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Abstract

This systematic review discusses the proposed uses, dosing parameters, adverse effects, toxicology, interactions and mechanism of action of kava. The widespread concern regarding the potential hepatotoxicity of kava is discussed. A recommendation is made to consolidate and analyse available reports and to continue postmarket surveillance in an international repository to prevent duplicates and promote collection of thorough details at the time of each report so that any association with kava is clearly defined.

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... Kava kava (Piper methysticum) is generally consumed for its psychotropic, sedative and anti-anxiety effects [149]. Capsule and tablet formulations of kava extracts have been commercially available since the 1990s, being marketed with label claims of beneficial effects in insomnia, stress and anxiety disorders [150]. ...
... Capsule and tablet formulations of kava extracts have been commercially available since the 1990s, being marketed with label claims of beneficial effects in insomnia, stress and anxiety disorders [150]. Several countries including Australia, Canada and some European countries removed kava products from the markets following reports of hepatotoxicity, which also alerted the US FDA to warn of possible liver-related toxicity with kava supplementation [149]. Documented case reports of kava-related hepatotoxicity were associated with prolonged usage and concurrent consumption with prescription drugs and/or other herbal products [149]. ...
... Several countries including Australia, Canada and some European countries removed kava products from the markets following reports of hepatotoxicity, which also alerted the US FDA to warn of possible liver-related toxicity with kava supplementation [149]. Documented case reports of kava-related hepatotoxicity were associated with prolonged usage and concurrent consumption with prescription drugs and/or other herbal products [149]. It has thus been postulated that the inhibition of the human drug metabolism and/or transport is a principal mechanism of liver toxicity associated with kava. ...
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For healthcare professionals, the volume of literature available on herb-drug interactions often makes it difficult to separate experimental/potential interactions from those deemed clinically relevant. There is a need for concise and conclusive information to guide pharmacotherapy in HIV/AIDS. In this review, the bases for potential interaction of medicinal herbs with specific antiretroviral drugs are presented, and several botanicals are discussed for which clinically relevant interactions in humans are established. Such studies have provided, in most cases, sufficient ground to warrant the avoidance of concurrent administration of antiretroviral (ARVs) drugs with St John's wort (Hypericum perforatum), black pepper (Piper species) and grapefruit juice. Other botanicals that require caution in the use with antiretrovirals include African potato (Hypoxis hemerocallidea), ginkgo (Ginkgo biloba), ginseng (Panax species), garlic (Allium sativum), goldenseal (Hydrastis canadensis) and kava kava (Piper methysticum). The knowledge of clinically significant herb-drug interaction will be important in order to avoid herb-induced risk of sub-therapeutic exposure to ARVs (which can lead to viral resistance) or the precipitation of toxicity (which may lead to poor compliance and/or discontinuation of antiretroviral therapy).
... The kava regimen selected for this study was based on product label recommendations, and while supplementation at higher doses or of longer duration may have produced different results, such practices may increase the risk of kava-related hepatotoxicity. Reports linking kava use to liver toxicity led to removal of these products from Europe, Australia, and Canada, 40 and prompted the Food and Drug Administration (FDA) to issue warnings of possible hepatotoxic side effects associated with kava supplementation. 41 For those case reports documenting possible kava-related hepatotoxicity, prolonged usage (460 days) and co-medication with prescription drugs or other botanical supplements were frequent and confounding variables. ...
... 41 For those case reports documenting possible kava-related hepatotoxicity, prolonged usage (460 days) and co-medication with prescription drugs or other botanical supplements were frequent and confounding variables. 40 In contrast, 14 days of supplementation with the kava product described here produced no evidence of liver toxicity or CYP3A modulation. ...
... Telephone and electronic mail reminders were used to facilitate compliance, whereas pill counts and supplementation usage records were used to verify compliance. Owing to recent concerns regarding kava kava use and hepatotoxicity, 40 clinical liver function indices (i.e., aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transpeptidase, alkaline phosphatase, total bilirubin, direct bilirubin, and serum albumin) were monitored on days 0, 7, and 14 of both supplementation phases. ...
Article
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The effects of goldenseal (Hydrastis canadensis) and kava kava (Piper methysticum) supplementation on human CYP3A activity were evaluated using midazolam (MDZ) as a phenotypic probe. Sixteen healthy volunteers were randomly assigned to receive either goldenseal or kava kava for 14 days. Each supplementation phase was followed by a 30-day washout period. MDZ (8 mg, per os) was administered before and after each phase, and pharmacokinetic parameters were determined using standard non-compartmental methods. Comparisons of pre- and post-supplementation MDZ pharmacokinetic parameters revealed significant inhibition of CYP3A by goldenseal (AUC(0-infinity), 107.9+/-43.3 vs 175.3+/-74.8 ng x h/ml; Cl/F/kg, 1.26+/-0.59 vs 0.81+/-0.45 l/h/kg; T(1/2), 2.01+/-0.42 vs 3.15+/-1.12 h; Cmax, 50.6+/-26.9 vs 71.2+/-50.5 ng/ml). MDZ disposition was not affected by kava kava supplementation. These findings suggest that significant herb-drug interactions may result from the concomitant ingestion of goldenseal and CYP3A substrates.
... Kava has reportedly been associated with hepatotoxi-cities in humans, including functional disturbances, hepatitis, cirrhosis, and liver failure (Campo et al., 2002; Gruenwald, 2003; Hefner, 2002; Humberston, 2003; Teschke et al., 2003). The sale of kava has been suspended in France, Germany, Switzerland, Canada, and Britain (Gruenwald, 2003; Teschke et al, 2003; Ulbricht et al., 2005). The US FDA has not regulated consumption, though the potential risk of liver injury raises concern (Food and Drug Administration (FDA),, 2002 Hefner, 2002; Ulbricht et al., 2005). ...
... The sale of kava has been suspended in France, Germany, Switzerland, Canada, and Britain (Gruenwald, 2003; Teschke et al, 2003; Ulbricht et al., 2005). The US FDA has not regulated consumption, though the potential risk of liver injury raises concern (Food and Drug Administration (FDA),, 2002 Hefner, 2002; Ulbricht et al., 2005). The Natural Standard Research Collaboration is working with Advisory Committee on Safety of Medicinal Products of the World Health Organization (WHO) on a new official report on kava and hepatotoxicity (Ulbricht et al., 2005). ...
... The US FDA has not regulated consumption, though the potential risk of liver injury raises concern (Food and Drug Administration (FDA),, 2002 Hefner, 2002; Ulbricht et al., 2005). The Natural Standard Research Collaboration is working with Advisory Committee on Safety of Medicinal Products of the World Health Organization (WHO) on a new official report on kava and hepatotoxicity (Ulbricht et al., 2005). The cytochrome P450 (CYP)s are Phase I enzymes that play critical roles in the bioactivation and detoxification of a wide variety of xenobiotic substances (Guengerich, 2001; Omiecinski et al., 1999; Zuber et al., 2002). ...
Article
Kava (Piper methysticum), used for relaxation and pain relief, has been one of the leading dietary supplements and several reports linking hepatic functional disturbances and liver failure to kava have resulted in a ban on sales in Europe and Canada and the issuance of warnings by the US FDA. The National Toxicology Program conducted 14-week rat studies to characterize the toxicology of kava exposure in Fischer 344 rats [National Toxicity Program. 90 day gavage toxicity studies of KAVA KAVA EXTRACT in Fischer rats and B6C3F1 mice. Research Triangle Park, NC; 2005a; National Toxicity Program. Testing status of agents at NTP (KAVA KAVA EXTRACT M990058). Research Triangle Park, NC; 2005b. (http://ntp.niehs.nih.gov/index.cfm?objectid=071516E-C6E1-7AAA-C90C751E23D14C1B)]. Groups of 10 male and 10 female rats were administered kava extract by gavage at 0, 0.125, 0.25, 0.5, 1.0, and 2.0 g/kg/day. Increased gamma-glutamyl-transpeptidase (GGT) activities were observed in the 2.0 g/kg males and 1.0 and 2.0 g/kg females, as well as increased serum cholesterol levels in males and females at 0.5 g/kg and higher. Increases in incidence and severity of hepatocellular hypertrophy (HP) were noted in males at 1.0 g/kg and females at 0.5 g/kg and higher, as well as increased liver weights. Immunohistochemical analyses of the expression of cytochrome-P450 (CYP) enzymes in liver of the control and 1.0- and 2.0-g/kg-treated groups indicated decreased expression of CYP2D1 (human CYP2D6 homolog) in 2.0 g/kg females and increased expression of CYP1A2, 2B1, and 3A1 in 1.0 and 2.0 g/kg groups of both sexes. The no observed adverse effect levels were decided as 0.25 g/kg in both genders, based on neurotoxic effects, increases in GGT, cholesterol, liver weight, and HP and decreases in body weight. Kava-induced hepatic functional changes in the F344 rat might be relevant to human clinical cases of hepatotoxicity following exposure.
... Recent in vitro studies have demonstrated that an isoquinoline alkaloid present in goldenseal, berberine, is a substrate for P-gp (Tsai and Tsai, 2004;Pan et al., 2002;Maeng et al., 2002) that exhibits disparate modulatory effects on P-gpmediated drug efflux (Maeng et al., 2002;He and Liu, 2002;Efferth et al., 2002;Tsai et al., 2001;Lin et al, 1999aLin et al, , 1999b. Kava kava has long been a traditional beverage consumed among South Pacific islanders to imbue psychotropic, hypnotic, and anxiolytic effects (Ulbricht et al, 2005). Since the 1990s, commercial kava extracts formulated as tablets and/or capsules have been marketed as dietary supplements for the alleviation of stress, anxiety, or insomnia (Ulbricht et al, 2005;Côté et al., 2004). ...
... Kava kava has long been a traditional beverage consumed among South Pacific islanders to imbue psychotropic, hypnotic, and anxiolytic effects (Ulbricht et al, 2005). Since the 1990s, commercial kava extracts formulated as tablets and/or capsules have been marketed as dietary supplements for the alleviation of stress, anxiety, or insomnia (Ulbricht et al, 2005;Côté et al., 2004). The kavalactones (kavain, dihydrokavain, methysticin, dihydromethysticin, yangonin, desmethoxyyangonin), a collection of phytochemicals unique to kava, have also been shown to modulate P-gp activity in vitro (Weiss et al., 2005;Mathews et al, 2005). ...
... Telephone and electronic mail reminders were used to facilitate compliance, while pill counts and supplementation usage records, were used to verify compliance. Due to recent concerns regarding kava kava use and hepatotoxicity (Ulbricht et al, 2005), clinical liver function indicies (i.e. AST, ALT, GGT, alkaline phosphatase, total bilirubin, direct bilirubin, and serum albumin) were monitored on days 0, 7, and 14 of both supplementation phases. ...
Article
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Phytochemical-mediated modulation of P-glycoprotein (P-gp) and other drug transporters may underlie many herb-drug interactions. Serial serum concentration-time profiles of the P-gp substrate, digoxin, were used to determine whether supplementation with milk thistle or black cohosh modified P-gp activity in vivo. Sixteen healthy volunteers were randomly assigned to receive a standardized milk thistle (900 mg daily) or black cohosh (40 mg daily) supplement for 14 days, followed by a 30-day washout period. Subjects were also randomized to receive rifampin (600 mg daily, 7 days) and clarithromycin (1000 mg daily, 7 days) as positive controls for P-gp induction and inhibition, respectively. Digoxin (Lanoxicaps, 0.4 mg) was administered orally before and at the end of each supplementation and control period. Serial digoxin serum concentrations were obtained over 24 h and analyzed by chemiluminescent immunoassay. Comparisons of area under the serum concentration time curves from 0 to 3 h (AUC(0-3)), AUC(0-24), Cmax, apparent oral clearance of digoxin (CL/F), and elimination half-life were used to assess the effects of milk thistle, black cohosh, rifampin, and clarithromycin on digoxin pharmacokinetics. Rifampin produced significant reductions (p < 0.01) in AUC(0-3), AUC(0-24), and Cmax, whereas clarithromycin increased these parameters significantly (p < 0.01). Significant changes in digoxin half-life and CL/F were also observed with clarithromycin. No statistically significant effects on digoxin pharmacokinetics were observed following supplementation with either milk thistle or black cohosh, although digoxin AUC(0-3) and AUC(0-24) approached significance (p = 0.06) following milk thistle administration. When compared with rifampin and clarithromycin, supplementation with these specific formulations of milk thistle or black cohosh did not appear to affect digoxin pharmacokinetics, suggesting that these supplements are not potent modulators of P-gp in vivo.
... Side effects of kava consumption include skin reactions and central nervous system effects. Kava dermopathy has been well documented among Pacific Islanders [26] and is a reversible condition characterised by dry scaly yellow skin covering the palms of the hands, soles of the feet, and back [27]. It is speculated to have a link to cholesterol metabolism and hepatotoxicity due to the presence of jaundice [28]. ...
... It is speculated to have a link to cholesterol metabolism and hepatotoxicity due to the presence of jaundice [28]. Short-term kava use can produce extrapyramidal side effects resulting in oral dyskinesia and serious exacerbations of parkinsonism-like symptoms, while heavy use may predispose individuals to seizures [27]. However, a doubleblind placebo controlled trial showed kava has no effect on motor vehicle performance. ...
... However, a doubleblind placebo controlled trial showed kava has no effect on motor vehicle performance. In another study, no statistically significant difference between kava and placebo was present in participants performing tracking tasks [27]. ...
Article
Full-text available
Kava is traditionally consumed by South Pacific islanders as a drink and became popular in Western society as a supplement for anxiety and insomnia. Kava extracts are generally well tolerated, but reports of hepatotoxicity necessitated an international reappraisal of its safety. Hepatotoxicity can occur as an acute, severe form or a chronic, mild form. Inflammation appears to be involved in both forms and may result from activation of liver macrophages (Kupffer cells), either directly or via kava metabolites. Pharmacogenomics may influence the severity of this inflammatory response.
... Kava kava (Piper methysticum G. Forst.; family Piperaceae) has long been a traditional beverage consumed among South Pacific islanders to imbue psychotropic, hypnotic, and anxiolytic effects [244]. Since the 1990s, commercial kava extracts formulated as tablets and/or capsules have been marketed as dietary supplements for the alleviation of stress, anxiety, or insomnia [244,245]. ...
