aggression scale (EAAS), the brief personality structure scale (KEPS), the adjective checklist (EWL 60-S) and clinical global impressions scale (CGI), a trend in favour of the active treatment was detectable. [Kava extract] WS 1490 was well tolerated and showed a safety profile with no drug-related adverse events or post-study withdrawal symptoms. It can be concluded that the applied 150 mg WS 1490 per day is an effective and safe treatment of non-psychotic anxiety syndromes in the described population.
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This study (IN VIVO and on HUMANS) reports that KAVA KAVA modulates the GABA PATHWAY without IMPAIRING COGNITION, which implies its mechanism of action is not that of full GABA RECEPTOR AGONIST:

Hum Psychopharmacol. 2011 Mar;26(2):102-11. doi: 10.1002/hup.1180. Epub 2011 Mar
16.

Neurocognitive effects of kava (Piper methysticum): a systematic review.

LaPorte E, Sarris J, Stough C, Scholey A.

Source
Brain Sciences Institute, University of Technology, Melbourne, Victoria, Australia. emma.laporte@live.com

Abstract
RATIONALE: Kava (Piper methysticum) elicits dose-dependent psychotropic effects and thus may potentially deleteriously affect cognitive performance. Clinical trials have assessed the effects of kava on cognition, however, to our knowledge no systematic review has been conducted in this area.

OBJECTIVE: To systematically review the effects of kava on cognition, providing an analysis of the individual study's methodological quality, results and effect sizes.

METHODS: A systematic review was conducted of publications up to June 15th 2010, using the electronic databases MEDLINE, PsychINFO, CINAHL, Web of Science and The Cochrane Library. The search criteria involved kava and cognition related terms, e.g. memory and attention.

RESULTS: Ten human clinical trials met inclusion criteria (acute n = 7, chronic n = 3). One acute study found that kava significantly improved visual attention and working memory processes while another found that kava increased body sway. One chronic study found that kava significantly impaired visual attention during high-cognitive demand. Potential enhanced cognition may be attributed to the ability of kava to inhibit re-uptake of noradrenaline in the pre-frontal cortex, while increased body sway may be due to GABA pathway modulation.

CONCLUSIONS: The majority of evidence suggests that kava has no replicated significant negative effects on cognition.
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Another study (IN VIVO and on HUMANS) that reports KAVA KAVA does NOT IMPAIR COGNITION, which again implies its mechanism of action is not that of full GABA RECEPTOR AGONIST; but found that KAVA KAVA usage ELEVATED LIVER ENZYMES demonstrating HEPATOTOXICITY (N.B. Whether or not KAVA KAVA is in fact HEPATOTOXIC is a whole other discussion, and this singular study is not conclusive proof of this and should not be taken as such):

Neuropsychopharmacology. 2003 Feb;28(2):389-96.

Saccade and cognitive function in chronic kava users.

Cairney S, Clough AR, Maruff P, Collie A, Currie BJ, Currie J.

Source
Mental Health Research Institute of Victoria, Parkville, Victoria, Australia.
scairney@mhri.edu.au

Abstract
Kava is an extract from the Piper methysticum Forst. f. plant that has been consumed in the Pacific islands for millennia and more recently, among indigenous populations, in northern Australia and throughout the Western world as an herbal medicine. Through alterations on neuronal excitation, kava induces muscle relaxation, anasthesia, and has anxiolytic properties. There have been several isolated reports of psychotic syndromes, severe choreoathetosis and possible seizures following kava use. However, there is no conclusive evidence that kava interferes with normal cognitive processes. We tested a group of current, ex, and nonkava users among an indigenous population in northern Australia, using saccade and cognitive tests that have proven cross-cultural validity and are sensitive to subtle disruptions of the brain arising from substance abuse or neuropsychiatric illness. Despite collecting data from among the heaviest reported kava drinkers in the world, we found no impairment in cognitive or saccade function in individuals who were currently heavy kava users (and had been for up to 18 years), nor was there any impairment in individuals who had been heavy kava users in the past but had abstained for longer than 6 months. Current and ex-kava users showed a higher rate of kava dermopathy, lower body mass index, lowered blood lymphocytes and, in addition, current kava users showed elevated liver enzymes. While there has recently been increasing concern about potentially fatal liver damage attributed to kava use, we have found no evidence of brain dysfunction in heavy and long-term kava users.
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These are added to the TWO STUDIES already posted by RAZA (Thank you!), which are as follows:

This study (whilst on RODENTS) reports that KAVA KAVA’s GABAergic mechanism of action is due to UPREGULATION of the GABA RECEPTORS:

Psychopharmacology (Berl). 1994 Dec;116(4):469-74.

Kavapyrone enriched extract from Piper methysticum as modulator of the GABA
binding site in different regions of rat brain.

Jussofie A, Schmiz A, Hiemke C.

Institut für Physiologische Chemie, Universitätsklinikum Essen, Germany.

Regional differences in the modulation of [3H] muscimol binding to GABAA receptor complexes by kavapyrones, compounds of the rhizome of the plant Piper methysticum which possess sedative activity, were demonstrated using membrane fractions obtained from target brain centers of kavapyrone action: hippocampus (HIP), amygdala (AMY) and medulla oblongata (MED), and from brain centers outside the main kavapyrone effects as frontal cortex (FC) and cerebellum (CER). The kava extract enhanced the binding of [3H] muscimol in a concentration-dependent manner with maximal potentiation of 358% over control in HIP followed by AMY and MED (main target brain centers). Minimal stimulation was observed in CER followed by FC. In contrast, apart from CER, the potency of kavapyrones was similar in the brain areas investigated with EC50 values ranging between 200 and 300 microM kavapyrones. Scatchard analysis revealed that the observed effects of kavapyrones were due to an increase in the number of binding sites (Bmax), rather than to a change in affinity. At a kavapyrone concentration of 500 microM the order of enhancement in Bmax was HIP = AMY > MED > FC > CER. When kavapyrones are included together with pentobarbital or HPO the two classes of compounds produced a more than additive, i.e., synergetic effect on [3H] muscimol binding. Our findings suggest that one way kavapyrones might mediate sedative effects in vivo is through effects on GABAA receptor binding.
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This study (whilst also on RODENTS) reports that KAVA KAVA’s GABAergic mechanism of action is due to UPREGULATION of the GABA RECEPTORS:

Arzneimittelforschung. 1991 Jul;41(7):673-83.

The action profile of D,L-kavain. Cerebral sites and sleep-wakefulness-rhythm in
animals.
[Article in German]

Holm E, Staedt U, Heep J, Kortsik C, Behne F, Kaske A, Mennicke I.

Source
Abteilung für Pathophysiologie, I. Medizinische Klinik Mannheim, Universität
Heidelberg, Mannheim.

