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German Kava Ban Lifted by Court: The Alleged Hepatotoxicity of Kava (Piper methysticum) as a Case of Ill-Defined Herbal Drug Identity, Lacking Quality Control, and Misguided Regulatory Politics
Abstract
Kava, the rhizome and roots of Piper methysticum, are one of the most important social pillars of Melanesian societies. They have been used for more than 1000 years in social gatherings for the preparation of beverages with relaxing effects. During the colonial period, extract preparations found their way into Western medicinal systems, with experience especially concerning the treatment of situational anxiety dating back more than 100 years. It therefore came as a surprise when the safety of kava was suddenly questioned based on the observation of a series of case reports of liver toxicity in 1999 and 2000. These case reports ultimately led to a ban of kava products in Europe - a ban that has been contested because of the poor evidence of risks related to kava. Only recently, two German administrative courts decided that the decision of the regulatory authority to ban kava as a measure to ensure consumer safety was inappropriate and even associated with an increased risk due to the higher risk inherent to the therapeutic alternatives. This ruling can be considered as final for at least the German market, as no further appeal has been pursued by the regulatory authorities. However, in order to prevent further misunderstandings, especially in other markets, the current situation calls for a comprehensive presentation of the cardinal facts and misconceptions concerning kava and related drug quality issues.
... Using the Roussel Uclaf Causality Assessment Method (RUCAM) recommended by expert consensus for the assessment of herb-induced liver injury (HILI) [16], there were only two cases with a probable causality by kava, and six cases where there were indications for a participation of or a causality by co-medication [15]. The court rulings of 2014 and 2015 confirmed that the very low incidence rate did not justify a general ban of medicinal products containing preparations of noble kava [17,18]. Questions of deviating quality, or of differences in the extraction solvent had not been taken into account in the ban [7,19]. ...
... After a lengthy debate following the kava ban, two German court rulings in 2014 and 2015 ascertained a positive benefit-torisk ratio for medically used kava preparations when used as recommended [17,18]. Thereafter, the debate shifted to a new field. ...
... Until the initiation of the German drug safety protocol in 2001, kava was always considered a very safe treatment option [23]. Adverse liver effects were unknown, despite the extensive use of kava preparations, which points to a potential change in quality of certain kava products [18,19]. The safety and the anxiolytic effects of the specific study preparation has been examined in an observational study [24], and in a clinical double-blind trial [25]. ...
Aim Prior to the kava ban of 2002, the indication for kava (Piper methysticum) extracts defined by the German Commission E was “nervous anxiety, tension and restlessness”. In 2000, an observational trial was started in Germany with the aim of defining symptoms of these indications best treated with kava extract. The trial was interrupted and archived “unevaluated” in 2001 due to the upcoming safety debate on kava. The data from this study has now been analyzed in order to identify symptoms best treated with kava.
Methods Documentation was available from 156 patients. Twelve typical symptoms of nervous anxiety, tension and restlessness were assessed on a five-item rating scale, together with the therapeutic context, the perceived time of onset of effects and the safety of application.
Results The median duration of treatment was 28 days. All individual symptoms showed significant and clinically relevant improvements. The most effective results were seen for nervous tension and restlessness, with better effects in patients with acute versus chronic complaints. The safety of the treatment was found to be excellent, which included the assessment of laboratory data.
Conclusions Overall, the study confirms the effective and safe short-term use of kava in the Commission E-defined indication of “nervous anxiety, tension and restlessness”, especially in other than chronic cases. The clinical use of kava might be translated into context-related phobias according to ICD-10 F40, or to nervous tension (ICD10 R45.0) or restlessness and excitation (ICD-10 R45.1).
... Due to the potential risk of hepatotoxicity from these products, Germany banned kava's clinical anxiolytic use in 2002. Although the ban was lifted in 2014 [27], more clinical data are required before its reentry as a clinical anxiolytic agent. ...
... Hepatotoxic risk has become a central topic since the early 2000s, due to a number of hepatotoxicity cases reported in Western countries [35,[155][156][157][158][159][160][161][162][163][164][165]. These adverse events led to a ban on kava use as an herbal anxiolytic drug in Germany between 2002 and 2014 [27]. The U.S. Food and Drug Administration (FDA) also issued an advisory in March 2002. ...
... Thus, there is an unmet clinical need for novel anxiolytics to achieve better anxiety management with minimal adverse effects [177]. Given its relaxing properties and questionable hepatotoxic risk, kava may reemerge as an anxiolytic drug in the future, which is further supported by the recent ruling in the German court [27]. It is therefore important to review the hepatotoxic cases associated with kava's anxiolytic use, particularly those cases that might have a potential causal relationship. ...
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.
... Kava has been banned in some countries due to hepatotoxicity cases in the beginning of 2000s (White, 2018). Consequently, some bans have been lifted due to the lack of results obtained by most recent Good Clinical Practice (GCP) standards (Kuchta et al., 2015). Nevertheless, the US Food and Drug Administration has issued a consumer advisory warning of the potential for liver injury (FDA, 2002) while some countries have regulated kava marketing due to hepatotoxicity reports. ...
... Several theories have been proposed for kava hepatotoxicity over the years. These theories were summarized in various papers in the literature (Anke and Ramzan, 2004a;Clouatre, 2004;Fu et al., 2008;Zhang et al., 2011;Olsen et al., 2011;Kuchta et al., 2015). However, some of them have been debated (Teschke et al., 2013). ...