... Kava kava (Piper methysticum G. Forst.; family Piperaceae) has long been a traditional beverage consumed among South Pacific islanders to imbue psychotropic, hypnotic, and anxiolytic effects [244]. Since the 1990s, commercial kava extracts formulated as tablets and/or capsules have been marketed as dietary supplements for the alleviation of stress, anxiety, or insomnia [244,245]. Reports linking kava use to liver toxicity have led to the removal of these products from Australia, Canada, and several European countries, and prompted the FDA to issue warnings of possible hepatotoxic side effects associated with kava supplementation [244]. For those case reports documenting possible kava-related hepatotoxicity, prolonged usage (> 60 days), and co-medication with prescription drugs or other botanical supplements were frequent and confounding variables [244]. ...
... Since the 1990s, commercial kava extracts formulated as tablets and/or capsules have been marketed as dietary supplements for the alleviation of stress, anxiety, or insomnia [244,245]. Reports linking kava use to liver toxicity have led to the removal of these products from Australia, Canada, and several European countries, and prompted the FDA to issue warnings of possible hepatotoxic side effects associated with kava supplementation [244]. For those case reports documenting possible kava-related hepatotoxicity, prolonged usage (> 60 days), and co-medication with prescription drugs or other botanical supplements were frequent and confounding variables [244]. ...
Article
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Phytochemicals have been components of man's diet for millennia and are believed to have played a significant role in steering the functional development of xenobiotic metabolizing enzymes and transporters within the human gastrointestinal tract. Only recently, however, have plant secondary metabolites been recognized as modulators of human drug disposition. Despite exposure to thousands of structurally diverse dietary phytochemicals, only a few appear to significantly modulate human drug metabolizing enzymes and transporters. In some instances, these interactions may have beneficial effects like cancer prevention, whereas others may dramatically affect the pharmacokinetics of concomitantly administered drugs. In today's global economy, the opportunity for exposure to more exotic phytochemicals is significantly enhanced. Formulated as concentrated phytochemical extracts, botanical dietary supplements are vehicles for a host of plant secondary metabolites rarely encountered in the normal diet. When taken with conventional medications, botanical dietary supplements may give rise to clinically significant herb-drug interactions. These interactions stem from phytochemical-mediated induction and/or inhibition of human drug metabolizing enzymes and transporters.
... The natural products research has focus on the chemical properties, bio-synthesis and biological functions of secondary metabolites as a central theme of examine and bordering chemistry and biology [2]. So, simple definition is: A living organism produced a chemical substance; a term normally used in reference to chemical substances found in nature which have characteristic pharmacological impacts [3]. Natural products have an important role in the scientific field of pharmacognosy through its study of identification, isolation and characterization. ...
... Galactitol is a known compoundbecause its spectral data and chemical properties are similar as reported earlier [20,21]. Arabitol (3) compound was identified by analytical methods along with chemical test. Compound3 was isolated as colorless amorphous solid with melting point of 100 -103°C. ...
... HNMR spectrum of isolated compound Arabitol(3). ...
... Kava kava (Piper methysticum G. Forst.; family Piperaceae) has long been a traditional beverage consumed among South Pacific islanders to imbue psychotropic, hypnotic, and anxiolytic effects [244]. Since the 1990s, commercial kava extracts formulated as tablets and/or capsules have been marketed as dietary supplements for the alleviation of stress, anxiety, or insomnia [244,245]. ...
... Kava kava (Piper methysticum G. Forst.; family Piperaceae) has long been a traditional beverage consumed among South Pacific islanders to imbue psychotropic, hypnotic, and anxiolytic effects [244]. Since the 1990s, commercial kava extracts formulated as tablets and/or capsules have been marketed as dietary supplements for the alleviation of stress, anxiety, or insomnia [244,245]. Reports linking kava use to liver toxicity have led to the removal of these products from Australia, Canada, and several European countries, and prompted the FDA to issue warnings of possible hepatotoxic side effects associated with kava supplementation [244]. For those case reports documenting possible kava-related hepatotoxicity, prolonged usage (> 60 days), and co-medication with prescription drugs or other botanical supplements were frequent and confounding variables [244]. ...
... Since the 1990s, commercial kava extracts formulated as tablets and/or capsules have been marketed as dietary supplements for the alleviation of stress, anxiety, or insomnia [244,245]. Reports linking kava use to liver toxicity have led to the removal of these products from Australia, Canada, and several European countries, and prompted the FDA to issue warnings of possible hepatotoxic side effects associated with kava supplementation [244]. For those case reports documenting possible kava-related hepatotoxicity, prolonged usage (> 60 days), and co-medication with prescription drugs or other botanical supplements were frequent and confounding variables [244]. ...
Article
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In Part 2 of this review, a critical examination of the pertinent scientific literature is undertaken in order to assess the interaction risk that popular dietary supplements may pose when taken concomitantly with conventional medications. Botanicals most likely to produce clinically important herb-drug interactions are those whose phytochemicals act as mechanism-based inhibitors of cytochrome P450 enzyme activity (e.g., HYDRASTIS CANADENSIS, PIPER NIGRUM, SCHISANDRA CHINENSIS) or function as ligands for orphan nuclear receptors (e.g., HYPERICUM PERFORATUM). In addition, several external factors unrelated to phytochemical pharmacology can augment the drug interaction potential of botanical supplements.
... x The following drugs interacted with HMPs (Table 2): anaesthetics [16], anti-arrhythmic agents [15,27], antibiotics [19,34,36,39,40,42,46,48,49,52,53], anticoagulants [13, 15, 16, 18, 24, 26, 27, 29, 33, 34, 36, 37, 39, 40, 44-46, 49, 50, 52, 53], anticholinergics [17,22], antidepressants [25,26,33,45], antidiabetics [26,27,38,40,43,47,[50][51][52][53], antihypertensives [16, 29, 33, 41, 43-46, 49, 53], anti-inflammatory agents [13,16,35,46,52,53], antimicrobials [31], antineoplastics [11,14,31,36,[39][40][41][42][43][51][52][53], antiplatelet agents [13,15,24,25,27,29,33,34,36,37,39,40,44,45,49,50,52,53], anti-epileptic drugs [13,41,45], antivirals [31,40,45,51,52], calcium channel blockers [24,26,30], cholesterol lowering agents [10,13,24,26,27,40,41,44,45,50,53], CYP-450 metabolized agents [18,21,25,29,32,34,40,42,45,48,49,53], diuretics [26,30,43], hormonal agents [18,24,26,31,40,41,43,45,49,53,54], hypoglycaemics [9,10,19,20,28], immunnosupressants [31,34,37,40,43,46,48] laxatives [27,37,50], leukotriene inhibitors [14], sedatives [12,13,23,25,45], selective serotonin re-uptake inhibitors [23,33] and vasolidators [30,44]. ...
... x The following drugs interacted with HMPs (Table 2): anaesthetics [16], anti-arrhythmic agents [15,27], antibiotics [19,34,36,39,40,42,46,48,49,52,53], anticoagulants [13, 15, 16, 18, 24, 26, 27, 29, 33, 34, 36, 37, 39, 40, 44-46, 49, 50, 52, 53], anticholinergics [17,22], antidepressants [25,26,33,45], antidiabetics [26,27,38,40,43,47,[50][51][52][53], antihypertensives [16, 29, 33, 41, 43-46, 49, 53], anti-inflammatory agents [13,16,35,46,52,53], antimicrobials [31], antineoplastics [11,14,31,36,[39][40][41][42][43][51][52][53], antiplatelet agents [13,15,24,25,27,29,33,34,36,37,39,40,44,45,49,50,52,53], anti-epileptic drugs [13,41,45], antivirals [31,40,45,51,52], calcium channel blockers [24,26,30], cholesterol lowering agents [10,13,24,26,27,40,41,44,45,50,53], CYP-450 metabolized agents [18,21,25,29,32,34,40,42,45,48,49,53], diuretics [26,30,43], hormonal agents [18,24,26,31,40,41,43,45,49,53,54], hypoglycaemics [9,10,19,20,28], immunnosupressants [31,34,37,40,43,46,48] laxatives [27,37,50], leukotriene inhibitors [14], sedatives [12,13,23,25,45], selective serotonin re-uptake inhibitors [23,33] and vasolidators [30,44]. ...
... x The following drugs interacted with HMPs (Table 2): anaesthetics [16], anti-arrhythmic agents [15,27], antibiotics [19,34,36,39,40,42,46,48,49,52,53], anticoagulants [13, 15, 16, 18, 24, 26, 27, 29, 33, 34, 36, 37, 39, 40, 44-46, 49, 50, 52, 53], anticholinergics [17,22], antidepressants [25,26,33,45], antidiabetics [26,27,38,40,43,47,[50][51][52][53], antihypertensives [16, 29, 33, 41, 43-46, 49, 53], anti-inflammatory agents [13,16,35,46,52,53], antimicrobials [31], antineoplastics [11,14,31,36,[39][40][41][42][43][51][52][53], antiplatelet agents [13,15,24,25,27,29,33,34,36,37,39,40,44,45,49,50,52,53], anti-epileptic drugs [13,41,45], antivirals [31,40,45,51,52], calcium channel blockers [24,26,30], cholesterol lowering agents [10,13,24,26,27,40,41,44,45,50,53], CYP-450 metabolized agents [18,21,25,29,32,34,40,42,45,48,49,53], diuretics [26,30,43], hormonal agents [18,24,26,31,40,41,43,45,49,53,54], hypoglycaemics [9,10,19,20,28], immunnosupressants [31,34,37,40,43,46,48] laxatives [27,37,50], leukotriene inhibitors [14], sedatives [12,13,23,25,45], selective serotonin re-uptake inhibitors [23,33] and vasolidators [30,44]. ...
Article
Objectives: The aim of this overview of systematic reviews (SRs) is to evaluate critically the evidence regarding interactions between herbal medicinal products (HMPs) and synthetic drugs. Methods: Four electronic databases were searched to identify relevant SRs. Results: Forty-six SRs of 46 different HMPs met our inclusion criteria. The vast majority of SRs were of poor methodological quality. The majority of these HMPs were not associated with severe herb-drug interactions. Serious herb-drug interactions were noted for Hypericum perforatum and Viscum album. The most severe interactions resulted in transplant rejection, delayed emergence from anaesthesia, cardiovascular collapse, renal and liver toxicity, cardiotoxicity, bradycardia, hypovolaemic shock, inflammatory reactions with organ fibrosis and death. Moderately severe interactions were noted for Ginkgo biloba, Panax ginseng, Piper methysticum, Serenoa repens and Camellia sinensis. The most commonly interacting drugs were antiplatelet agents and anticoagulants. Conclusion: The majority of the HMPs evaluated in SRs were not associated with drug interactions with serious consequences. However, the poor quality and the scarcity of the primary data prevent firm conclusions.
... of drug interactions. [13][14][15][16][17]21,23,27,[32][33][34][35][36][37][38][39][40]45,47,[50][51][52][53][54][55][56][57][58][59][60][61] The number of primary studies included in the SRs ranged from 1 38 to 216. 28 The types of primary reports varied from case studies to epidemiological investigations. ...
... [13][14][15][16][17][18][19][20][21][23][24][25][26]29,31,32,35,38,39,[42][43][44][45]47,50,53,55,[57][58][59][60] Fifteen SRs reported moderately severe AEs, 12,22,27,28,30,36,40,41,46,48,49,51,52,54,56 and four SRs concluded that the HM in question was not safe (see Supplemental Tables S1 and S2). 33,34,37,61 Thirteen SRs mentioned the duration of AEs, 18,20,22,24,26,28,33,42,[44][45][46]48,50 which ranged from 48 hours to 11 months. Forty-two SRs failed to mention conflict of interest of the authors. ...
... Forty-two SRs failed to mention conflict of interest of the authors. [13][14][15][16][17][18]22,23,[25][26][27][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][47][48][49][50][51][52][53][54][55][56][57][58][59][60][61] Thirty-two SRs made no mention of any source of funding. [13][14][15][16][17]22,23,27,30,[34][35][36][37][38][39][40][41]44,47,48,[50][51][52][53][54][55][56][57][58][59][60][61] The quality of the methods of the included SRs was mixed ( ...
Article
This overview of systematic reviews (SRs) aims to evaluate critically the evidence regarding the adverse effects of herbal medicines (HMs). Five electronic databases were searched to identify all relevant SRs, with 50 SRs of 50 different HMs meeting our inclusion criteria. Most had only minor weaknesses in methods. Serious adverse effects were noted only for four HMs: Herbae pulvis standardisatus, Larrea tridentate, Piper methysticum and Cassia senna. The most severe adverse effects were liver or kidney damage, colon perforation, carcinoma, coma and death. Moderately severe adverse effects were noted for 15 HMs: Pelargonium sidoides, Perna canaliculus, Aloe vera, Mentha piperita, Medicago sativa, Cimicifuga racemosa, Caulophyllum thalictroides, Serenoa repens, Taraxacum officinale, Camellia sinensis, Commifora mukul, Hoodia gordonii, Viscum album, Trifolium pratense and Stevia rebaudiana. Minor adverse effects were noted for 31 HMs: Thymus vulgaris, Lavandula angustifolia Miller, Boswellia serrata, Calendula officinalis, Harpagophytum procumbens, Panax ginseng, Vitex agnus-castus, Crataegus spp., Cinnamomum spp., Petasites hybridus, Agave americana, Hypericum perforatum, Echinacea spp., Silybum marianum, Capsicum spp., Genus phyllanthus, Ginkgo biloba, Valeriana officinalis, Hippocastanaceae, Melissa officinalis, Trigonella foenum-graecum, Lagerstroemia speciosa, Cnicus benedictus, Salvia hispanica, Vaccinium myrtillus, Mentha spicata, Rosmarinus officinalis, Crocus sativus, Gymnema sylvestre, Morinda citrifolia and Curcuma longa. Most of the HMs evaluated in SRs were associated with only moderately severe or minor adverse effects.