EXTRACT FROM FULL TEXT:

Kavalactones increase GABA receptor density in specific areas of rodent brain (especially hippocampus and amygdala) suggesting GABA-a receptor mediation of the sedative effects of kava, although earlier studies did not find GABA or benzodiazepine receptor binding. German EEG studies have confirmed the limbic structures, especially the amygdylar complex, mediate the sedative effects of kava
(Holm E, et al. Arzneimittelforschung 1991 Jul;41(7):673-683.)

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‘NEGATIVE’ STUDIES:

This study refers to KAVA KAVA as being a GABA RECEPTOR AGONIST:

J Ethnopharmacol. 2005 Aug 22;100(1-2):108-13.

Potential for interaction of kava and St. John's wort with drugs.

Singh YN.

Source
College of Pharmacy, South Dakota State University, Brookings, SD 57007, USA.
yadhu.singh@sdstate.edu

Abstract
The present interest and widespread use of herbal remedies has created the possibility of interaction between them and pharmaceutical drugs if they are used simultaneously. Before the recent reports of apparent hepatotoxicity associated with its use, kava (Piper methysticum Forst. F.), was one of the top 10 selling herbal remedies in Europe and North America. This adverse effect was not previously encountered with the traditional beverage which was prepared as a water infusion in contrast to the commercial products which are extracted with organic solvents. Kavalactones, the active principles in kava, are potent inhibitors of several of the CYP 450 enzymes, suggesting a high potential for causing pharmacokinetic interactions with drugs and other herbs which are metabolized by the same CYP 450 enzymes. Furthermore, some kavalactones have been shown to possess pharmacological effects, such as blockade of GABA receptors and sodium and calcium ion channels, which may lead to pharmacodynamic interactions with other substances which possess similar pharmacological proprieties. St. John's wort (Hypericum perforatum L.), used extensively for the treatment of mild to moderate clinical depression, has long been considered safer than the conventional pharmaceutical agents. However, its ability, through its active constituents hypericin, pseudohypericin and hyperforin, to induce intestinal P-glycoprotein/MRD1 and both intestinal and hepatic CYP3A4 enzyme, could markedly reduce the distribution and disposition of their co-substrates. In addition, St. John's wort is a potent uptake inhibitor of the neurotransmitters serotonin, norepinephrine and dopamine all of which have a role in mood control. Consequently, the very real potential for a pharmacodynamic interaction between the herb and pharmaceutical drugs which share this mechanism of action and, like St. John's wort, are used for mood elevation. However, presently there is very little evidence to substantiate actual pharmacokinetic and/or pharmacodynamic interaction between drugs and kava or St. John's wort. This review provides a brief overview of the existing data on interactions of kava and St. John's wort with pharmaceutical agents and as a result reveals the urgent need for detailed investigations to identify clinically significant interactions for these herbal remedies that have the potential to cause adverse effects.
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This study (whilst IN VITRO and on RODENTS) indicates KAVA KAVA to exert AGONISM of the GABA-A RECEPTOR specifically, but not the GABA-B RECEPTOR:

Planta Med. 2002 Dec;68(12):1092-6.

Kavalactones and dihydrokavain modulate GABAergic activity in a rat
gastric-brainstem preparation.

Yuan CS, Dey L, Wang A, Mehendale S, Xie JT, Aung HH, Ang-Lee MK.

Source
Tang Center for Herbal Medicine Research, The Pritzker School of Medicine,
University of Chicago, Chicago 60637, USA. cyuan@midway.uchicago.edu

Abstract
Using an in vitro neonatal rat gastric-brainstem preparation, the activity of majority neurons recorded in the nucleus tractus solitarius (NTS) of the brainstem were significantly inhibited by GABA A receptor agonist, muscimol (30 microM), and this inhibition was reversed by selective GABA A receptor antagonist, bicuculline (10 microM). Application of kavalactones (300 microg/ml) and dihydrokavain (300 microM) into the brainstem compartment of the preparation also significantly reduced the discharge rate of these NTS neurons (39 % and 32 %, respectively, compared to the control level), and this reduction was partially reversed by bicuculline (10 microM). Kavalactones or dihydrokavain induced inhibitory effects were not reduced after co-application of saclofen (10 microM; a selective GABA B receptor antagonist) or naloxone (100 nM; an opioid receptor antagonist). Pretreatment with kavalactones (300 microg/ml) or dihydrokavain (300 microM) significantly decreased the NTS inhibitory effects induced by muscimol (30 microM), approximately from 51 % to 36 %. Our results demonstrated modulation of brainstem GABAergic mechanism by kavalactones and dihydrokavain, and suggested that these compounds may play an important role in regulation of GABAergic neurotransmission.
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This study also indicates that KAVA KAVA is a GABA-A RECEPTOR AGONIST:

CNS Drugs 2002;16(11):731-43.

Therapeutic potential of kava in the treatment of anxiety disorders.

Singh YN, Singh NN.

Source
College of Pharmacy, South Dakota State University, Brookings, South Dakota 57007, USA. yadhu_singh@sdstate.edu

Abstract
Anxiety disorders are among the most common psychiatric disorders that affect all age groups of the general population. Currently, the preferred treatment is with pharmacological drugs that have antidepressant or anti-anxiety properties. However, these agents have numerous and often serious adverse effects, including sedation, impaired cognition, ataxia, aggression, sexual dysfunction, tolerance and dependence. Withdrawal reactions on termination after long-term administration are also a major limiting factor in the use of these agents. Herbal remedies, including kava (Piper methysticum), have been shown to be effective as alternative treatments, at least in mild to moderate cases of anxiety. Kava is a social and ceremonial herb from the South Pacific. It is available in the west as an over-the-counter preparation. Its biological effects, due to a mixture of compounds called kavalactones, are reported to include sedative, anxiolytic, antistress, analgesic, local anaesthetic, anticonvulsant and neuroprotective properties. The pharmacological properties of kava are postulated to include blockade of voltage-gated sodium ion channels, enhanced ligand binding to gamma-aminobutyric acid (GABA) type A receptors, diminished excitatory neurotransmitter release due to calcium ion channel blockade, reduced neuronal reuptake of noradrenaline (norepinephrine), reversible inhibition of monoamine oxidase B and suppression of the synthesis of the eicosanoid thromboxane A(2), which antagonises GABA(A) receptor function. Clinical studies have shown that kava and kavalactones are effective in the treatment of anxiety at subclinical and clinical levels, anxiety associated with menopause and anxiety due to various medical conditions. Until recently, the adverse effects attributed to kava use were considered mild or negligible, except for the occurrence of a skin lesion. This disorder, called kava dermopathy, occurs only with prolonged use of large amounts of kava and is reversible on reduced intake or cessation. Rare cases of interactions have occurred with pharmaceutical drugs that share one or more mechanisms of action with the kavalactones. In the past few years, about 35 cases of severe liver toxicity associated with kava intake have been reported in Europe and the US. However, a direct causal relationship with kava use has been difficult to establish in the majority of the cases, and there is insufficient evidence to implicate kava as the responsible agent. Nevertheless, until further research clarifies any causality, kava should be used with caution.
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This study (whilst IN VITRO but on HUMANS) also indicates that KAVA KAVA is a GABA-A RECEPTOR AGONIST:

Planta Med. 2001 Jun;67(4):306-11.