... Kava kava (Piper methysticum G. Forst.) has long been a traditional beverage consumed among South Pacific islanders to imbue psychotropic, hypnotic, and anxiolytic effects [441]. Since the 1990s, commercial kava extracts formulated as tablets and/or capsules have been marketed as dietary supplements for the alleviation of stress, anxiety, or insomnia [441,442]. ...
... Kava kava (Piper methysticum G. Forst.) has long been a traditional beverage consumed among South Pacific islanders to imbue psychotropic, hypnotic, and anxiolytic effects [441]. Since the 1990s, commercial kava extracts formulated as tablets and/or capsules have been marketed as dietary supplements for the alleviation of stress, anxiety, or insomnia [441,442]. Reports linking kava use to liver toxicity has led to the removal of these products from Australia, Canada, and several European countries, and prompted the FDA to issue warnings of possible hepatotoxic side effects associated with kava supplementation [441]. For those case reports documenting possible kava-related hepatotoxicity, prolonged usage (>60 days) and comedication with prescription drugs or other botanical supplements were frequent and confounding variables [441]. ...
... Since the 1990s, commercial kava extracts formulated as tablets and/or capsules have been marketed as dietary supplements for the alleviation of stress, anxiety, or insomnia [441,442]. Reports linking kava use to liver toxicity has led to the removal of these products from Australia, Canada, and several European countries, and prompted the FDA to issue warnings of possible hepatotoxic side effects associated with kava supplementation [441]. For those case reports documenting possible kava-related hepatotoxicity, prolonged usage (>60 days) and comedication with prescription drugs or other botanical supplements were frequent and confounding variables [441]. ...
... Kava consumption has been well tolerated and is non-addictive at therapeutic dosages. Allergic reactions are usually mild and include itchy skin or itchy throat, and hives on the skin usually prevalent on the abdominal region; however, potential side effects can occur when very high doses are taken for extended periods, including headache, dizziness, drowsiness, diarrhea, and occasionally dermatologic manifestations [70]. Heavy use of kava could cause malnutrition, weight loss, renal dysfunction, rashes, pulmonary hypertension, macrocytosis of red cells, lymphocytopenia, and decreasing platelet volumes [70][71][72]. ...
... Allergic reactions are usually mild and include itchy skin or itchy throat, and hives on the skin usually prevalent on the abdominal region; however, potential side effects can occur when very high doses are taken for extended periods, including headache, dizziness, drowsiness, diarrhea, and occasionally dermatologic manifestations [70]. Heavy use of kava could cause malnutrition, weight loss, renal dysfunction, rashes, pulmonary hypertension, macrocytosis of red cells, lymphocytopenia, and decreasing platelet volumes [70][71][72]. More importantly, unexpected high liver toxicity/damage (e.g., increased serum γ-glutamyltransferase and high-density lipoprotein cholesterol levels) has been reported during kava consumption [28,73]. ...
... More importantly, unexpected high liver toxicity/damage (e.g., increased serum γ-glutamyltransferase and high-density lipoprotein cholesterol levels) has been reported during kava consumption [28,73]. Therefore, many countries took actions and regulated or restricted kava consumption [70]. ...
Chapter
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Kava has been widely used as a herbal medicine for alternative treatment of anxiety and insomnia. In Europe, kava has been used for the treatment of anxiety and nervous disorders such as stress and restlessness, and in the United States kava is used as a natural alternative to anti-anxiety drugs and sleeping remedies. The most important medical application of kava is associated with its anti-psychotic effects. This chapter discusses the detailed mechanisms of kava-mediated hepatotoxicity, including (i) inhibition of cytochrome P450 enzyme activities that are important for drug metabolism; (ii) decreasing liver glutathione content that is linked to drug detoxification; (iii) inhibition of cyclooxygenase enzyme activity; (iv) induction of inflammatory responses; (v) inhibition of hepatic transporter function, which results in accumulation of drugs, toxins, and bile acids; and (vi) direct mitochondrial damage that plays a central role in drug-induced liver injury.
... Several putative causes for liver toxicity have been pointed out, ranging from the potential low-quality cultivars and inadequate extraction solvents to possible interactions with other drugs. Kava overdose can be associated with necrotic hepatitis and cholestatic hepatitis [60]. In such cases, nearly 80% of the individuals consumed 2-fold the maximum daily recommended dose and consumed kava for a prolonged time (more than 3 months up to two years), as mentioned in the WHO report [59]. ...
... An example is kava dermopathy, also known as kavaism. It is a systemic dermatitis and erythema that can be observed first in the head, spreading down to the body (arms, body, neck, and breast), and resulting in a dry, scaly, and yellow discoloration [7,60,70]. ...
Article
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Kava (Piper methysticum) has been widely consumed for many years in the South Pacific Islands and displays psychoactive properties, especially soothing and calming effects. This plant has been used in Western countries as a natural anxiolytic in recent decades. Kava has also been used to treat symptoms associated with depression, menopause, insomnia, and convulsions, among others. Along with its putative beneficial health effects, kava has been associated with liver injury and other toxic effects, including skin toxicity in heavy consumers, possibly related to its metabolic profile or interference in the metabolism of other xenobiotics. Kava extracts and kavalactones generally displayed negative results in genetic toxicology assays although there is sufficient evidence for carcinogenicity in experimental animals, most likely through a non-genotoxic mode of action. Nevertheless, the chemotherapeutic/chemopreventive potential of kava against cancer has also been suggested. Both in vitro and in vivo studies have evaluated the effects of flavokavains, kavalactones and/or kava extracts in different cancer models, showing the induction of apoptosis, cell cycle arrest and other antiproliferative effects in several types of cancer, including breast, prostate, bladder, and lung. Overall, in this scoping review, several aspects of kava efficacy and safety are discussed and some pertinent issues related to kava consumption are identified.
... Suggestions and discussions have emerged during the past years regarding possible causative mechanisms leading to the development of kava hepatotoxicity (2-4, 6, 7, 10, 11, 13, 14, 16, 17, 23, 25, 32, 37-66), and other relevant data (67)(68)(69)(70)(71)(72)(73)(74)(75)(76)(77)(78)(79)(80)(81)(82) have to be considered (Table 1). Proposals include areas such as ethnic origin predisposing to liver injury (3,6,17,42,66); solvents and solubilizers used for kava extract preparation (2,4,6,7,10,11,14,16,32,37,43,(45)(46)(47); quality of the kava raw material regarding cultivar and used plant part, adulteration and impurities (2,4,6,14,16,23,25,44); hepatic glutathione depletion (4,11,16,43,45,48,49,63); cyclooxygenase inhibition (13,50); P-glycoprotein alterations (51,58); genetic enzyme deficiencies (3,4,6,11,40,42,66); interactions at the level of hepatic microsomal cytochrome P450 (CYP, P450) between drugs, kavalactones and alcohol (2-4, 6, 7, 11, 14, 16, 17, 19, 42, 52-60); comedication (1-7, 13, 16-20, 32, 33); daily overdose of kavalactones and prolonged treatment (3,6,7,17,19); and the existence of one or more toxic constituents within or outside the kavalactones or of toxic metabolites (14,16,23,42,(61)(62)(63)(64)(65). A shortcoming of the overall assessment is the fact that in only one patient (2, 33) out of the 31 cases with primarily suspected kava hepatotoxicity (1, 3, 6, 7, 44, 67) was a batch analysis of the used kava product performed regarding the presence of kava or other compounds as ingredients or contaminants. ...
... Metabolic interactions of kava with alcohol have been suggested as a possible mechanism of kava hepatotoxicity in alcohol-consuming patients; reactive metabolites generated via CYP 2E1 during chronic alcohol intake or increased kavalactone exposure via hepatic enzyme inhibition during acute alcohol ingestion have been implicated (60). Alcohol is partially metabolized by the hepatic microsomal ethanol-oxidizing system involving cytochrome P450 (44,(75)(76)(77) with special reference to its isoenzyme CYP 2E1 (77,78), and kavalactones may also be substrates of P450 (2,4,60). The clinical issue of alcohol consumption for the development of kava hepatotoxicity may be less important in Western countries (2,3,6,7,16), but a major role of alcohol could be implicated in kava-consuming populations with increased serum gGT activities (7,16,17) such as those in Australia (38,39), New Caledonia (40) or Tonga (72). ...
Article
Kava hepatotoxicity is a well-defined herb-induced liver injury, caused by the use of commercial anxyolytic ethanolic and acetonic kava extracts, and of traditional recreational aqueous kava extracts. The aim of this review is to elucidate possible pathogenetic factors for the development of kava-induced liver injury, considering also confounding variables. In patients with liver disease in a causal relation to kava ± comedication, confounding factors include non-adherence to therapy recommendations and comedication consisting of synthetic and herbal drugs and dietary supplements including herbal ones and herbs-kava mixtures. Various possible pathogenetic factors have to be discussed and comprise metabolic interactions with exogenous compounds at the hepatic microsomal cytochrome P450 level; genetic enzyme deficiencies; toxic constituents and metabolites derived from the kava extract including impurities and adulterations; cyclooxygenase inhibition; P-glycoprotein alterations; hepatic glutathione depletion; solvents and solubilizers of the extracts; and kava raw material of poor quality. In particular, inappropriate kava plant parts and unsuitable kava cultivars may have been used sometimes for manufacturing the kava extracts instead of the rhizome of a noble cultivar of the kava plant (Piper methysticum G. Forster). In conclusion, kava hepatotoxicity occurred independently of the extraction medium used for the kava extracts and may primarily be attributed to daily overdose, prolonged treatment and to a few kava extract batches of poor quality; by improving kava quality and adherence to therapy recommendation under avoidance of comedication, liver injury by kava should be a preventable disease, at least to a major extent.
... The most concerning potential toxicity of kava is its effect on the liver (15). At least 78 case reports exist of hepatotoxicity associated with the use of kava supplements (16). ...
... Liverrelated problems range from increased liver enzyme tests, hepatitis, cirrhosis, liver failure, liver transplant, and death. As a result, several countries have banned the sale of kava (15). Kava proponents suggest that the case reports sometimes lack the necessary documentation to assign kava as the single causative agent, many of the patients were taking other drugs that can cause liver problems, and a few already had existing liver problems. ...
Article
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To determine the effects of traditionally prepared kava beverages on the liver function tests of regular kava beverage consumers in a population of Tongan and non-Tongan residents of Hawaii (Oahu). The liver function tests of 31 healthy adult kava drinkers were compared against a control group of 31 healthy adult non-kava drinkers. Subjects were recruited from the general population, a kava bar, and Tongan kava drinking circles. The liver function profile included AST, ALT, ALP, GGT, and bilirubin (total and direct). Other tests included total protein, albumin, and screens for viral hepatitis and hemochromatosis when indicated. Chronic kava beverage consumption was associated with elevation of GGT in 65% of the kava drinkers versus 26% in the controls (P = .005). ALP was elevated in 23% of kava drinkers versus 3% in the controls (P = .053). Heavy kava beverage consumption was associated with significantly elevated GGT levels.
... cinnamic acid derivatives (bornyl ester of 3,4-methylene dioxycinnamic acid, cinnamic acid bornyl ester), long-chain fatty acids and alcohols, and sterols [6][7][8]. Over a decade ago, potential safety issues with kava applications arose when several cases of liver damage were associated with kava consumption [9][10][11]. Given the concerns around potential liver toxicity with kava usage, the possible mechanisms for hepatotoxicity were investigated [12][13][14]. ...
... The (U)HPLC methods were fully validated based on the AOAC Guideline [24] for Single-Laboratory Validation of Chemical Methods and ICH Q2 Guideline [25]. Over a decade ago, potential safety issues with kava applications arose when several cases of liver damage were associated with kava consumption [9][10][11]. Given the concerns around potential liver toxicity with kava usage, the possible mechanisms for hepatotoxicity were investigated [12][13][14]. ...
Article
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An ultra-high-performance liquid chromatographic (UHPLC) separation was developed for six kava pyrones (methysticin, dihydromethysticin (DHM), kavain, dihydrokavain (DHK), desmethoxyyangonin (DMY), and yangonin), two unidentified components, and three Flavokavains (Flavokavain A, B, and C) in Piper methysticum (kava). The six major kavalactones and three flavokavains are completely separated (Rs > 1.5) within 15 min using a HSS T3 column and a mobile phase at 60 °C. All the peaks in the LC chromatogram of kava extract or standard solutions were structurally confirmed by LC-UV-MS/MS. The degradations of yangonin and flavokavains were observed among the method development. The degradation products were identified as cis-isomerization by MS/MS spectra. The isomerization was prevented or limited by sample preparation in a non-alcoholic solvent or with no water. The method uses the six kava pyrones and three flavokavains as external standards. The quantitative calibration curves are linear, covering a range of 0.5–75 μg/mL for the six kava pyrones and 0.05–7.5 μg/mL for the three flavokavains. The quantitation limits for methysticin, DHM, kavain, DHK, DMY, and yangonin are approximately 0.454, 0.480, 0.277, 0.686, 0.189, and 0.422 μg/mL. The limit of quantification (LOQs) of the three flavokavains are about 0.270, 0.062, and 0.303 μg/mL for flavokavain C (FKC), flavokavain A (FKA), and flavokavain B (FKB). The average recoveries at three different levels are 99.0–102.3% for kavalactones (KLs) and 98.1–102.9% for flavokavains (FKs). This study demonstrates that the method of analysis offers convenience and adequate sensitivity for determining methysticin, DHM, kavain, DHK, yangonin, DMY, FKA, FKB, and FKC in kava raw materials (root and CO2 extract) and finished products (dry-filled capsule and tablet).
... Tem como princípios ativos (substâncias que exercerão efeito farmacológico) as cavapironas, dentre as principais a cavaína, dihidrocavaína, iangonina, desmetoxi-iangonina, metisticina e dihidrometisticina (Arruda et al., 2005), responsáveis pelas propriedades ansiolítica e antidepressiva do fi toterápico. No entanto, dados relativos à hepatoxicidade têm limitado o uso de medicamentos à base de kava-kava (Clouatre, 2004;Ulbricht et al., 2005). ...
Article
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The objective of this study was to evaluate the effect of dietary kava-kava (Piper methysticum) during the laying period on performance (feed intake, feed conversion, weight of eggs and production), egg quality, tonic immobility time (TIT), intensity of injuries and blood heterophil/lymphocyte ratio (H:L). A total of 90 female Japanese quails of 21 weeks of age were distributed in a completely randomized experimental design and submitted to three treatments (0, 300 and 600mg of dried extract of kava-kava/kg of feed), with fi ve replicates and six birds, in each batch. Kava-kava fed to laying quails has no effect on performance, egg quality, intensity of injury or H:L ratio. However, there is a reduction in time spent in tonic immobility with the inclusion of kava-kava that predisposes the quail to a reduction of stress.
... Although whole rhizome extracts and purified preparations of the pharmacologically active kavalactones such as kavain are generally well tolerated, side effects include dermopathy and central nervous system effects (Norton and Ruze, 1994;Ulbricht et al., 2005). The most serious adverse effect observed is hepatotoxicity (Fu et al., 2008a). ...
Article
Previous studies with kava components such as kavalactones, pipermethystine and flavokavain B have demonstrated hepatotoxicity from these constituents. Regardless, there has recently been speculation that adulterants or impurities such as the mould hepatotoxin aflatoxin are a more likely cause of kava hepatotoxicity, despite a paucity of supporting evidence. Although there is limited similarity between acute kava hepatotoxicity and acute aflatoxicosis, and background levels of aflatoxin have been detected in kava samples, unless epidemiological investigations can uncover direct evidence implicating mould hepatotoxins, it remains more likely that chemical constituents of kava are the cause of the hepatotoxicity from kava. Copyright © 2012 John Wiley & Sons, Ltd.
... Acknowledging the widespread use of kava in some Pacific countries with high rates of MVCs (compared to Australia and New Zealand), 36,37 and the cautionary advice about driving following the use of kava provided by several regulatory agencies in high-income settings, [38][39][40] we investigated the available published evidence regarding the effect of kava on MVCs, MVC-related injuries or driving performance. Given that there is no published protocol for this review, we present the methods and results in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement (PRISMA). ...
Article
Kava is marketed as a herbal anxiolytic in several countries and is consumed recreationally in high doses in many indigenous Pacific and Australian Aboriginal communities. We reviewed the published literature examining the association (if any) between kava use and motor vehicle crashes (MVCs), MVC-related injuries or driving performance. Search of MEDLINE, EMBASE, PsycINFO, CINAHL, Scopus, AMED, Australian Medical Index, Australian Transport Index and trials registries and injury journals up to August 2014. No studies quantifying the effects of kava on MVCs or related injury were located. Four experimental studies using computer-based driving simulation examined the effects of pharmacological doses of kavalactones on cognitive and visuomotor performance. While no statistically significant adverse changes attributable to kava were found, there was weak evidence of slowed reaction time. One study found the visuo-motor performance on driving simulation to be significantly impaired when kava was consumed with alcohol. With equivocal evidence limited to experimental studies using simulated driving settings, the contribution of kava to MVCs is unknown. The gap in knowledge regarding the potential risk of injuries associated with therapeutic and recreational use of kava requires priority attention. © 2015 Public Health Association of Australia.
... In addition to the possibility that the effect of KKE on the retina is specific to albino rats, the dose level of 1.0 g/kg used in this rat study is largely higher (more than 30-fold) than human equivalent dose for herbal supplement (Ulbricht et al. 2005) based on the body surface area conversion (FDA 2005). Therefore, the risk of retinal toxicity resulting from KKE exposure may be low in humans. ...
Article
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There was a significant increase in the incidence of retinal degeneration in F344/N rats chronically exposed to Kava kava extract (KKE) in National Toxicology Program (NTP) bioassay. A retrospective evaluation of these rat retinas indicated a similar spatial and morphological alteration as seen in light-induced retinal degeneration in albino rats. Therefore, it was hypothesized that KKE has a potential to exacerbate the light-induced retinal degeneration. To investigate the early mechanism of retinal degeneration, we conducted a 90-day F344/N rat KKE gavage study at doses of 0 and 1.0 g/kg (dose which induced retinal degeneration in the 2-year NTP rat KKE bioassay). The morphological evaluation indicated reduced number of phagosomes in the retinal pigment epithelium (RPE) of the superior retina. Transcriptomic alterations related to retinal epithelial homeostasis and melatoninergic signaling were observed in microarray analysis. Phagocytosis of photoreceptor outer segment by the underlying RPE is essential to maintain the homeostasis of the photoreceptor layer and is regulated by melatonin signaling. Therefore, reduced photoreceptor outer segment disc shedding and subsequent lower number of phagosomes in the RPE and alterations in the melatonin pathway may have contributed to the increased incidences of retinal degeneration observed in F344/N rats in the 2-year KKE bioassay.
... Ginger may decrease thromboxane production and prolong bleeding time (Srivastava, 1984;Lumb, 1994;Afzal et al., 2001). It is suggested that a specific kavalactone, kawain in herb kava-kava may decrease thromboxane 2 production and inhibit cyclooxygenase, indicating that it may have significant inhibitory effect on platelet aggregation (Ulbricht et al., 2005). Grape seed and grape skin extracts might have antiplatelet effects and might prolong PT and INR (Shanmuganayagam et al., 2002). ...
Article
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The potential risk of herb drug interactions is of particular focus today owing to the increasing and inadvertent use of herbs in recent times. It is a major safety concern for the drugs with narrow therapeutic index like warfarin, a most common anticoagulant with the maximum number of interactions reported. The objective of the present study was to conduct a systemic review of literature to consolidate the clinical case reports of warfarin¿herb interactions and to assess the report reliabilities. We reviewed the published clinical literature to consolidate and assess the interactions between various herbs and warfarin, based on reported adverse events, descriptions of the clinical case reports and case series using electronic databases as well as hand picked references from the year 1971 to year 2007 and ranked them on likely causality using Naranjo¿s algorithm. Out of 72 cases of documented case reports of warfarin with various herbs, 84.7% cases were evaluated as possible interactions (61/72) and 15.3% cases (11/72) as probable interactions. Cranberry juice was most commonly involved in interactions with warfarin with 34.7% of cases (25/72) of which 92% cases were possible interactions (23/25) and 8% cases (2/25) were probable interactions. Hence, we conclude that combining anticoagulant medicines with herbs appears to be a risky proposition. The number of herbs reported to interact with warfarin continues to expand. Patients on warfarin are specifically advised to avoid taking herbal medicines or to have their INR measured within two weeks of starting the drug, to be on a safer side. Further, more systematic studies pertaining to warfarinherb interactions are urgently warranted.
... In any case, further studies, that might hopefully restore the reputation of kava, are required. However, a recommendation has already been made by Natural Standard Research Collaboration, Cambridge, MA, USA to consolidate and analyse available reports and to continue postmarket surveillance in an international repository to prevent duplication and to promote the collection of thorough details at the time of each report so that any association with kava is clearly defined (Ulbricht et al., 2005). Wheatley (2005) demonstrated that Kava-kava is a well-established hypnotic drug, with a rapid onset of effect, adequate duration of action and minimal morning after-effects. ...
Article
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Although very few drugs are currently approved by regulatory authorities for treating multi-factorial ailments and disorders of cognition such as Alzheimer's disease, certain plant-derived agents, including, for example, galantamine and rivastigmine (a semi-synthetic derivative of physostigmine) are finding an application in modern medicine. However, in Ayurveda, the Indian traditional system of medicine which is more than 5000 years old, selected plants have long been classified as 'medhya rasayanas', from the Sanskrit words 'medhya', meaning intellect or cognition, and 'rasayana', meaning 'rejuvenation'. These plants are used both in herbal and conventional medicine and offer benefits that pharmaceutical drugs lack. In the present article, an attempt has been made to review the most important medicinal plants, including Ginkgo biloba, St John's wort, Kava-kava, Valerian, Bacopa monniera and Convolvulus pluricaulis, which are widely used for their reputed effectiveness in CNS disorders.
... Tem como princípios ativos (substâncias que exercerão efeito farmacológico) as cavapironas, dentre as principais a cavaína, dihidrocavaína, iangonina, desmetoxi-iangonina, metisticina e dihidrometisticina (Arruda et al., 2005), responsáveis pelas propriedades ansiolítica e antidepressiva do fi toterápico. No entanto, dados relativos à hepatoxicidade têm limitado o uso de medicamentos à base de kava-kava (Clouatre, 2004; Ulbricht et al., 2005). Estudos farmacológicos demonstraram que os princípios ativos da kava-kava promovem efeito relaxante nos músculos, particularmente útil em estados de tensão, possuem efeito analgésico, controlam a ansiedade, previnem convulsões e podem proteger o cérebro contra as injúrias provocadas por pancadas. ...
Article
Full-text available
The objective of this study was to evaluate the effect of dietary kava-kava (Piper methysticum) during the laying period on performance (feed intake, feed conversion, weight of eggs and production), egg quality, tonic immobility time (TIT), intensity of injuries and blood heterophil/lymphocyte ratio (H:L). A total of 90 female Japanese quails of 21 weeks of age were distributed in a completely randomized experimental design and submitted to three treatments (0, 300 and 600mg of dried extract of kava-kava/kg of feed), with five replicates and six birds, in each batch. Kava-kava fed to laying quails has no effect on performance, egg quality, intensity of injury or H:L ratio. However, there is a reduction in time spent in tonic immobility with the inclusion of kava-kava that predisposes the quail to a reduction of stress.
... Ginger may decrease thromboxane production and prolong bleeding time (Srivastava, 1984;Lumb, 1994;Afzal et al., 2001). It is suggested that a specific kavalactone, kawain in herb kava-kava may decrease thromboxane 2 production and inhibit cyclooxygenase, indicating that it may have significant inhibitory effect on platelet aggregation (Ulbricht et al., 2005). Grape seed and grape skin extracts might have antiplatelet effects and might prolong PT and INR (Shanmuganayagam et al., 2002). ...
... However, there was compelling evidence that kava consumption was related to some toxicities which led to its restriction or warning in many countries since 2002 [8,9]. Several studies have reported a series of adverse health effects including kava dermopathy [10], hepatotoxicity [11,12], and the disruption of cognition [13,14] which were associated with kava consumption. ...
Article
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Kava (Piper methysticum Forst) is a popular and favorable edible medicinal herb which was traditionally used to prepare a nonfermented beverage with relaxant beneficial for both social and recreational purposes. Numerous studies conducted on kava have confirmed the presence of kavalactones and flavokawains, two major groups of bioactive ingredients, in this miraculous natural plant. Expectedly, both kavalactone and flavokawain components exhibited potent antianxiety and anticancer activities, and their structure-activity relationships were also revealed. However, dozens of clinical data revealed the hepatotoxicity effect which is indirectly or directly associated with kava consumption, and most of the evidence currently seems to point the compounds of flavokawains in kava were responsible. Therefore, our aim is to conduct a systematic review of kavalactones and flavokawains in kava including their biological activities, structure-activity relationships, and toxicities, and as a result of our systematic investigations, suggestions on kava and its compounds are supplied for future research.
... Studies on the safety of products containing these herbs are also lacking. Licorice root, for example, is known to cause congestive heart failure at doses as low as 500 mg/day (96), and kava has also been the subject of concern due to hepatotoxicity associated with its use (97). St. John's wort interacts with drug-metabolizing enzymes, and so it is contraindicated in cases where patients are on other medications (98). ...
Article
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Concerns regarding the safety of hormone replacement therapy are causing women to seek out alternative treatments, particularly botanicals. Of these botanicals, black cohosh appears to be the most promising; however, reports of hepatotoxicity have reached high enough numbers that the FDA has decided to take the action of posting warning labels on products containing the herb. Soy and red clover are also popular phytotherapies for menopause despite the fact that their efficacy has yet to be proven. Although the hops plant contains the potent phytoestrogen 8-prenylnaringenin, it has only been tested in two clinical trials as a therapy for menopause. Based on positive results in these two trials, further studies on hops are warranted. Other herbs, such as dong quai, licorice, ginseng, kava, chasteberry and St. John's wort, are marketed as therapies for menopause; however, there is no evidence that they have any effect on the vasomotor symptoms associated with menopause. This review is focused on the relevant clinical trials, chemistry and pharmacology of these phytomedicines.
... 17 The Therapeutic Goods Administration in Australia placed a limit on the maximum amount of P. methysticum permitted per dosage form (for example, tablets or teabags) in 2003. 18 Pharmacology and pharmacokinetics Over 40 compounds have been isolated from P. methysticum, including a group of pyrone derivatives, known as kavalactones. Nineteen have been identified, with only six suggested as being active constituents in the reported biological effects of kava. ...
Article
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Kava dermopathy is a common cutaneous effect of regular or heavy use of Kava, a psychoactive beverage consumed widely throughout the Pacific. In Fiji in 2012, over 1000 study participants underwent full skin examination, and kava dermopathy was a common cutaneous finding. The clinical manifestations of kava dermopathy share similarities with the spectrum of autosomal recessive congenital ichthyoses, predominantly lamellar ichthyosis. The pathogenesis of Kava dermopathy may be associated with a functional defect in one or more cytochrome P450 enzymes implicated in epidermal integrity, thus mimicking the genetic defect as seen in lamellar ichthyosis type 3.
... Kavalactones are a group of compounds found in kava, a beverage or extract prepared from the rhizome of the kava plant (Piper methysticum) [1]. Kava extracts have been used for many centuries among South Pacific islanders for their anxiolytic and sedative properties [2,3]. These properties are due to kavalactones, which are pyrone-or dihydropyrone-containing components (Fig. 1). ...
... In adversely, other some studies indicated that wati plant might have implications on liver damage for users (Anon. 2002;Anke and Ramzan 2004;Ulbricht et al. 2005;Amorim et al. 2007;Martin et al. 2014;Hussein 2015). ...