Interaction of various Piper methysticum cultivars with CNS receptors in vitro.

Dinh LD, Simmen U, Bueter KB, Bueter B, Lundstrom K, Schaffner W.

Source
Institute of Pharmaceutical Biology, University of Basel, Witterswil, Switzerland.

Abstract
Methanolic leaf and root extracts of the Hawaiian kava (Piper methysticum Forst.) cultivars, Mahakea, Nene, Purple Moi and PNG, were tested on binding affinities to CNS receptors including GABAA (GABA and benzodiazepine binding site), dopamine D2, opioid (mu and delta), serotonin (5-HT6 and 5-HT7) and histamine (H1 and H2). HPLC analysis was carried out in order to determine the amount of the main kavalactones kavain, 7,8-dihydrokavain, methysticin, 7,8-dihydromethysticin, yangonin and 5,6-demethoxyyangonin. The most potent binding inhibition was observed for leaf extracts to GABAA receptors (GABA binding site) with IC50 values of approximately 3 micrograms/ml, whereas root extracts were less active with IC50 values ranging from 5 micrograms/ml (Nene) to 87 micrograms/ml (Mahakea). Since the leaf extracts generally contained lower amounts of the kavalactones than the root extracts, there might exist additional substances responsible for these activities. Leaf extracts also inhibited binding to dopamine D2, opioid (mu and delta) and histamine (H1 and H2) receptors more potently than the corresponding root extracts with IC50 values ranging from 1 to 100 micrograms/ml vs. > or = 100 micrograms/l, respectively. Significant differences in the potential of binding inhibition were also observed between cultivars. Binding to serotonin (5-HT6 and 5-HT7) and benzodiazepine receptors was only weakly inhibited by both root and leaf extracts of all four cultivars. In conclusion, our investigation indicates that the GABAA, dopamine D2, opioid (mu and delta) and histamine (H1 and H2) receptors might be involved in the pharmacological action of kava extracts. Since the cultivars contained similar amounts of kavalactones, while their pharmacological activities differed markedly, other constituents may play a role in the observed activities. Additionally, leaves generally exhibited more potent binding inhibition than roots, therefore leaf of P. methysticum might be an interesting subject for further pharmacological studies.
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‘NEUTRAL’ STUDIES:

This study (whilst IN VITRO but on HUMANS) in my opinion pretty much ‘hits the nail on the head’ so to speak, in that it reports that the scientific evidence supporting whether or not KAVA KAVA is a GABA RECEPTOR AGONIST is conflicting:

Altern Med Rev. 1998 Dec;3(6):458-60.

Piper methysticum (kava kava).

[No authors listed]

Abstract
Piper methysticum (kava kava) is a plant native to the Pacific Island region, and has been used ceremonial for thousands of years. The active ingredients are a group of substances know as kava lactones (AKA kava pyrones). Four lactones in kava have been found to have significant analgesic and anesthetic effects via non-opiate pathways. Kava's most popular application is as a natural anxiolytic, comparing favorably in several studies to a number prescription medications, including benzodiazepines. CNS effects seem to be mediated by several mechanisms. Studies have been conflicting regarding its GABA-receptor-binding capacity, although this has been found to occur in some studies. In vitro kava has been found to block norepinephrine uptake. It also has some anti-convulsant capabilities, which appear to be mediated by Na+ channel receptor sites. The therapeutic dosage is in the range of 50-70 mg kava lactones three times daily. The most common side effect, usually seen only with long-term, heavy usage of the herb, is a scaly skin rash called "kava dermopathy." It has also been know to potentiate other medications such as barbiturates and Xanax.
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#6 adamh

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Posted 16 September 2012 - 09:52 PM

My non scientific hunch here is that the op is correct in this statement

>So while Kava Kava extracts are well established to be gabaergics, it seems they aren't agonists at the GABA-a receptor so much as that they potentiate their signal through some other mechanism...

Could it be that kava potentiates the gaba a receptors rather than simply agnonizing them? I'm not talking about increasing gaba a receptors though it does seem to do that as well. I realize that without studies or a detailed phamacological explanation this will be seen by many of the more serious people as in the league of "fairies did it" rather than a serious theory.

The gaba receptors are agonized at all times to a low degree by natural chems in the body. They are not just there for in case some exogenous compound comes along to stimulate them. There must be natural way to clear these endogenous natural compounds same as chemical gaba a receptor agonists are cleared. Perhaps kava slows the clearing process and therefore causes the user to feel as though his/her gaba receptors were being stimulated when in actuality it was simply natural stimulation that was amplified by kava compounds which either increased the action of natural gaba a stimulation?

This would explain why it potentiates other gaba a agonizing compounds such as xanax or st john's. Kava lactones may act to simply "guide" receptor agonists into the correct site, as an alternative explanation for its effects

I'm not offering this as a fully developed theory, which it clearly is not. Rather as suggesting a different way of looking at the situation. We are conditioned to think a chemical must either agonize or antagonize a receptor if it has an effect on it. We are familiar with the concept of potentiation but usually think of it as additive such a when a receptor agonist adds to the effect of another agonist. I'm thinking it neither agonizes or antagonizes directly but instead potentiates indirectly. This would explain why it does not lead to down regulation as all other receptor agonizers seem to do.

#7 Raza

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Posted 17 September 2012 - 12:17 AM

Raza,

Firstly, thank you for this... You have raised an EXCELLENT question regarding precisely what is KAVA KAVA's mechanism of action with regards to GABA RECEPTORS; and as such I have digged deeper into the matter and I have to agree that my perspective is not entirely accurate, and consequently you have caused me to change it. ;)

However, upon review of the existing scientific evidence up to date, I find that I do not in fact entirely agree with you... wherein IMO either neither of us is correct or we both are... UGH? I hear you say? :)

Hey ScienceGuy! Glad to finally engage you on this topic.

No 'ugh', it's a complex matter. I'm not seeing any methodological shortcomings in these studies (would be difficult without the full texts), so for now, I'm assuming that all of them are correct and the information simply needs to be consolidated between them.

Leading from that, I stand by my assessment. I'll dig into the various 'negative' studies you posted below, because I think most of them don't contradict my proposed mechanism at all, but first and foremost I maintain that even if Kavalactones are GABA-A agonists, the direct observation of receptor upregulation trumps the hypothetical receptor downregulation from GABA-A Agonism. If both are true, this merely indicates that Kavalactones upregulate GABA-A receptors through a secondary mechanism that, at least at some doses, upregulates receptors more rapidly than its agonist downregulates them.

However, I don't think Kavalactones look to be a GABA agonist at this time.


]‘NEGATIVE’ STUDIES:[/u]

This study refers to KAVA KAVA as being a GABA RECEPTOR AGONIST:

J Ethnopharmacol. 2005 Aug 22;100(1-2):108-13.

Potential for interaction of kava and St. John's wort with drugs.