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Suharno, Tanjung RHR, Sufaati S, Agustini V. 2016. Wati (Piper methysticum L.) medicinal plant: The ethnobiological and ethnomedicinal values of the Marind tribe in Merauke, Papua, Indonesia. Biodiversitas 17: 814-822. Biological resources around neighborhood play important roles in the cultural development of the surrounding communities, including the use of plants. Wati (kava, Piper methysticum) is one of the species that has long been used as a traditional medicine and cultivated by Marind tribal community in the lowlands of Merauke, Papua. The aim of this study is to examine the use and domestication of wati plant by Marind tribe in Papua.Results of the study showed that wati plant has long been used by the Marind tribal community as a medicinal plant with high customary value. Each customary event includes wati plant as a complementary requirement for legitimate activities by the Marind tribe. It is the importance of customary values that led the domestication of wati plant done since 60 years ago on a small scale to eventually develop into plant called as “the Marind people’s gold”. Results of the observation showed that 93.8% of the Marind people have largely recognized wati plant, while 53.3% of the immigrant communities from outside the area recognized it, but only 33.3% knew about its utilization. Although not all indigenous elders cultivate it, they recognize, utilize, and understand the rules of using wati plant in traditional events and as traditional medicine. As traditional medicine, the parts used by Marind people use root (100.0%), stem (96.6%), and leaves (89.7%). For customary events, the most important parts are the whole plant (100.0%), stem (100.0%), leaves (98.3%) and roots (93.1%). Their children even recognize it and know its benefits, but most of them 31.25% only utilize it but are prohibited from participating in its preparation (0.0%). The domestication of this plant is quite unique because it is closed to the public and is still done by a conventional method.
... Kava, also known as kava kava, 'Awa, or 'awa, is a type of perennial shrub that belongs to the pepper family, known as Piperaceae [1]. Piper methysticum is its botanical name, which derives from the Latin "methysticum". ...
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Kava beverages are typically prepared from the root of Piper methysticum. They have been consumed among Pacific Islanders for centuries. Kava extract preparations were once used as herbal drugs to treat anxiety in Europe. Kava is also marketed as a dietary supplement in the U.S. and is gaining popularity as a recreational drink in Western countries. Recent studies suggest that kava and its key phytochemicals have anti-inflammatory and anticancer effects, in addition to the well-documented neurological benefits. While its beneficial effects are widely recognized, rare hepatotoxicity had been associated with use of certain kava preparations, but there are no validations nor consistent mechanisms. Major challenges lie in the diversity of kava products and the lack of standardization, which has produced an unmet need for quality initiatives. This review aims to provide the scientific community and consumers, as well as regulatory agencies, with a broad overview on kava use and its related research. We first provide a historical background for its different uses and then discuss the current state of the research, including its chemical composition, possible mechanisms of action, and its therapeutic potential in treating inflammatory and neurological conditions, as well as cancer. We then discuss the challenges associated with kava use and research, focusing on the need for the detailed characterization of kava components and associated risks such as its reported hepatotoxicity. Lastly, given its growing popularity in clinical and recreational use, we emphasize the urgent need for quality control and quality assurance of kava products, pharmacokinetics, absorption, distribution, metabolism, excretion, and foundational pharmacology. These are essential in order to inform research into the molecular targets, cellular mechanisms, and creative use of early stage human clinical trials for designer kava modalities to inform and guide the design and execution of future randomized placebo controlled trials to maximize kava's clinical efficacy and to minimize its risks.
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Phytochemical-mediated modulation of P-glycoprotein (P-gp) and other drug transporters may give rise to many herb-drug interactions. Serial plasma concentration-time profiles of the P-gp substrate, digoxin, were used to determine whether supplementation with goldenseal or kava kava modified P-gp activity in vivo. Twenty healthy volunteers were randomly assigned to receive a standardized goldenseal (3210 mg daily) or kava kava (1227 mg daily) supplement for 14 days, followed by a 30-day washout period. Subjects were also randomized to receive rifampin (600 mg daily, 7 days) and clarithromycin (1000 mg daily, 7 days) as positive controls for P-gp induction and inhibition, respectively. Digoxin (Lanoxin, 0.5 mg) was administered p.o. before and at the end of each supplementation and control period. Serial digoxin plasma concentrations were obtained over 24 h and analyzed by chemiluminescent immunoassay. Comparisons of area under the curve (AUC)((0-3)), AUC((0-24)), C(max,) CL/F, and elimination half-life were used to assess the effects of goldenseal, kava kava, rifampin, and clarithromycin on digoxin pharmacokinetics. Rifampin produced significant reductions (p < 0.01) in AUC((0-3)), AUC((0-24)), CL/F, t(1/2), and C(max), whereas clarithromycin increased these parameters significantly (p < 0.01). With the exception of goldenseal's effect on C(max) (14% increase), no statistically significant effects on digoxin pharmacokinetics were observed following supplementation with either goldenseal or kava kava. When compared with rifampin and clarithromycin, supplementation with these specific formulations of goldenseal or kava kava did not appear to affect digoxin pharmacokinetics, suggesting that these supplements are not potent modulators of P-gp in vivo.
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This paper reviews the commonly used botanicals for treatment of mood and anxiety disorders in perimenopausal and postmenopausal women and presents information on their safety and efficacy. The MEDLINE and EMBASE databases were searched for clinical trials related to the use of botanicals for depression, anxiety, and mood disturbances. Papers were excluded if they were in a language other than English, did not include midlife women as study participants, or did not report on changes in mood, depression, or anxiety. Five of seven trials of St. John's wort for mild to moderate depression showed a significant improvement. The one randomized, controlled trial of ginseng in postmenopausal women reported improvements in mood and anxiety. All three randomized, controlled trials of ginkgo found no effect on depression. In four of eight controlled trials, kava significantly reduced anxiety. Black cohosh significantly reduced depression and anxiety in all studies reviewed. St. John's wort and black cohosh appear to be the most useful in alleviating mood and anxiety changes during menopause. Ginseng may be effective, but more research needs to be done. Kava holds promise for decreasing anxiety in peri- and postmenopausal women; however, women should be careful in the amount and duration of use. Finally, ginkgo and valerian do not appear to be useful in reducing depression or anxiety in this population.
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The consumption of medicinal plants has increased in recent decades due to the fact that they biosynthesize compounds with many biological activities; thus, some plant species with biological potential are being utilized as raw material by the industries for preparation of drugs, phytodrugs, or food supplements. This has the consequence of overexploitation and deforestation, which endangers plant species-of-interest. In recent years, alternatives have been sought to eradicate this problem. A solution that was given and is maintained is plant biotechnology, which favors the production of secondary metabolites (SMt) with important biological activity. Plant biotechnology allows us to increase the yield of a compound-of-interest, reduces its production times and costs, and allows constant and controlled production of the raw material, while aiding in the protection of medicinal plants that are found in danger of extinction. In the scientific literature, procuring the SMt by means of biotechnological processes is described, highlighting the study of five species from Mexican traditional medicine (Lopezia racemosa, Galphimia glauca, Cnidoscolus chayamansa, and Buddleja cordata), and the main biological activities are as follows: anti-inflammatory, hepatoprotector, neuroprotector, anxiolytic, antitumoral, antibacterial, and antioxidant, among others. Key points • Secondary metabolites produce by biotechnology processes • Active secondary metabolites isolated from Mexican medicinal plants • Recent advances on the production of some bioactive secondary metabolites
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To report on the design, significance and potential impacts of the first documented human clinical trial assessing the anxiolytic and thymoleptic efficacy of an aqueous mono-extract of Piper methysticum (kava). The significance of the qualitative element of our clinical trial is also explored. The Kava Anxiety Depression Spectrum Study (KADSS) is a 3-week placebo-controlled, double-blind, cross-over trial involving 60 adult participants (18-65) with elevated stable anxiety and varying levels of depressive symptoms. The aims of KADSS are: (1) to determine whether an aqueous standardised extract of kava is effective for the treatment of anxiety; (2) to assess the effects of kava on differing levels of depression; and (3) to explore participants' experience of taking kava via qualitative research. The study also provides preliminary assessment of the safety of an aqueous extract of kava in humans. If results reveal that the aqueous kava preparation exerts significant anxiolytic effects and appears safe, potentially beneficial impacts may occur. Data supporting a safe and effective kava extract may encourage a re-introduction of kava to Europe, UK and Canada. This may provide a major socioeconomic benefit to Pacific Island nations, and to sufferers of anxiety disorders.
Chapter
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Medicinal plants are being utilized as raw material and the use has increased in recent decades due that these biosynthesize compounds with several pharmacological activities. Some plant species with biological potential are of interest to the industry for preparation of drugs, phytodrugs, or food supplements. This causes overexploitation and deforestation, which endangers plant species-of-interest. In recent years, alternatives have been sought to eradicate this problem. A solution that was give and is maintained is plant biotechnology, which favors the production of active Secondary Metabolites (SMt). Plant biotechnology allows us to increase the yield of a compound-of-interest, reduces its production times and costs, and allows constant and controlled production of the raw material, and while aiding in the protection of medicinal plants that are found in danger of extinction. In the scientific literature, procuring the SMt by means of biotechnological processes is described, highlighting the study of four species from Mexican traditional medicine (Lopezia racemosa, Galphimia glauca, Cnidoscolus chayamansa, Sphaeralceae angustifolia and Buddleja cordata), and the main biological activities are as follows: anti-inflammatory, hepatoprotector, neuroprotector, anxiolytic, antitumoral, antibacterial, and antioxidant, among others.
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Kava is known for its recreational, ceremonial and medicinal use in the Pacific. The aqueous non-alcoholic drink of kava rhizome produces intoxicating, relaxing and soothing effects. While kava's medicinal effects receive worldwide recognition, kava-containing products came under scrutiny after over 100 reports of spontaneous adverse hepatic effects. Many mechanisms have been postulated to explain the unexpected toxicity, one being pharmacokinetic interactions between kavalactones and co-administered drugs involving cytochrome P450 enzyme system. Alcohol is often co-injested in kava hepatotoxicity cases. This review evaluates the possible hepatotoxicity mechanisms involving alcohol and kava.
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Anxiety is a very prevalent mental disorder. γ-Aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the mammalian brain and many anxiolytic drugs exert their action through interactions with the GABA receptors. In addition to the GABAergic system, serotonergic, dopaminergic, and noradrenergic systems are also implicated in the development of anxiety and stress in various animal models and humans. Furthermore, involvement of the hypothalamic–pituitary–adrenal axis and dysregulation of the immune system may also mediate stress and anxiety in humans and animals. While a number of anxiolytic drugs are available on the market, dietary supplements and herbal extracts are shown to exert equivalent calming effects with minimal to no addictive or adverse side effects. This chapter describes the pharmacological targets involved in the development of stress and anxiety and the role of various nutraceuticals and dietary supplements that have the potential to reduce anxiety and stress.
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This chapter discusses adverse effects and interactions of treatments used in complementary and alternative medicine. Owing to extensive modifications of drug formulations and chemical extracts from an expanding range of natural products, herbal formulations may contain ingredients that are particularly harmful to individuals with G6PD deficiency. A 73-year-old man developed a cholinergic syndrome, with dizziness, sweating, chills, lacrimation, salivation, rhinorrhea, nausea, and vomiting after taking the Chinese patent medicine “Ting Kung Teng” for arthritis. Severe liver damage has been attributed to Chinese herbal mixtures. Lead contamination has been reported in herbal medicines. Bleeding caused by impaired platelet function has been attributed to garlic. Hepatocellular injury after oral administration of infusions of Breynia officinalis has been described. Ginkgo biloba has well-documented antiplatelet effects, and bleeding complications can occur, including strokes. High doses of Panax ginseng can cause insomnia, headache, diarrhea, and cardiovascular and endocrine disorders. Parkinsonism has been attributed to kava.
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Rare cases of hepatotoxicity emerged with the use of kava drugs and dietary supplements prepared from rhizomes and roots of the South Pacific plant kava (Piper methysticum). Their psychoactive, anxiolytic, relaxing, and recreational ingredients are the kavalactones kavain, dihydrokavain, methysticin, dihydromethysticin, yangonin, and desmethoxyyangonin, but there is little evidence that these kavalactones or the non-kavalactones pipermethystine and flavokavain B are the culprits of the adverse hepatic reactions. It rather appears that poor quality of the kava material was responsible for the liver toxicity. Analysis of existing kava quality standardizations with focus on chemical, agricultural, manufacturing, nutritional, regulatory, and legislation backgrounds showed major shortcomings that could easily explain quality problems. We therefore suggest a uniform, internationally accepted device for kava quality standardizations that are in the interest of the consumers because of safety reasons and will meet the expectations of kava farmers, pharmaceutical manufacturers, regulators of agencies, and legislators. The initial step resides in the establishment of Pan-Pacific kava quality legislation as an important part of the proposed Kava Quality Standardization Code. In conclusion, a sophisticated approach to establish kava quality standardizations is needed for safe human use of kava as relaxing traditional beverages, the anxiolytic drugs, and recreational dietary supplements.
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The objective of this study was to examine the methods used in systematic reviews of safety across a range of complementary therapies to assess the variation in approach and the potential for developing guidance on conduct and reporting. Systematic reviews focusing on safety were retrieved from NHS Evidence and searches of major databases. A pre-prepared template was used for data extraction. Information extracted included details of search strategies, sources, participants, interventions, reported adverse event/effect(s) and causality assessment. Data extraction was carried out by one researcher and a check for accuracy by a second researcher. Methods were assessed against criteria based on guidance provided by the Cochrane Adverse Effects Methods Group. A total of 2563 citations were screened and 88 systematic reviews were selected for inclusion. The majority focused on the safety of herbs and nutritional supplements. Approximately half the reviews covered all aspects of safety; other reviews addressed specific adverse effects or interactions. Types of data included in the reviews did not always reflect the focus of the review. Search strategies, sources used, quality assessment and assessment of causality also varied. Detailed examination and comparison of the methods has highlighted several areas in which there is potential for development of guidelines and consensus on standards. These include search strategies, sources of information, data extraction and assessment of causality. The value of systematic reviews in relation to large outcome studies requires further consideration.
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Kava is a plant with numerous kavapyrones that can induce pharmacologic effects and drug interactions through the cytochrome P450 and P‐glycoprotein systems. Kava is used recreationally and for the treatment of anxiety. Clinical trials verify anxiolytic effects in excess of placebo, but the effects are not seen immediately and the optimal dose and dosing schedule needs to be determined. Clinical trials usually lasting for 4 weeks found generally good tolerability and safety; however, dermatologic, hepatologic, and cognitive adverse effects may occur. Some of these adverse effects are known to occur from the kavapyrones themselves, while others can be caused or exacerbated by use of substandard kava products. There is tremendous variability in the constitution of a kava product based on the parts of the plant that are being extracted and the extraction method. The most commonly studied extract for the treatment of anxiety is the acetone extract.