Singh YN.

Source
College of Pharmacy, South Dakota State University, Brookings, SD 57007, USA.
yadhu.singh@sdstate.edu

Abstract
The present interest and widespread use of herbal remedies has created the possibility of interaction between them and pharmaceutical drugs if they are used simultaneously. Before the recent reports of apparent hepatotoxicity associated with its use, kava (Piper methysticum Forst. F.), was one of the top 10 selling herbal remedies in Europe and North America. This adverse effect was not previously encountered with the traditional beverage which was prepared as a water infusion in contrast to the commercial products which are extracted with organic solvents. Kavalactones, the active principles in kava, are potent inhibitors of several of the CYP 450 enzymes, suggesting a high potential for causing pharmacokinetic interactions with drugs and other herbs which are metabolized by the same CYP 450 enzymes. Furthermore, some kavalactones have been shown to possess pharmacological effects, such as blockade of GABA receptors and sodium and calcium ion channels, which may lead to pharmacodynamic interactions with other substances which possess similar pharmacological proprieties. St. John's wort (Hypericum perforatum L.), used extensively for the treatment of mild to moderate clinical depression, has long been considered safer than the conventional pharmaceutical agents. However, its ability, through its active constituents hypericin, pseudohypericin and hyperforin, to induce intestinal P-glycoprotein/MRD1 and both intestinal and hepatic CYP3A4 enzyme, could markedly reduce the distribution and disposition of their co-substrates. In addition, St. John's wort is a potent uptake inhibitor of the neurotransmitters serotonin, norepinephrine and dopamine all of which have a role in mood control. Consequently, the very real potential for a pharmacodynamic interaction between the herb and pharmaceutical drugs which share this mechanism of action and, like St. John's wort, are used for mood elevation. However, presently there is very little evidence to substantiate actual pharmacokinetic and/or pharmacodynamic interaction between drugs and kava or St. John's wort. This review provides a brief overview of the existing data on interactions of kava and St. John's wort with pharmaceutical agents and as a result reveals the urgent need for detailed investigations to identify clinically significant interactions for these herbal remedies that have the potential to cause adverse effects.


This one's a bit vague, since the blockage in question isn't part of this studies results, but rather a reference to a different study. However, I've read one study before that showed that Kavalactones competed with GABA-A agonists, showing reduced cumulative effects in the presense of both. This seems to be what they're talking about, and is the single most compelling piece of evidence for Kava as a GABA agonist... however, it is far from conclusive. All it really establishes is that it's influence on the GABA-A signal replaces and/or adds up with ordinary activation, rather than multiplying with it like benzos and barbituates do.

I do think that this is evidence that GABA-A receptor upregulation is not it's primary means of enhancing the GABA-A signal, since that would multiply or at least not compete with increased ligand availability.

This study (whilst IN VITRO and on RODENTS) indicates KAVA KAVA to exert AGONISM of the GABA-A RECEPTOR specifically, but not the GABA-B RECEPTOR:

Planta Med. 2002 Dec;68(12):1092-6.

Kavalactones and dihydrokavain modulate GABAergic activity in a rat
gastric-brainstem preparation.

Yuan CS, Dey L, Wang A, Mehendale S, Xie JT, Aung HH, Ang-Lee MK.

Source
Tang Center for Herbal Medicine Research, The Pritzker School of Medicine,
University of Chicago, Chicago 60637, USA. cyuan@midway.uchicago.edu

Abstract
Using an in vitro neonatal rat gastric-brainstem preparation, the activity of majority neurons recorded in the nucleus tractus solitarius (NTS) of the brainstem were significantly inhibited by GABA A receptor agonist, muscimol (30 microM), and this inhibition was reversed by selective GABA A receptor antagonist, bicuculline (10 microM). Application of kavalactones (300 microg/ml) and dihydrokavain (300 microM) into the brainstem compartment of the preparation also significantly reduced the discharge rate of these NTS neurons (39 % and 32 %, respectively, compared to the control level), and this reduction was partially reversed by bicuculline (10 microM). Kavalactones or dihydrokavain induced inhibitory effects were not reduced after co-application of saclofen (10 microM; a selective GABA B receptor antagonist) or naloxone (100 nM; an opioid receptor antagonist). Pretreatment with kavalactones (300 microg/ml) or dihydrokavain (300 microM) significantly decreased the NTS inhibitory effects induced by muscimol (30 microM), approximately from 51 % to 36 %. Our results demonstrated modulation of brainstem GABAergic mechanism by kavalactones and dihydrokavain, and suggested that these compounds may play an important role in regulation of GABAergic neurotransmission.


It does not say that. All it says it that Kavalactones have a GABAergic mechanism, which is obvious at this point. They established this by showing the effect of Kavalactones to be partially reversible with a GABA-A antagonist, which would also be true for a positive alosteric modulator, or a receptor density increaser, or any other kind of GABAergic.


This study also indicates that KAVA KAVA is a GABA-A RECEPTOR AGONIST:

CNS Drugs 2002;16(11):731-43.

Therapeutic potential of kava in the treatment of anxiety disorders.

Singh YN, Singh NN.

Source
College of Pharmacy, South Dakota State University, Brookings, South Dakota 57007, USA. yadhu_singh@sdstate.edu

Abstract
Anxiety disorders are among the most common psychiatric disorders that affect all age groups of the general population. Currently, the preferred treatment is with pharmacological drugs that have antidepressant or anti-anxiety properties. However, these agents have numerous and often serious adverse effects, including sedation, impaired cognition, ataxia, aggression, sexual dysfunction, tolerance and dependence. Withdrawal reactions on termination after long-term administration are also a major limiting factor in the use of these agents. Herbal remedies, including kava (Piper methysticum), have been shown to be effective as alternative treatments, at least in mild to moderate cases of anxiety. Kava is a social and ceremonial herb from the South Pacific. It is available in the west as an over-the-counter preparation. Its biological effects, due to a mixture of compounds called kavalactones, are reported to include sedative, anxiolytic, antistress, analgesic, local anaesthetic, anticonvulsant and neuroprotective properties. The pharmacological properties of kava are postulated to include blockade of voltage-gated sodium ion channels, enhanced ligand binding to gamma-aminobutyric acid (GABA) type A receptors, diminished excitatory neurotransmitter release due to calcium ion channel blockade, reduced neuronal reuptake of noradrenaline (norepinephrine), reversible inhibition of monoamine oxidase B and suppression of the synthesis of the eicosanoid thromboxane A(2), which antagonises GABA(A) receptor function. Clinical studies have shown that kava and kavalactones are effective in the treatment of anxiety at subclinical and clinical levels, anxiety associated with menopause and anxiety due to various medical conditions. Until recently, the adverse effects attributed to kava use were considered mild or negligible, except for the occurrence of a skin lesion. This disorder, called kava dermopathy, occurs only with prolonged use of large amounts of kava and is reversible on reduced intake or cessation. Rare cases of interactions have occurred with pharmaceutical drugs that share one or more mechanisms of action with the kavalactones. In the past few years, about 35 cases of severe liver toxicity associated with kava intake have been reported in Europe and the US. However, a direct causal relationship with kava use has been difficult to establish in the majority of the cases, and there is insufficient evidence to implicate kava as the responsible agent. Nevertheless, until further research clarifies any causality, kava should be used with caution.
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This study also doesn't call it a GABA-A agonist. What it does, is refer to Kava's mechanism of action to include "enhanced ligand binding to GABA-A receptors", which again would also be true for a positive alosteric modulator or a receptor density increaser.


This study (whilst IN VITRO but on HUMANS) also indicates that KAVA KAVA is a GABA-A RECEPTOR AGONIST:

Planta Med. 2001 Jun;67(4):306-11.

Interaction of various Piper methysticum cultivars with CNS receptors in vitro.

Dinh LD, Simmen U, Bueter KB, Bueter B, Lundstrom K, Schaffner W.

Source
Institute of Pharmaceutical Biology, University of Basel, Witterswil, Switzerland.

Abstract
Methanolic leaf and root extracts of the Hawaiian kava (Piper methysticum Forst.) cultivars, Mahakea, Nene, Purple Moi and PNG, were tested on binding affinities to CNS receptors including GABAA (GABA and benzodiazepine binding site), dopamine D2, opioid (mu and delta), serotonin (5-HT6 and 5-HT7) and histamine (H1 and H2). HPLC analysis was carried out in order to determine the amount of the main kavalactones kavain, 7,8-dihydrokavain, methysticin, 7,8-dihydromethysticin, yangonin and 5,6-demethoxyyangonin. The most potent binding inhibition was observed for leaf extracts to GABAA receptors (GABA binding site) with IC50 values of approximately 3 micrograms/ml, whereas root extracts were less active with IC50 values ranging from 5 micrograms/ml (Nene) to 87 micrograms/ml (Mahakea). Since the leaf extracts generally contained lower amounts of the kavalactones than the root extracts, there might exist additional substances responsible for these activities. Leaf extracts also inhibited binding to dopamine D2, opioid (mu and delta) and histamine (H1 and H2) receptors more potently than the corresponding root extracts with IC50 values ranging from 1 to 100 micrograms/ml vs. > or = 100 micrograms/l, respectively. Significant differences in the potential of binding inhibition were also observed between cultivars. Binding to serotonin (5-HT6 and 5-HT7) and benzodiazepine receptors was only weakly inhibited by both root and leaf extracts of all four cultivars. In conclusion, our investigation indicates that the GABAA, dopamine D2, opioid (mu and delta) and histamine (H1 and H2) receptors might be involved in the pharmacological action of kava extracts. Since the cultivars contained similar amounts of kavalactones, while their pharmacological activities differed markedly, other constituents may play a role in the observed activities. Additionally, leaves generally exhibited more potent binding inhibition than roots, therefore leaf of P. methysticum might be an interesting subject for further pharmacological studies.
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I'm having some trouble making sense of this study's method - 'binding inhibition' at the GABA-A receptor? - but their conclusion is only that he GABA-A receptor is involved in its MoA, which again is well-established.


In my opinion, it's pretty clear that Kavalactones are either not agonists or some kind of atypical agonist/positive modulator at the GABA-A receptor. Everything added up, nobody seems to know how Kava works the GABA-A receptor, but the observed result is both immediate activation and receptor upregulation. The specifics of the mechanism aside, none of these studies contradict each other on that outcome, and I'll take that gratefully. =)

Could it be that kava potentiates the gaba a receptors rather than simply agnonizing them? I'm not talking about increasing gaba a receptors though it does seem to do that as well. I realize that without studies or a detailed phamacological explanation this will be seen by many of the more serious people as in the league of "fairies did it" rather than a serious theory.


It definitely looks that way, and I don't think that's a "faeries did it" hypothesis at all. Benzos and bartituates, and positive alosteric modulators in general, are known to potentiate receptor signals without binding where the neurotransmitter itself would - and those generally cause downregulation of the receptor in question, they work in all sorts of different ways, setting plenty of presedent for unexpected mechanisms of action.

Hell, our best buddies the 'racetams all potentiate glutamate receptors without binding on them, and I've never heard of those downregulating any of them. Possibly even the contrary.

The gaba receptors are agonized at all times to a low degree by natural chems in the body. They are not just there for in case some exogenous compound comes along to stimulate them. There must be natural way to clear these endogenous natural compounds same as chemical gaba a receptor agonists are cleared. Perhaps kava slows the clearing process and therefore causes the user to feel as though his/her gaba receptors were being stimulated when in actuality it was simply natural stimulation that was amplified by kava compounds which either increased the action of natural gaba a stimulation?

This would explain why it potentiates other gaba a agonizing compounds such as xanax or st john's. Kava lactones may act to simply "guide" receptor agonists into the correct site, as an alternative explanation for its effects


Slowing the clearing of natural GABA would make it a reuptake inhibitor, GABAtransaminase inhibitor, or something more esoteric among those lines. Wouldn't explain the receptor upregulation though, since those generally cause downregulation from increased exposure. We'd need an additional explanation for that, still.

And potentiating Xanax and barbituates, like that one study noted it to do, is entirely unsurprising. Benzos and barbituates are known to multiply with every other GABAergic except ones in their own categories (with which they add up with diminishing returns); this is a quality inherent to their effects, and therefore tells us nothing about Kava's.

Edited by Raza, 17 September 2012 - 12:20 AM.

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#8 ScienceGuy

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Posted 17 September 2012 - 01:06 AM

Hi Raza,

Thank you for your detailed reply.

I stand by what I have already said about there currently being insufficient and conflicting information from published studies to date that prevents one from being able to conclusively ascertain precisely what is or is not the mechanism of action of KAVA KAVA in relation to the GABA SYSTEM.

I agree with some of what you say; however, I must point out that you are guilty of stating that KAVA KAVA UPREGULATES GABA RECEPTORS as if scientific FACT, when your basis is in fact simply two number RODENT STUDIES, which hardly qualifies as conclusive substantiated scientific evidence ;)

Do you have any other scientific evidence to support the belief that KAVA KAVA UPREGULATES GABA RECEPTORS other than this? That would be the most persuasive evidence :)

Incidentally with the utmost respect, and please do not take this the wrong way, your argument with regards to KAVA KAVA possibly being a POSITIVE ALLOSTERIC MODULATOR of the GABAA RECEPTOR as opposed to full AGONIST is in fact irrelevant, since in both instances adminstration would be ill advised; wherein I am sure that you surely must realise that if KAVA KAVA were to be demonstrated to be a POSITIVE ALLOSTERIC MODULATOR of the GABAA RECEPTOR then this would mean it is akin to BENZODIAZEPINE DRUGS, and hence you whole argument would be self-defeating ;)

#9 thegron

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Posted 17 September 2012 - 01:18 AM

It could be a partial agonist as one of the above studies mentions. From the research I have done on benzo PAWS, it seems as if partial agonists do not cause a lot of the same effects (i.e. cognitive dysfunction) as full agonists.