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Discuss the current regulations concerning the manufacturing and marketing of dietary supplements in the United States. Discuss the prevalence of dietary supplement use. Describe the most common dietary supplements with a potential for having an interaction with a medication based on the current clinical and scientific literature
Chapter
This chapter focuses on the interactions of diet/nutrients with drug transporters arising from in vitro and in vivo studies, with specific emphasis on several major efflux transporters and uptake transporters. Most in vivo interaction studies reported to date are focused primarily on the interactions between dietary supplements and P-glycoprotein (P-gp). Given the facts that multidrug resistance associated protein (MRP) and breast cancer resistance protein (BCRP), organic anion-transporting polypeptide (OATP), and organic anion transporter (OAT) are also essential in drug disposition, it is important to appreciate the potential PK interactions of diet/nutrients with these transporters. The concentrations of many flavonoids required to produce significant modulation on activities of these transporters appear to be, in general, within the micro-molar range, which is achievable in the intestine after intake of food and, especially, after ingestion of dietary supplements.
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Purpose: The aim of this overview of systematic reviews is to summarise and critically evaluate the evidence from systematic reviews of the adulteration and contamination of herbal medicinal products (HMPs). Methods: Five electronic databases were searched to identify all relevant systematic reviews. Results: Twenty-six systematic reviews met our inclusion criteria. The most commonly HMPs were adulterated or contaminated with dust, pollens, insects, rodents, parasites, microbes, fungi, mould, toxins, pesticides, toxic heavy metals and/or prescription drugs. The most severe adverse effects caused by these adulterations were agranulocytosis, meningitis, multi-organ failure, perinatal stroke, arsenic, lead or mercury poisoning, malignancies or carcinomas, hepatic encephalopathy, hepatorenal syndrome, nephrotoxicity, rhabdomyolysis, metabolic acidosis, renal or liver failure, cerebral edema, coma, intracerebral haemorrhage, and death. Adulteration and contamination of HMPs were most commonly noted for traditional Indian and Chinese remedies, respectively. Conclusions: Collectively these data suggest that there are reasons for concerns with regards to the quality of HMPs. Adulteration and contamination of HMPs can cause serious adverse effects. More stringent quality control and its enforcement seem to be necessary to avoid health risks.
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Kava is a neuroactive medicinal herb that can induce pharmacological effects when ingested. As an herbal remedy, kava exhibits sedative, anesthetic, euphoriant, and entheogenic effects. Kava is used as a relaxant, pain reliever, and remedy for anxiety and insomnia. In the United States, kava is marketed as a safe dietary supplement. Kava's popularity is on the rise due to heightened awareness and interest in natural plant-based health alternatives. Although meta-analyses and systematic reviews of kava use in treating anxiety are favorable, results remain inconsistent. Due to poor quality control, diversity of kava products, and lack of standardization, health care professionals, such as nurses, advanced practice nurses, physicians, physician assistants, and pharmacists, need to be familiar with the pharmacology, possible polydrug interactions, and management of kava use as a remedy for anxiety-related conditions. The purpose of the current article is to provide an overview of kava and its use as a remedy for psychological issues, such as anxiety and nervousness. [Journal of Psychosocial Nursing and Mental Health Services, xx(xx), xx-xx.].
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Despite a perception that herbal and dietary supplements (HDS) are safe, devastating liver injury has been reported resulting from their use. The difficulty in characterizing liver injury attributable to HDS stems from the permissive regulatory environment, the complexity of marketed products, and an under reporting by the patients who use them. Despite these limitations, researchers, clinicians, and regulators have increasing awareness of the need for study in this area.
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There is appropriate concern about the potential risk for hepatotoxicity from herbal products because they are unregulated and therefore not standardized with regard to their contents. This is particularly the case for the crude herbals that are commonly formulated as a mixture, so that their ingredients may be ambiguous and even contain harmful contaminants. Presented here is an overview of the more commonly recognized herbal products that have been reported to be associated with liver injury. Although many of them are clearly implicated, there are some, particularly those identified solely through an occasional case report, for which the relationship is uncertain.
Article
The International Conference on Harmonisation considers older people a ‘special population’, as they differ from younger adults in terms of comorbidity, polypharmacy, pharmacokinetics and greater vulnerability to adverse drug reactions (ADRs). Medical practice is often based on single disease guidelines derived from clinical trials that have not included frail older people, or those with multiple morbidities. This presents a challenge caring for older people, as drug doses in trials may not be achievable in real world patients and risks of ADRs are underestimated in clinical trial populations. The majority of ADRs in older people are Type A, potentially avoidable and associated with commonly prescribed medications. Several ADRs are particularly associated with major adverse consequences in the elderly, their reduction is therefore a clinical priority. Falls are strongly associated with benzodiazepines, neuroleptics, antidepressants and antihypertensives. There is good evidence for medication review as part of a multifactorial intervention to reduce falls risk in community dwelling elderly. Multiple medications also contribute to delirium - another multifactorial syndrome resulting in excess mortality particularly in frail older people. Clostridium difficile associated with use of broad spectrum antibiotics mainly affects frail older people and results in prolonged hospital stay with substantial morbidity and mortality. Antipsychotics increase the risk of stroke by more than 3 fold in patients with dementia. Inappropriate prescribing can be reduced by adherence to prescribing guidelines, suitable monitoring and regular medication review. Given the heterogeneity within the older population, providing individualised care is pivotal to preventing ADRs.
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Herbals and dietary supplements (HDS) can cause hepatotoxicity. Regulation of HDS varies across the globe. In the United States, it is defined by a law that is now two decades old. More recent regulatory approaches in Europe still do not require testing for premarket safety. The true incidence of hepatotoxicity from HDS is unknown. The presentation is most often with a hepatocellular enzyme pattern, and the outcomes can be severe, leading to transplantation in some circumstances. The diagnosis of hepatotoxicity due to HDS is made in the same way as for drugs. However, patients often must be coaxed into revealing a history of use. No causality assessment approach is perfectly suited for hepatotoxicity from HDS, but the Roussel Uclaf Causality Assessment Method is most used. Future endeavors must focus on defining epidemiology, establishing an accepted nomenclature, and identifying culprit ingredients, predisposing host factors, and useful biomarkers for injury.
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Background. Herbal preparations are available widely and regarded generally by the public as harmless remedies for a variety of medical ailments. We report a case of acute hepatitis associated with the use of kava kava, derived from the root of the pepper plant, Piper methysticum. It is used in the United States as an antianxiety and sedative agent. Case report. A previously healthy 14-year-old female was admitted to the hospital with hepatic failure. Initial therapy, including plasmapheresis, was unsuccessful and she deteriorated. She ultimately required a liver transplant and now remains well. The liver biopsy showed hepatocellular necrosis consistent with chemical hepatitis. A work-up for alternative causes of liver failure was negative. The patient gave a history of taking a kava kava - containing product for four months. The use of kava kava and liver failure, is supported by kava kava use, a negative work-up for alternative causes of liver failure, and histological changes in the liver. Conclusions. Health care professionals need to be aware of the possibility of kava kava- induced hepatotoxicity. The toxicity of these alternative remedies emphasizes the importance of surveillance programs and quality control in the manufacture of these products. Clinicians must remain aware of the toxic potential of herbal products and always inquire about their intake in cases of unexplained liver injury.
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Anamnese und klinischer Befund: Eine 60-jährige Patientin wurde bei progredienter Abgeschlagenheit, Gewichtsverlust und Ikterus stationär aufgenommen. Die Medikamentenana- mnese ergab eine Behandlung mit Kava-Kava-Präparaten. Alko- holgenuss wurde verneint. Bei beginnendem Leber- und Nieren- versagen und zunehmender Enzephalopathie wurde die Patien- tin intensivbehandlungspflichtig. Untersuchungen: Klinisch-chemisch zeigte sich bei Aufnahme die Konstellation eines akuten Leberversagens mit stark erhöhten Transaminasen- (GOT und GPT initial > 1000 U/l) und Bilirubin- Werten (30 mg/dl) sowie beginnendem Nierenversagen (Kreati- nin 1,5 mg/dl, Harnstoff 45 mg/dl). Virale, metabolisch bedingte oder autoimmune Ursachen des Leberversagens konnten ausge- schlossen werden. Weder in der Abdomensonographie noch im Computertomogramm fanden sich morphologische Leberverän- derungen, insbesondere kein Hinweis auf Pfortaderthrombose, fokale Läsionen der Leber oder extrahepatische Cholestase. Die Leberhistologie ergab den Befund ausgedehnter, teils konfluie- render hepatozellulärer Nekrosen mit intrahepatischer Chole- stase sowie keinen Anhalt für einen zirrhotischen Umbau. Therapie und Verlauf: Bei progredienter Enzephalopathie und intubationspflichtiger respiratorischer Globalinsuffizienz, stei- genden Bilirubin-Werten und sich stark verschlechternder Le- bersyntheseleistung musste eine orthotope Lebertransplantati- on durchgeführt werden. Folgerungen: Auf Grund der vorliegenden Befunde muss von ei- nem kausalen Zusammenhang zwischen fulminantem Leberver- sagen und der Einnahme des Phytotherapeutikums Kava-Kava ausgegangen werden. Inzwischen sind den deutschen und schweizerischen Regulierungsbehörden 18 Patienten mit Leber- schäden durch Kava-Kava angezeigt worden. Fulminant liver failure after administration of the herbal antidepressant Kava-Kava
Article
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This paper, originated as a submission (now updated) to the U.K. Medicines Control Agency and Committee of Safety of Medicines (CSM) on January 11, 2002, in response to a report circu- lated by the German Federal Institute for Drugs and Medical Products (German initials are BfArM), a compilation of which is summarized in Appendix 2. This agency issued notification in late No- vember 2001 of some thirty adverse events associated with the use of concentrated standardized preparations of kava (Piper methysticum, Forst. f.) reported from Germany and Switzerland. An analysis of the summary of the BfArM case reports (see Appendix 2) shows that these contain du- plications among the cases cited. The original submission that was sent to the CSM January 2002 has been updated to the version published here. This new version was completed in April 2002. As a result of the alert from BfArM, the evaluation of kava's safety is now occurring on a worldwide basis and, being that this a matter of considerable importance to the public, the health care community, and regulatory authorities as well as to kava farmers throughout Polynesia, it is it important to depict this progress report. As such, this updated report does not provide fi- nal answers. The material released by the BfArM is lacking in detail; however, it is hoped that this report will shed light on the kava controversy. It is anticipated that there will be further up- dates shortly. This report, prepared on behalf of the Traditional Medicines Evaluation Committee, a subcom- mittee of the European Herbal Practitioners Association, argues that many of the adverse events cited by the BfArM should not be attributed to kava. In addition, the report states that the prop- erties of concentrated standardized kava extracts—as opposed to preparations that closely ap- proximate those created for traditional use—contribute to causing adverse events. This report pro- poses a number of simple measures that will ensure that safe kava preparations may continue to be available in the United Kingdom.
Article
In a controlled, double-blind, randomized, 3-times cross-over clinical study 12 healthy volunteers received single doses of either one tablet Antares 120 (extract of the kava-kava rhizome, standardized on 120 mg kava-pyrones) or one tablet diazepam 10 mg or one tablet 'placebo'. All tests were done immediately before, 2 hours and 6 hours after application of the preparations. The wash-out period between cross-over was seven days. After application of Antares and diazepam the EEG showed an increase of the relative intensities of the slow waves and a decrease of the relative intensity of alpha-waves, which was recorded in the occipital area for both preparations, in the frontal area only for Antares. Maximum effects for diazepam were often recorded two hours after application, however the kava-kava preparation showed the most distinct effects after six hours. The benzodiazepine-specific increase of the beta-activity was not recorded for the kava-kava preparation. During the observation period the placebo group showed a time-dependent decrease of the relative intensity in the zone of the slow delta- and theta-waves and an increase in the zone of the alpha-waves. The marked beta-activity in the diazepam group is the result of frequent significant differences between the two test preparations. In psychophysiological tests the critical flicker frequency was more distinctly reduced by Antares and diazepam than by placebo. Opposite to these results the volunteers showed in the Pauli-test, the simple reaction time test and the complex multiple choice reaction time test with Antares already after 2 hours significantly better results. For diazepam and placebo an improvement of performance could not be proven statistically.
Article
The kava-pyrones kavain and dihydromethysticin are constituents of Piper methysticum which possess muscle relaxant, anticonvulsant, analgesic and anxiolytic properties. In the present study the effect of both kava-pyrones were tested on field potential changes induced by the serotonin-1A agonist ipsapirone in the area CA1 and CA3 of the hippocampal slice preparation of guinea pigs. Ipsapirone induced positive field potential changes which were decreased in amplitude by the serotonin-1A antagonist NAN. The ipsapirone response was reduced by extracellular administration of kavain and dihydromethysticin in a dose-dependent manner down to 22.2 and 33.6%, respectively. It is suggested that kavain and dihydromethysticin modulate serotonin-1A receptor activity which may be of importance in the anti-anxiety action of kava-pyrones.
Article
For kava-kava five controlled clinical trials, four of these placebo-controlled, were published yielding positive results for the phytopharmaceutical. The inclusion criteria were insufficiently operationalized, like 'anxiety' of non-psychotic origin'. For rac.-kavain, a synthetical product, more placebo-controlled trials with a positive result are available so that the efficacy is more proved than for kava-kava. Again, the inclusion criteria are mostly insufficient. For both compound-classes a favourable side effect profile seems to exist. Therefore, there might be a place for them in the treatment of mild anxiety syndromes. Further trials with exactly defined inclusion criteria according to DSM-IV or ICD-10 (like Generalized Anxiety Disorders or Somatoform Disorders) are urgently required.
Article
BACKGROUND: Synthetic anxiolytic drugs are effective for anxiety, but they are burdened with adverse events. Constraints on resources and time often render treatments such as psychological interventions impracticable. Thus, an effective and safe oral medication would be of considerable interest and a welcome addition to the therapeutic repertoire. OBJECTIVES: To systematically review the evidence regarding the efficacy and safety of kava extract for the symptomatic treatment of anxiety. SEARCH STRATEGY: Computerized literature searches were performed in the databases Medline, Embase, Biosis, AMED, CISCOM and the Cochrane Library (all from their respective inception to June 1998). The search terms used were kava, kawa, kavain, Piper methysticum and Rauschpfeffer (German common name for Piper methysticum). Manufacturers of kava preparations and experts on the subject were contacted and asked to contribute published and unpublished material. In addition, our own files were searched and the bibliographies of all of the studies identified were scanned for further trials. There were no restrictions regarding the language of publication. SELECTION CRITERIA: Randomized, double-blind trials of oral kava extract mono-preparations for the treatment of anxiety were included. Trials comparing kava with placebo were included. Trials assessing kava as one of several active constituents in a combination preparation or as a part of a combination treatment were excluded. DATA COLLECTION AND ANALYSIS: All publications were blinded prior to assessment by a person not involved in the study. Data on patients, interventions, methods, results and adverse events were extracted systematically. Methodological quality of all trials was evaluated using the scoring system developed by Jadad and colleagues. The screening of studies, selection, data extraction and the assessment of methodological quality were performed independently by the two reviewers. Disagreements in the evaluation of individual trials were resolved through discussion. MAIN RESULTS: Seven trials met the inclusion criteria. All of the reviewed trials suggest superiority of kava extract over placebo. The meta-analysis of three studies using the Hamilton Anxiety Score as a common outcome measure suggests a significant differential treatment effect in favour of kava extract (weighted mean difference: 9.69, 95% confidence interval: 3.54 - 15.83). Adverse events as reported in the reviewed trials were mild, transient and infrequent. REVIEWER'S CONCLUSIONS: These data imply that kava extract is superior to placebo and relatively safe as a symptomatic treatment for anxiety. These findings warrant further and more rigorous investigations into the efficacy and safety of kava extract.
Article
The herb kava has recently been associated with numerous drug interactions, but its interaction with cytochrome P450 (P450) enzymes has not been investigated. In the present work the inhibition of P450 enzymes by kava extract and individual kavalactones in human liver microsomes (HLMs) was investigated. Whole kava extract (normalized to 100 μM total kavalactones) caused concentration-dependent decreases in P450 activities, with significant inhibition of the activities of CYP1A2 (56% inhibition), 2C9 (92%), 2C19 (86%), 2D6 (73%), 3A4 (78%), and 4A9/11 (65%) following preincubation for 15 min with HLMs and NADPH; CYP2A6, 2C8, and 2E1 activities were unaffected. The activities of CYP2C9, 2C19, 2D6, and 3A4 were also measured after incubation of HLMs with the major kavalactones kawain (K), desmethoxyyangonin (DMY), methysticin (M), dihydromethysticin (DHM) (each at 10 μM), and NADPH. Whereas K did not inhibit these enzymes, there was significant inhibition of CYP2C9 by DMY (42%), M (58%), and DHM (69%); of 2C19 by DHM (76%); of 2D6 by M (44%); and of 3A4 by DMY (40%), M (27%), and DHM (54%). Consistent with their potency as inhibitors, the two major kavalactones bearing a methylenedioxyphenyl moiety (M and DHM) formed “455 nm” metabolic intermediate complexes after incubation with HLMs and NADPH, but K and DMY did not. These data indicate that kava has a high potential for causing drug interactions through inhibition of P450 enzymes responsible for the majority of the metabolism of pharmaceutical agents.
Article
The amounts of kawa pyrones (e.g. I and II) in ether extracts of Piper methysticum were determined using two-dimensional thin-layer chromatography on aluminium oxide. The concentrations of desmethoxyyangonin, yangonin, dihydromethysticin, methysticin, dihydrokawain, and kawain were determined by u.v. spectroscopy after elution of the spots with methanol. Recoveries of known compounds were 80–85 per cent for yangonin and 90–95 per cent for all others.
Article
The kava lactone compositions of the leaves, stems and roots of Piper methysticum from Fiji were markedly different but no differences were found between two cultivars. The leaves also contain the alkaloid pipermethystine as a major component.
Article
Aqueous extracts of Piper methysticum Forst, were tested for pharmacological activity. The roots of this plant have been used by the natives of many of the islands of the South Pacific in a beverage known as Kava to allay anxiety and reduce fatigue. The extracts were shown to have a depressant action on the central nervous system, evidenced by depression of spontaneous motor activity, marked reduction in irritability of rats having bilateral septal lesions, inhibition of the conditioned avoidance response in rats, and blockade of EEG arousal patterns in cats.
Article
Anamnese und klinischer Befund: Wegen eines »neuerlichen Schubes einer ätiologisch ungeklärten akuten Hepatitis« wurden zwei Patientinnen im Alter von 39 und 42 Jahren aufgenommen. In der Vorgeschichte beider Patientinnen war vor Monaten erstmals eine akute Hepatitis mit maximalen GPT-Konzentrationen von 796 bzw. 755 U/I aufgetreten. Die Medikamentenanamnese ergab eine jedem Hepatitisschub vorausgehende Einnahme eines pflanzlichen Heilmittels (Kavapyrone bzw. Schöllkraut). Die klinische Untersuchung war bei beiden Patientinnen unauffällig. Untersuchungen: Die Maximalwerte der GPT lagen bei 422 bzw. 350 U/I. Virale, autoimmune oder metabolisch bedingte Ursachen der Hepatitis konnten ausgeschlossen werden, histologisch fand sich jeweils das Bild einer akuten nekrotisierenden Hepatitis. Diagnose, Therapie und Verlauf: Unter dem dringenden Verdacht einer medikamentös-toxischen Hepatitis kam es nach Absetzen der Phytopharmaka zu einer spontanen Normalisierung der Leberwerte. Folgerung: In beiden Fällen muß, auch angesichts der Folgen der Re-Exposition, von einem kausalen Zusammenhang zwischen der Einnahme der pflanzlichen Präparate und dem Auftreten der akuten Hepatitis ausgegangen werden.
Article
A procedure is described for the quantitative determination of seven known major constituents in sun-dried roots, rhizomes and commercially powdered samples of Piper methysticum. A 3.0–8.0-g amount of powdered sample is extracted with chloroform in a Soxhlet apparatus for 6 h. After evaporation of solvent the extract (about 0.35 g) is dried at 100 °C for 2 h and then dissolved in chloroform to about 0.7%m/V concentration. The resulting solution is analysed by gas-liquid chromatography using dual 1.5 m × 4 mm i.d. glass columns, containing 3%m/m of OV-1 on Chromosorb W HP, and dual differential flame-ionisation detectors with nitrogen as carrier gas, the column temperature being 210 °C. There is no interference from the eight other trace constituents, non-polar low-boiling compounds or polar “tarry” material.
Article
Volunteer subjects were assigned to receive a mixture of the intoxicating substance, kava, in a mixture with fruit juice, or juice alone. Subjects then undertook tasks of acute cognitive functioning, including reaction time and tracking tasks, and a measure of body sway. Heart rate, respiration rate, blood pressure were recorded and subjects were asked to rate their degree of intoxication and complete a stress/arousal check list. Subjects receiving kava reported feelings of intoxication which peaked approximately one hour after kava ingestion. Compared to the group receiving juice alone, the group receiving kava also had increased body sway. There were no other statistically significant differences between groups, although the mean cognitive performance of the group receiving kava was generally poorer.
Article
In a double-blind, placebo-controlled study the encephalotropic and psychotropic effects of kavain-a synthetic kava plant derivative as compared with clobazam were investigated, utilizing EEG brain mapping, psychometric and psychopysiological analyses. 15 normal volunteers received randomized in weekly intervals single oral doses of placebo, 200 mg, 400 mg and 600 mg kavain as well as 30 mg clobazam as reference compound. EEG recordings, psychometric tests, evaluations of pulse, blood pressure and side effects were carried out at the hours 0, 1, 2, 4, 6 and 8. Brain maps of drug induced pharmaco-EEG changes (pharmaco-EEG maps) demonstrated that kavain exerted a significant action on the human brain function as compared with placebo characterized by a dose-dependent increase of delta, theta and alpha 1 activity while alpha 2, beta activity and the centroid of the total activity decreased. These findings are indicative of a sedative effect which was, however, in type quite different from that of the 1·5 benzodiazepine. The latter produced a decrease of delta, theta, alpha 1 and alpha 2 and an increase of beta activity while the total centroid was accelerated. Interestingly, 200 mg kavain induced with a decrease of delta and beta activity and an increase of alpha activity and of total power also vigilance promoting effects. Psychometric investigations demonstrated also clear differences between the two compounds at the behavioural level. Kavain improved the noopsyche as compared with placebo in all 3 doses as there was a significant improvement in intellectual performance (Pauli test), attention, concentration, reaction time and motor speed (rigidity test), while opposite findings were observed after 30 mg clobazam. In regard to thymopsychic variables such as drive, wakefulness, affectivity, mood, well-being, 200 mg kavain produced an improvement as compared with placebo while 600 mg kavain produced sedation as did 30 mg clobazam. Psychophysiological evaluations resulted in only minimal findings. Time efficacy calculations demonstrated after kavain a pharmacodynamic peak in the 1st to the 2nd hour then a drop and a second peak in the 8th hour while clobazam produced maximal central effects in the 1st hour which declined thereafter to show a second peak in the 6th hour. Topographically, most encephalotropic effects were found after kavain in the frontal, after clobazam in the central and parietal areas. Evaluations of pulse, blood pressure and side effect demonstrated good tolerability of both compounds with 30 mg clobazam producing more sedation than kavain.
Article
Methane chemical ionization mass spectrometry has been used to investigate the components of kava resin prepared by solvent extraction of commercial Piper methysticum Forst. All the known constitutents of this resin were identified together with several new compounds which of formally result from decarboxylation of the 4-methoxy-2-pyrone ring system in the known compounds. Chemical ionization mass spectrometry is a useful probe for the identification of these compounds because all gave easily recognized protonated molecular ions and the fragmentation patterns were related to molecular structure. Using this technique, the steam distillation products of commercial P. methysticum were identified, as was the product distribution from base hydrolysis of the known kava pyrone, yangonin.
Article
Electron impact (EI) and methane negative ion chemical ionization (NICI) gas chromatographic/mass spectrometric analyses of kava resin, derived from commercial Piper methysticum, are described. The resulting mass spectra are correlated with the known major and trace constituents of this resin. Several of the kava lactones (kawain, methysticin, desmethoxyyangonin and yangonin) produced abundant molecular anions when analysed by methane NICI mass spectrometry, in contrast to their 7,8-dihydro analogues which ionized with poor efficiency to yield weak [M − H]− anions. Deuterium labelling established that the origin of the [M − CH3]− anion in the methane NICI mass spectrum of yangonin resulted from the elimination of a methyl radical from the 4-methoxyl substituent. As a result of the present study, an additional four trace components of kava have been identified.
Article
The increasing promotion of herbal drugs may lead to allergic problems. A case of systemic contact-type dermatitis after oral administration of kava extract illustrates this special problem. The kava plant is a member of the black pepper family; an intoxicant beverage prepared from the roots of this plant is used ceremonially by many traditional societies of the Southern Pacific. The beverage induces relaxation, enhances a sense of sociability and promotes sleep. These effects are utilized in herbal drugs containing kava, which are sold for insomnia, nervousness and depression. The ichthyosiform kava dermopathy is a well-known side effect of excessive use of kava; in this case report we describe an acute allergic side-effect of kava extract.
Article
The kava lactones from different plant parts of piper methysticum have been examined using normal and reversed-phase high-performance liquid chromatography. An unexpected photoisomerisation of yangonin in the mobile phase occurred during sample preparation which complicated the analysis.
Article
Kava, an intoxicating beverage prepared from the pepper plant Piper methysticum, is widely consumed by the indigenous peoples in the islands of the South Pacific. As the first of a series of studies on the neuropharmacological interactions of kava with CNS receptors we tested purified pyrones and kava resin for activity on GABA and benzodiazepine binding sites in rat and mouse brain membranes. Only weak activity was observed on GABAA binding sites in washed synaptosomal membranes prepared from rat brain and this was abolished by extraction of the membranes with Triton X-100, suggesting that lipid soluble components were involved. No effects were observed on GABAB binding sites in rat brain membranes in vitro. Kava resin and pyrones exerted some weak effects on benzodiazepine binding in vitro but this did not correlate with pharmacological activity. In addition, in ex vivo studies, no effects were observed on [3H]diazepam binding to brain membranes prepared from mice in which selected kava constituents were injected intraperitoneally, whereas similarly administered diazepam (5 mg/kg) inhibited [3H]diazepam binding by greater than 95%. Similar lack of activity was observed in in vivo binding studies; injection of kava resin failed to influence the CNS binding of the benzodiazepine-receptor ligand [3H]Ro15-1788 injected into mice prior to sacrifice. The pharmacological activities of kava resin and pyrones do not appear to be explained by any significant interaction with GABA or benzodiazepine binding sites.
Article
The purpose of the present study was to test whether kava extract and its constituents kawain, dihydrokawain, methysticin, dihydromethysticin and yangonin provide protection against ischemic brain damage. To this end, we used a model of focal cerebral ischemia in mice and rats. Ischemia was induced by microbipolar coagulation of the left middle cerebral artery (MCA). To quantify the size of the lesion in mice, the area of the infarct on the brain surface was assessed planimetrically 48 h after MCA occlusion by transcardial perfusion of carbon black. In the rat model infarct volume was determined 48 h after MCA occlusion by planimetric analysis and subsequent integration of the infarct areas on serial coronal slices. Compounds were administered i.p., except the kava extract, which was administered orally. The effects of the kava extract and its constituents were compared with those produced by the typical anticonvulsant, memantine. The kava extract, methysticin and dihydromethysticin produced effects similar to those of the reference substance memantine. The kava extract (150 mg/kg, 1 h before ischemia) diminished the infarct area (P less than 0.05) in mouse brains and the infarct volume (P less than 0.05) in rat brains. Methysticin, dihydromethysticin (both 10 and 30 mg/kg, 15 min before ischemia) and memantine (20 mg/kg, 30 min before ischemia) significantly reduced the infarct area in mouse brains. All other compounds failed to produce a beneficial effect on the infarct area in mouse brains. In conclusion, the kava extract exhibited neuroprotective activity, which was probably mediated by its constituents methysticin and dihydromethysticin.