#10 ScienceGuy

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Posted 17 September 2012 - 02:05 AM

It could be a partial agonist as one of the above studies mentions. From the research I have done on benzo PAWS, it seems as if partial agonists do not cause a lot of the same effects (i.e. cognitive dysfunction) as full agonists.


I agree that this is probably the most likely scenario; however, IMO until there is published more conclusive research this is all sheer academic conjecture :)

#11 Raza

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Posted 17 September 2012 - 08:47 AM

Hi Raza,

Thank you for your detailed reply.

I stand by what I have already said about there currently being insufficient and conflicting information from published studies to date that prevents one from being able to conclusively ascertain precisely what is or is not the mechanism of action of KAVA KAVA in relation to the GABA SYSTEM.

Thank you. M'enjoying the discussion, and the chance to revisit all this in detail.

I agree that the information available is insufficient to establish a MoA. I don't agree that it is conflicting; it merely doesn't fit any of the well-known kinds of receptor interaction. No study observations have conflicted with each other so far, they've merely conflicted with our expectations.

I agree with some of what you say; however, I must point out that you are guilty of stating that KAVA KAVA UPREGULATES GABA RECEPTORS as if scientific FACT, when your basis is in fact simply two number RODENT STUDIES, which hardly qualifies as conclusive substantiated scientific evidence ;)

Do you have any other scientific evidence to support the belief that KAVA KAVA UPREGULATES GABA RECEPTORS other than this? That would be the most persuasive evidence :)

There are many anecdotal reports of human consumers of Kava experiencing reverse resistance (as in, increased sensitivity) to the stuff over periods of continued use. The receptor upregulation observed in rats explains this nicely, while nothing else I can think of could. I think that justifies generalizing the effect seen in rats to humans for individual practical purposes, even if it isn't scientific fact yet.

Incidentally with the utmost respect, and please do not take this the wrong way, your argument with regards to KAVA KAVA possibly being a POSITIVE ALLOSTERIC MODULATOR of the GABAA RECEPTOR as opposed to full AGONIST is in fact irrelevant, since in both instances adminstration would be ill advised; wherein I am sure that you surely must realise that if KAVA KAVA were to be demonstrated to be a POSITIVE ALLOSTERIC MODULATOR of the GABAA RECEPTOR then this would mean it is akin to BENZODIAZEPINE DRUGS, and hence you whole argument would be self-defeating ;)

Well, yes and no. I agree that it doesn't much matter whether it is an agonist or a positive allosteric modulator, but not that either of these would make it ill-adviced to use when the usual problem with their use is uniquely reversed (except perhaps in that it might still be able to trigger relapse in previous GABA-A-ergic addicts because it feels the same). I'm just trying to make sense of what it is so as to reduce the confusion between studies delivering unexpected results.

And for what it's worth, Kava is clearly unlike benzos and barbiturates in that its effect adds up (with diminishing returns) alongside a regular agonist, rather than multiplying with it. If it is a positive allosteric modulator, it acts at a third and heretofore unknown site somewhere.

Edited by Raza, 17 September 2012 - 08:49 AM.

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#12 deon10

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Posted 17 September 2012 - 02:04 PM

Did all the studies use only kava extracts? or did some maybe use the ground root?

Maybe this is a factor worth looking into. I'm not as good as some people at reading the studies, but I know Kava from the root and from capsules seems to have different effects on some people.

#13 thegron

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Posted 17 September 2012 - 11:05 PM

I thought that the extracts were from the root.

#14 deon10

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Posted 17 September 2012 - 11:35 PM

Yes they are.

But there are chances taking the actual root, ground, and preparing it through the traditional process, which is squeezing the powder in water and drinking the result, is different than popping a capsule with only kavalactones. It's like taking marijuana in capsules with just the active ingredients instead of using the actual weed.

I also noticed, from personal experience that many people don't react much to the capsules, but almost everybody reacts to the actual Kava.

I personally never tried the capsules, and went straight to the ground root. After the fifth day of use or so, i started feeling it, and I felt it goood! I didn't even try the strongest kava (there are different potencies).

Now... this might not be relevant to the OP's point... and maybe the studies all used capsules...
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#15 ScienceGuy

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Posted 19 September 2012 - 06:57 PM

There are many anecdotal reports of human consumers of Kava experiencing reverse resistance (as in, increased sensitivity) to the stuff over periods of continued use. The receptor upregulation observed in rats explains this nicely, while nothing else I can think of could. I think that justifies generalizing the effect seen in rats to humans for individual practical purposes, even if it isn't scientific fact yet.


That is seriously interesting... Is the REVERSE TOLERANCE effect consistent for all users of KAVA KAVA? :)

I have come across instances wherein individuals have in fact reported the opposite... so I am wondering what might be going on here? :wacko:

Of course, this is all academic speculation, but I would be very interested to hear more details regarding those anecdotal reports of the REVERSE TOLERANCE ;)

Edited by ScienceGuy, 19 September 2012 - 08:21 PM.


#16 thegron

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Posted 19 September 2012 - 08:16 PM

:|o

#17 Raza

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Posted 24 September 2012 - 07:15 PM


There are many anecdotal reports of human consumers of Kava experiencing reverse resistance (as in, increased sensitivity) to the stuff over periods of continued use. The receptor upregulation observed in rats explains this nicely, while nothing else I can think of could. I think that justifies generalizing the effect seen in rats to humans for individual practical purposes, even if it isn't scientific fact yet.


That is seriously interesting... Is the REVERSE TOLERANCE effect consistent for all users of KAVA KAVA? :)

I wouldn't claim that. It gets reported regularly, though. Let me find you some quotes.

"Yes, you can definitely experience reverse tolerance. I have been drinking Kava for a couple years and definitely feel it more now than I have ever have."

"I actually use less than when I started. I get about the same or better effects from a smaller amount with more water."

"I have been a kava drinker for about a year now, recently a pretty heavy drinker. I only need 1 tbsp per cup of water for generally mild effects and 2 tbsp per cup of water for strong effects. This is a huge decrease in kava powder from say, two months ago when I would use 7 tbsp of kava per 2 cups of water. If my tolerance has done anything in the last few months, it has gone way, way down. To the point where I popped 2 Kona Kava Pill capsules this morning before meeting with a few counselors at university, and was totally mellowed out. Still am."

"I'd personally define the tolerance curve of kava as a camels humps type of curve. I notice there was an initial phase of working through the reverse tolerance where I had to consume fairly large amounts of kava to achieve even mild effects and then after around a month I began experiencing much more profound effects and started to taper my dosage down. Then I noticed a tolerance that began to build after using kava for a week consecutively where I would again have to increase my dosage to achieve desired affects. Basically now I try and session kava 4-5 days a week with a day or two in between so that my reverse tolerance stays intact but my dosage tolerance doesn't get high and I can still enjoy the effects of kava at quantities that are not excessive."