Article
Since the first significant contact with Europeans in the 18th century, the Oceanic plant, Piper methysticum Forst. (Piperaceae) and the beverage prepared from it, both of which are called kava, have become familiar to much of the outside world through both the written and visual media. The ceremonial preparation and consumption of the beverage are probably its most conspicuous and spectacular features. Kava continues to occupy a central place in everyday life in the islands concerned, although its role has been somewhat diminished by time and outside influences. Despite the large body of literature on kava--about 800 entries are listed in a recent bibliography by Singh (1986)--there has been no comprehensive review on the subject. Earlier contributions by Keller and Klohs (1963) and Shulgin (1973) were selective in treatment and dealt primarily with chemical and pharmacological aspects. The monograph by Steinmetz (1960) remains a standard reference but understandably some of the information in it has become dated. The attention of the reader is also drawn to two excellent additions to the recent kava literature, by Lebot and Cabalion (1988) and Brunton (1989), which are, although somewhat restricted in focus, are very significant contributions to the subject. The present review paper provides an updated and a multidisciplinary overview of the subject. It was prepared on the basis of the author's personal experience--he is a native of Fiji and lived in that country for about 30 years--as well as the relevant literature listed in the Singh (1986) bibliography and some more recent publications.
Article
To investigate neurophysiological effects of D,L-kavain, two studies were conducted on unrestrained cats with chronically implanted electrodes. In group A animals (n = 26) we recorded the blood pressure, the EEG of cortical and subcortical areas, the electromyogram, EEG arousal reactions, and subcortical evoked potentials elicited by central stimulation. This was done before and after injection of D,L-kavain (10-50 mg/kg i.p.) or--for comparison--of a kava extract in Ol. arachidis (50-100 mg pyrones/kg i.p.). Group B cats (n = 9) served for polygraphic, 10-h analyses of the sleep-wakefulness rhythm; they received--in a random sequence--0.9% NaCl (3 ml i.p.), D,L-kavain (28 mg/kg p.o.), pentobarbital (1 mg/kg i.m.), or the combination D,L-kavain plus pentobarbital. With both D,L-kavain and the extract, muscle tone was seen to be diminished in about 50% of the experiments. It was only the extract which exerted marked effects on the EEG; it induced high amplitude delta waves, spindle-like formations, and a continuous alpha- or beta-synchronization in the amygdalar recordings (p less than 0.001). Neither D,L-kavain nor the kava extract changed the threshold of the EEG arousal reaction. As to the evoked potentials, the hippocampal response following stimulation of the amygdalar nucleus showed an increase in amplitude in the animals given D,L-kavain (50 mg/kg; p less than 0.05) and in those given the extract (100 mg pyrones/kg; p less than 0.01). In addition, after injection of the extract, further projections arising from the amygdala as well as the connection from the caudate nucleus to the amygdala proved to be activated. The percentage duration of active wakefulness was significantly shortened by both D,L-kavain and pentobarbital, as compared to placebo. There was a likewise significant prolongation of synchronized sleep with D,L-kavain, pentobarbital, and the combination of both these agents. However, a potentiation of drug effects failed to occur. It is concluded from the findings that limbic structures and, in particular, the amygdalar complex represent the preferential site of action for both D,L-kavain and the kava extract. The participation of these structures in modulating emotional processes may explain the promotion of sleep, even in the absence of sedation. There is no congruity of D,L-kavain with either the tricyclic thymoleptics or the benzodiazepines regarding the profile of neurophysiological effects.
Article
1. The development of tolerance to the aqueous extract of kava, and to the lipid soluble extract (kava resin) was tested in mice. 2. Tolerance to the unknown pharmacologically active ingredient(s) developed very rapidly, given parenterally, in the aqueous extract. A minimally effective daily dose (50 mg/kg) of the aqueous extract for 3 days was sufficient to produce tolerance to a test dose of 150 mg/kg, which is close to the ED50. As tolerance was evident at the first test period it can be assumed to be physiological tolerance. 3. Kava resin decreased spontaneous motility and caused a loss of muscle control. A minimally effective daily dose of kava resin (100 mg/kg) did not produce tolerance to the above effects of a weekly test dose of kava resin (166 mg/kg) within 7 weeks. In a further experiment the dose was raised to 150 mg/kg twice daily and this schedule caused partial tolerance to occur within 3 weeks, but very little further tolerance developed over the ensuing 2-week period. 4. To try to induce learned (behaviourally acquired) tolerance a dose of 166 mg/kg kava resin was injected daily and animals were tested each day while under the influence of the drug. However, even under these conditions, there was no tolerance evident within 3 weeks, when the experiment was terminated. 5. It appears difficult to induce the development of physiological or learned tolerance to kava resin in mice.
Article
Clinical Efficacy of a Kava Extract in Patients with Anxiety Syndrome/Double-blind placebo controlled study over 4 weeks. In a randomized, placebo-controlled double-blind study two groups each containing 29 patients with anxiety syndrome not caused by psychotic disorders were treated for a period of 4 weeks with kava extract WS 1490 (Laitan) 3 x 100 mg/day or a placebo preparation. Therapeutic efficacy was assessed by the Hamilton-Anxiety-Scale (main target variable), the Adjectives-List and the Clinical-Global-Impression-Scale (secondary target variables) after 1, 2 and 4 weeks of treatment. The HAMA overall score of anxiety symptomatology revealed a significant reduction in the drug receiving group already after one week of treatment. This difference between the two groups of patients increased in the course of the study. The results of the secondary target variables were in agreement with the HAMA-score and demonstrate the efficacy of WS 1490 in patients with anxiety disorders. No adverse experiences caused by the medication were noted during the 4 week administration of WS 1490.
Article
Heavy chronic consumption of kava (Piper methysticum) is associated with a pellagroid dermopathy that has been attributed to niacin deficiency. Over 200 male kava drinkers in the Tonga Islands were interviewed and examined regarding the characteristic skin changes. A scaly rash suggestive of ichthyosis and eye irritation were present in some heavy kava drinkers. 29 kava drinkers with prominent skin changes were randomised to receive either 100 mg oral nicotinamide or placebo daily for three weeks. Skin examinations and photographs showed clinical improvement in 5/15 of the nicotinamide group and 5/14 of the placebo group. These data, along with history and physical examination findings, suggest that niacin deficiency is not responsible for the rash, which is more characteristic of an acquired ichthyosis.
Article
Within the framework of a randomized, placebo-controlled double-blind study, two groups each containing 20 patients with climacteric-related symptomatology were treated for a period of 8 weeks with kava WS 1490 extract 3 X 100 mg/day or a placebo preparation. The target variable - the HAMA overall score of anxiety symptomatology - revealed a significant difference in the drug-receiving group vis-à-vis the placebo group already after only 1 week of treatment. The course of such further parameters as depressive mood (DSI), subjective well-being (patient diary), severity of the disease (CGI), and the climacteric symptomatology (Kuppermann Index and Schneider scale) over the overall period of treatment demonstrate a high level of efficacy of kava extract WS 1490 in neurovegetative and psychosomatic dysfunctions in the climacteric, associated with very good tolerance of the preparation.
Article
1. The lipid soluble extract of the psychoactive beverage kava has hypnosedative properties which can be measured by the length of time that the righting reflex is lost. 2. Ethanol and the lipid soluble extract (kava resin) have been shown greatly to increase each others hypnotic action in mice. Ethanol also increases the toxicity of kava markedly. 3. This interaction of kava and alcohol has important clinical and social consequences since, in contrast to traditional usage, kava is now often taken in conjunction with alcoholic drinks.
Article
1. The antinociceptive properties of the aqueous extract of the intoxicating beverage kava, and of the lipid soluble extract (kava resin) were tested in mice, by the tail immersion and abdominal constriction methods. Both extracts showed analgesic effects in both tests. 2. Eight purified pyrones from the lipid soluble extract were also tested for activity in the tail immersion test, and kawain, dihydrokawain, methysticin and dihydromethysticin were found to be very effective in producing analgesia. Using the tail immersion test the time course of action of the extracts of the four effective pyrones of kava were studied. 3. Naloxone, in doses which inhibited morphine-induced analgesia in both tests, was completely ineffective in reversing the antinociceptive activities of the kava extracts, showing that analgesia produced by kava occurs via non-opiate pathways.
Article
The aqueous, pyrone-free extract from kava (Piper methysticum) and the lipid-soluble extract (kava resin) were tested for their effect on amphetamine-induced hypermotility in mice and on conditioned avoidance response behavior in rats in a shelf-jump apparatus. Both kava extracts reduced amphetamine-induced hypermotility. Aqueous kava extract in i.p. doses of 30 mg/kg to 500 mg/kg had no effect on conditioned avoidance responses. At or below 100 mg/kg i.p. kava resin also failed to modify the number of conditioned avoidance responses obtained. However, 125 mg/kg of resin significantly reduced the number of conditioned avoidance responses by 18%. Increasing the dose of kava to 150 mg/kg caused ataxia and sedation which was so marked that a modified protocol was necessary. Only a marginally greater effect on conditioned avoidance response was obtained under these conditions. The effect of kava extract was slight compared to that of the standard antipsychotic drugs chlorpromazine and haloperidol in our procedure.
Article
The central nervous activity of the aqueous extract of kava was examined in mice, and compared to the effect of the lipid-soluble extract. The aqueous extract caused a loss of spontaneous activity without loss of muscle tone. No hypnotic effect was seen, but some analgesia was produced. The anticonvulsant effect against strychnine was very slight and there was no evidence of local anesthetic action. There was a slight anti-apomorphine effect and tetrabenazine-induced ptosis was decreased. The lipid-soluble extract (kava resin) also decreased spontaneous motility, together with a marked reduction of motor control. Hypnosis, determined by loss of righting reflex, was produced, analgesia was marked, and a local anesthetic action evident. Kava resin also decreased apomorphine-induced hyperreactivity and partially reversed tetrabenazine-induced ptosis. Kava resin produces a greater range of pharmacological actions than the aqueous extract, and the latter is orally inactive in mice and rats. The pharmacological effects of kava ingestion appear to be due to the activity of the compounds present in the lipid-soluble fraction.
Article
Methane chemical ionization (CI) gas chromatography-mass spectrometry (GC-MS) has been used to identify some of the human urinary metabolites of the kava lactones following ingestion of kava prepared by the traditional method of aqueous extraction of Piper methysticum. All seven major, and several minor, kava lactones were identified in human urine. Observed metabolic transformations include the reduction of the 3,4-double bond and/or demethylation of the 4-methoxyl group of the alpha-pyrone ring system. Demethylation of the 12-methoxy substituent in yangonin (or alternatively hydroxylation at C-12 of desmethoxyyangonin) was also recognised. This product was isolated by high-performance liquid chromatographic analysis of crude urine extracts and characterised by methane CI GC-MS. In contrast to the situation prevailing in the rat no dihydroxylated metabolites of the kava lactones, or products from ring opening of the 2-pyrone ring system, were identified in human urine. GC-MS analysis of urine can be readily utilised to determine whether donors have recently consumed kava.
Article
Health status was assessed in 39 kava users and 34 non-users in a coastal Aboriginal community in Arnhem Land. Twenty (27%) respondents were very heavy (mean consumption, 440 g/week) users of kava; 15 (21%) respondents were heavy (310 g/week) users of kava and four (5%) respondents were occasional (100 g/week) users of kava. Kava users were more likely to complain of poor health and a "puffy" face, and were more likely to have a typical scaly rash, and slightly-increased patellar reflexes. Very heavy users of kava were 20% underweight and their levels of gamma-glutamyl transferase were increased greatly. Albumin, plasma protein, urea and bilirubin levels were decreased in kava users, and high-density lipoprotein cholesterol levels were increased. Kava users were more likely to show haematuria, and to have urine which was poorly acidified and of low specific gravity. The use of kava was also associated with an increased red-cell volume, with a decreased platelet volume and with a decreased lymphocyte count. Shortness of breath in kava users was associated with tall P waves on a resting electrocardiogram, which provided suggestive evidence of pulmonary hypertension. In common with other Aboriginal communities, there was evidence of decreased lung volumes, a high carriage rate of hepatitis B surface antigen, and of other morbidity that was unrelated to the use of kava. On the basis of these findings, there is a strong rationale for urgent social action to improve health in Aboriginal communities and, in particular, to reduce the consumption of kava and to improve the nutritional status of kava users.
Article
The kava bowl, a traditional feature of Pacific Island societies, has been adopted and adapted by a number of Aboriginal (Yolngu) communities of northern Australia, where it was introduced in the hope that it would challenge alcohol. This paper reports a study of its usage at Elcho Island, Northern Territory. At the high level of intake in this community, medical effects hitherto unreported are being observed. Some, such as a condition of detachment, reminiscent of the archetypal 'blissful indolence' of the lotus-eaters of Greek tradition as limned by the poet Homer, are obvious to the lay observer. Other effects are apparently advantageous for the management of alcohol abuse and some forms of psychosis. A surprising effect is the occurrence of a pellagrinous reaction. These observations indicate that further studies of the clinical effects and the human metabolism of high dosage kava are needed. Looming over all are questions of pharmacology. Do the kava pyrones possess anxiolytic or antipsychotic properties? Do they indeed have the property for which Pacific missionaries introduced them to Australia, as an alternative to alcoholism?
Article
Kava is a drink produced from the plant Piper methysticum and used as a social and ceremonial beverage on many South Pacific islands. Visual functions were measured in one subject following the taking of this drink. A reduced near point of accommodation and convergence, an increase in pupil diameter and disturbance to the oculomotor balance were noted. No changes were recorded in visual or stereoacuity or in ocular refractive error.
Article
Zusammenfassung Aus dem Kawa-Rhizom isolierte Pyronverbindungen erwiesen sich in Versuchen an Mäusen als stark wirksame Antagonisten der tödlichen Strychninvergiftung.