"I didn't feel kava's effects nearly as much as I do now when I first started using it."

All from the thread I linked in the OP, and others like it from the same forum. There's plenty more like 'em, too.

I have come across instances wherein individuals have in fact reported the opposite... so I am wondering what might be going on here? :wacko:

Of course, this is all academic speculation, but I would be very interested to hear more details regarding those anecdotal reports of the REVERSE TOLERANCE ;)

Lots of possible reasons for that. If Kava enacts two simultaneous, opposed influences on GABA-A receptor density (which it should if it is also an agonist/positive modulator), then the final result would most likely be dependent on dose/time, which is consistent with the reports I quoted above. Different ratios of the various Kavalactones and Kavapyrones in the product consumed also likely make a difference.

Mind, I think ordinary tolerance also builds because the liver upregulates the enzymes responsible for breaking down commonly consumed foreign substances, so the fact that tolerance to Kava catches up again at some rates of consumption might not mean that the receptor balance isn't still positive.

Edited by Raza, 24 September 2012 - 07:23 PM.

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#18 Dark Vision

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Posted 24 September 2012 - 09:24 PM

I have just ordered 75g of kava root extract standardised to 40% kavalactones. I will be using it daily in relatively small doses to combat social and general anxiety, both of which are at moderate levels. The dose I use will be whatever gives me a nice reduction of anxiety but without any decrease in motivation or ability to concentrate. Obviously this will take a bit of working out at first :)

I'll report back on tolerance - whether I develop tolerance or reverse tolerance. I do hope it will be the latter..
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#19 Raza

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Posted 24 September 2012 - 10:24 PM

Cool. Keep us updated.

From the user accounts I've been reading, tolerance could go either way with daily use. Twice a week or so seems a safer bet for increasing sensitivity on the long run. But, find out for yourself - first hand accounts are more valuable than my guesswork from second hand information. =)

Might I suggest taking Milk Thistle with it once in a while, to protect your liver and normalize its enzymes? Kava's known for its liver load with regular use, even if the roots don't quite deserve to be called toxic, and it might even help reduce tolerance.

Edited by Raza, 24 September 2012 - 10:25 PM.

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#20 Dark Vision

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Posted 24 September 2012 - 10:39 PM

If I find that kava is effective and I want to take it regularly as an anxiolytic then I will certainly buy some milk thistle. I won't bother for this trial period though as milk thistle can have anxiolytic effects and could screw with my little experiment. I won't be trying to get high off the kava so hopefully my liver will be ok whilst I get through the 75g over the course of a couple of months or so.

I will continue to take Oxiracetam and CDP choline though as whilst I get a stimulating cognitive boost from this combo it has never relieved anxiety for me, or caused it. Oxi gave me a nice mood boost at first but this effect disappeared after a few days of use :(

Edited by Dark Vision, 24 September 2012 - 10:40 PM.


#21 Dark Vision

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Posted 25 September 2012 - 02:57 PM

I received my package of kava kava today and have been trying to find a good dosage. It is a rather attractive pale yellow, soft powder. I initially took 500mg of the powder, washed down with water. I waited 1 hr 30 mins and nothing happened. I took another 500mg, again washed down with water. Again nothing after 1 hr 30. I did a bit of reading on the kava lounge forum and saw that people were saying it doesn't work so well on a full stomach. The kava arrived after lunch so I had just eaten. Empty stomach things are not great for me because I exercise a lot and am contantly ravenous, and when I get hungry I can't concentrate and feel nauseous. So I eat every 2 hours or so. I can never hold out long enough to let my stomach empty, the only conceivable time would be first thing in the morning and this is would only last me until lunchtime at best according to the reported 3-5 hours duration of kava's effects.

So I tried what I try with all empty stomach type drugs/supplements - sublingual administration. I used 250mg of powder for this and I just sat with it under my tongue for 15 mins. It tasted ok, not as bad as people say it is, certainly much nicer than bacopa. It made the underside of my mouth go numb, but this passed very quickly thankfully. I have definitely felt an effect with this method.. my usual mental state is an excess of nervous energy, my mind and body buzzes throughout the day. Hence all the excercise. With the kava I feel very energetic still but less nervous. No trouble concentrating or thinking. I do not feel high exactly, but there is a definite mood boost and my head feels clear. I can certainly imagine taking 3 times this dose causing mild euphoria though.

I don't really understand why eating kava on a full stomach would nullify its effects. Unless it's an amino acid you're taking like L-theanine, shouldn't having a full stomach just slow the effects of a drug? I'm fine with sublingual but I do worry about staining of my teeth, or even erosion if kava is acidic to any degree.

{edit} I plan to take the 250mg sublingual dose twice a day until the powder runs out. Just for today I'll take the second dose before bedtime as I want to see it's effects on sleep, and how I feel in the morning. In future I'll probably take it in the morning and late afternoon. I'll post occasional updates on the tolerance question. If I find I am getting a tolerence I ight consider increasing the dose slightly, but not much, and then I will keep on taking it for a fortnight to see if some sort of reverse tolerance kicks in. If it doesn't I will stop as I don't want to nuke my GABA receptors. My thanks to Raza for making this topic as kava does seem helpful at the moment, and I had always avoided it in the past because I just assumed it would cause eventual GABA downregulation.

Edited by Dark Vision, 25 September 2012 - 03:06 PM.

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#22 Raza

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Posted 25 September 2012 - 07:35 PM

Sublingual Kava - interesting! Bypassing first pass metabolism might be worthwhile for this stuff long-term, with the negative effects it has in the liver and the potential for resistance building there.

I don't really understand why eating kava on a full stomach would nullify its effects. Unless it's an amino acid you're taking like L-theanine, shouldn't having a full stomach just slow the effects of a drug?

To the best of my drug knowledge, mostly, yes. Bioavailability could be reduced for more gradually absorbed doses if the stuff is significantly metabolized by an enzyme not usually used up by food, though. Still, it's not unlikely that those 500mg oral doses might've been affecting you unnoticed. If your second 250mg sublingual dose doesn't work as well as the first, that's probably the reason.

#23 Dark Vision

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Posted 25 September 2012 - 08:44 PM

Sublingual Kava - interesting! Bypassing first pass metabolism might be worthwhile for this stuff long-term, with the negative effects it has in the liver and the potential for resistance building there.


I think bypassing the first pass through the liver certainly makes a difference to bio-availability, but I'm not sure it would reduce liver damage. The various chemicals in the kava are still entering the bloodstream and being processed by the liver, it's just that the liver receives them from your systemic circulation rather than the
hepatic portal system. The actual strain on the liver is still the same. For example taking shots of vodka and holding them in your mouth gets you drunk quicker and on less alcohol than actual ingestion but is no less harmful to the liver, which needs to clean up all the booze or you will never sober up.

#24 Raza

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Posted 25 September 2012 - 09:47 PM

True, the only gain is in the amount you need less for avoiding the liver in that first round (which is still very significant, if 250mg SL beats out 2x500mg PO).

But I think that drugs that cause liver strain, in the process of doing so, usually also increase the liver's capacity to metabolize them - thereby building resistance which needs to be overcome by higher doses, the difference of which ends up purely affecting the liver and so on. It escalates, and every milligram of substance that hits the liver without first getting anywhere else is a loss in that sense. Starting right off with SL doses might nip this in the bud, ending in a more favorable steady state.

Anyway, do you have any typical GABA-A agonists lying around? Like valerian, or even a (small dose of a) benzo? One test that would be good to do before you take any more Kava is to take a single small dose of an ordinary GABA-A agonist and measure the effects, before continuing on with the Kava plan. This would allow you, further into the Kava treatment, to repeat that dose and compare the effects to find out whether Kava reverse sensitization really translates to GABA-A signal potentiation in general, and if so allow you to test whether any subsequent Kava resistance is also an effect on receptor density or rather a metabolic thing that applies purely to Kava.

Edited by Raza, 25 September 2012 - 09:53 PM.


#25 Dark Vision

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Posted 25 September 2012 - 10:42 PM

Ah yes of course, you are quite right. The only downside for SL then remains what it might do to teeth in terms of staining and enamel weakening. I can't find any info on kava's ph, and I don't have any litmus unfortunately.

That would be a very interesting test. I don't have any benzos and I don't have a source for them. Valerian I did have a bottle of once, but it had absolutely no effect on me even in high doses so I threw it out. I have a bottle of gotu kola that certainly has an obvious effect in high doses, feels like a GABA agonist. I use it very occasionally for impending stressful situations. I have no idea whether it effects GABA-A or GABA-B though, and I can't seem to find any info on this.

#26 Raza

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Posted 26 September 2012 - 10:16 AM

Gotu Kola looks to be a selective GABA-B agonist, from what I'm reading. Ah well.

Any general pro-gabaergics available then, like Theanine or Picamilon? Something selective for GABA-A would be preferable, but a test with one of these might still be better than nothing.

Ah yes of course, you are quite right. The only downside for SL then remains what it might do to teeth in terms of staining and enamel weakening. I can't find any info on kava's ph, and I don't have any litmus unfortunately.

Is it difficult to keep it mostly away from your teeth?

I have some Kava at home and I own a pack of PH strips, but they're at a friend's, who just left for a two week vacation. I'll test it for you when I can, if it's still relevant by then. Although from what little I know about chemistry, lactones are kind of complex where pH is concerned...

For what it's worth, beverages are kava's traditional mode of ingestion, and a google search isn't turning up much for teeth stains from regular consumption of those. There's one result for stains from continuously chewing the roots. Personally, considering the evidence and how with SL dosing you're basically only risking staining the inside of your bottom front row (which is rarely visible), I wouldn't be worried about it.

Edited by Raza, 26 September 2012 - 10:38 AM.


#27 OpaqueMind

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Posted 26 September 2012 - 12:32 PM

For you potential experiment of testing GABA-A receptor sensitization you can aquire some etizolam, a benzodiazepine analogue available legally over the internet. Just type it in google, there's a load of sites that sell it.

By the way Dark Vision, would you mind telling us what your kava source is? Thanks

#28 Dark Vision

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Posted 26 September 2012 - 02:00 PM

A very good way to see if something stains teeth is to see if it stains a white ceramic mug. I'd forgotten about this. Eg. coffee tea and red wine all quickly stain a mug if you tip out the liquid and leave the residue to dry, whereas cocoa doesn't - the mug cleans back to shiny white. Will mix a little powder with hot water in a clean mug and see if I can get it to leave a mark. My hunch is it won't, the powder doesn't have a dye like appearence it looks and feels more like chickpea flower or something similar.

Think I will stay clear of ordering legal benzos online (I didn't know you could do this!) just because I don't want to set a precedent.. I have tried valium before and I love it so I'd rather not have a source for something similar without a prescription. I do have l-theanine though, and it does work on me if I haven't used it in a while (which I haven't). I'll take a 400mg dose later today. I know theanine releases GABA rather than agonizing a particular GABA receptor group, but it should give a decent idea later on if GABA-A is being up or downregulated. It's hardly scientific I know.

My source was this ebay auction. There seems to be a lot of this 40% extract available. It looks exactly like this stuff, which is maybe the same product - it all comes from alibaba I'm guessing, and the root source seems to be Vanuatu. Of course I can't say for sure that this stuff is safe and doesn't contain leaf and bark. Ideally I would like to buy kava root powder rather than extract, from a reputable source, but the UK ban means that this is not cheap. If I am impressed by kava at the end of this experiment then I will pay to have a load shipped from the US.

#29 Dark Vision

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Posted 28 September 2012 - 01:19 PM

Ok, firstly I cannot get kava mixed with hot water to stain white ceramic. I don't think it's a strong dental enamel stain. No idea about acidity still.

The extract continues to have a moderate anxiolytic and mood boosting effect at the same dosage. I have noticed no increase or decrease in the effectiveness of each dose. However I am taking 3 of these doses now - 250mg in the morning, 250mg in the afternoon, and 250mg before bedtime. All sublingual. This is because whilst the stuff has very little sedative effect, the pre-bed dose helps me with a problem I've been having recently which is worrying about not being able to sleep, and therefore not being able to sleep. So the anxiety causes the insomnia and the anxiolytic cures it. Because there is little to no sedative effect this would not work if I was not already tired, as valium would for instance, and I have no trouble getting up in the morning after 7 hours of sleep. It has an odd influence on me in the morning - for three mornings in a row I have felt a sort of warm sense of excitement akin to when I was a kid around Christmas. It fades after a couple of hours. After this I take my morning dose, which does not give me this same feeling. The effect is so nice that I will continue with the night time dose.

I took l-theanine yesterday and just now. Both times I took it 2 hours after the last kava dose when it was starting to wear off. I took 400mg yesterday and 500mg today, sublingual both times as I had food in me. Does anybody know if l-theanine can be absorbed sublingually? I have had sedative effects once before off 500mg sublingual theanine but it could be placebo. There are sublingual amino acid products available online but they could be bullcrap of course. Anyway, both of these recent theanine doses did nothing really noticeable.

The only negative so far has been regarding excercise. Kava makes exercise unapealling, but only for 2 hours or so. After this I am good to go. I have experienced no nausea or other gastric symptoms perhaps because of the sublingual administration, although I do swallow the dose after 15 mins.

I am attending the premier of a film I worked on tomorrow. This would normally be a very stressful, though fun event for me. It will be interesting to see how well the kava helps me.
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#30 Raza

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Posted 28 September 2012 - 03:54 PM

I know from experience that Theanine absorbs well sublingually. For purposes of the experiment, though, it would be best to take it while not under influence of Kava at all - the effects are competitive, and the Kava might be the reason why you don't feel any additional relaxation from the Theanine.

Have fun at your movie premiere!

Edited by Raza, 28 September 2012 - 03:56 PM.





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