... The hepatotoxicity of kava is thought to be related to CYP2D6 deficiency in some patients, pointing out genetic polymorphism possibility (Russmann et al., 2001;FAO and WHO, 2016). However, the deficiency of CYP2D6 in 7-9% of Caucasians fails to support this theory since the proportion of hepatotoxicity cases among Kava users is much less (Kuchta et al., 2015). On the other hand, CYP2C19 is one of the metabolizers of kavain (Wang et al., 2019). ...
Herbal products as supplements and therapeutic intervention have been used for centuries. However, their toxicities are not completely evaluated and the mechanisms are not clearly understood. Dried rhizome of the plant kava (Piper methysticum) is used for its anxiolytic, and sedative effects. The drug is also known for its hepatotoxicity potential. Major constituents of the plant were identified as kavalactones, alkaloids and chalcones in previous studies. Kava hepatotoxicity mechanism and the constituent that causes the toxicity have been debated for decades. In this paper, we illustrated the use of computational tools for the hepatotoxicity of kava constituents. The proposed mechanisms and major constituents that are most probably responsible for the toxicity have been scrutinized. According to the experimental and prediction results, the kava constituents play a substantial role in hepatotoxicity by some means or other via glutathione depletion, CYP inhibition, reactive metabolite formation, mitochondrial toxicity and cyclooxygenase activity. Some of the constituents, which have not been tested yet, were predicted to involve mitochondrial membrane potential, caspase-3 stimulation, and AhR activity. Since Nrf2 activation could be favorable for prevention of hepatotoxicity, we also suggest that these compounds should undergo testing given that they were predicted not to be activating Nrf2. Among the major constituents, alkaloids appear to be the least studied and the least toxic group in general. The outcomes of the study could help to appreciate the mechanisms and to prioritize the kava constituents for further testing.
... 96 In addition to CNS effects discussed above, the use of kava and kavalactones raises concerns over their reported hepatotoxicity. 98 For example, while kavalactones and their metabolites have been suggested as hepatotoxic in some studies (see ref 99 for review), other studies found no hepatotoxicity for aqueous kava extracts in animals, 100 as well as for cultivars of kava in the Pacific Islands. 101 Moreover, toxic effects of kava may be related to the methods of extraction, the use of plant parts other than the rhizome for extraction, inappropriate cultivation conditions, and use of chemical reagents instead of water or coconut milk (the traditional extraction media). ...
... 112 In 1990, kava preparations were approved in Germany as nonprescription drugs for anxiety, stress, and restlessness, 113 marking a true "kava boom" before it crumbled in the early 2000s. 98,114 In 2002, based on case reports of liver damage, 98 Germany withdrew all kava products from the market, 115 7 In 2006, Russia further listed kava as an illegal drug along with other potent and toxic substances with sedative, intoxicating effects. 7 In 2014, the kava ban was lifted and kava was unscheduled in Germany, where it is now sold in health stores in liquid or capsule forms. ...
... 112 In 1990, kava preparations were approved in Germany as nonprescription drugs for anxiety, stress, and restlessness, 113 marking a true "kava boom" before it crumbled in the early 2000s. 98,114 In 2002, based on case reports of liver damage, 98 Germany withdrew all kava products from the market, 115 7 In 2006, Russia further listed kava as an illegal drug along with other potent and toxic substances with sedative, intoxicating effects. 7 In 2014, the kava ban was lifted and kava was unscheduled in Germany, where it is now sold in health stores in liquid or capsule forms. ...
Kava (kava kava, Piper methysticum) is a common drug-containing plant in the Pacific islands. Kavalactones, its psychoactive compounds, exert potent central nervous system (CNS) action clinically. However, the exact pharmacological profiles and mechanisms of action of kava on the brain and behavior remain poorly understood. Here, we discuss clinical and experimental data on kava psychopharmacology and summarize chemistry and synthesis of kavalactones. We also review its societal impact, drug use and abuse potential, and future perspectives on translational kava research.
... Originating from the nature, herbal products are confronted with risks of impurities such as aflatoxinosis evolving during their agricultural and manufacturing process of TCM herbs [5] and non-TCM herbs such as kava, Piper methysticum, a South Pacific medicinal plant [5,8,34]. On theoretical grounds, aflatoxins may contaminate kava plants due to the humid conditions and high temperatures of the South Pacific region during storage [5]. ...
... These and other issues of impurities as well as additional uncertainties about the kava product quality led to analyses, discussions, and a proposal for a kava quality standard to ultimately ensure all quality requirements of kava as herbal anxiolytic medicine [5,8]. Subsequently, this goal was achieved by providing good quality of kava to be used in clinical trials to treat patients with anxiety disorders, and kava therapy was found to be effective and safe [8,34], with a new trial underway in Australia [5,8,34,35]. Unlabeled contaminants of heavy metals are intentionally added [5] or taken up by the plant from soil contaminated by heavy metals as a result from vegetabilization, the cultivation of plants in soils pre-treated with diluted metal salts for herbal anthroposophical medicines [36] or Indian remedies [5]. ...
... These and other issues of impurities as well as additional uncertainties about the kava product quality led to analyses, discussions, and a proposal for a kava quality standard to ultimately ensure all quality requirements of kava as herbal anxiolytic medicine [5,8]. Subsequently, this goal was achieved by providing good quality of kava to be used in clinical trials to treat patients with anxiety disorders, and kava therapy was found to be effective and safe [8,34], with a new trial underway in Australia [5,8,34,35]. Unlabeled contaminants of heavy metals are intentionally added [5] or taken up by the plant from soil contaminated by heavy metals as a result from vegetabilization, the cultivation of plants in soils pre-treated with diluted metal salts for herbal anthroposophical medicines [36] or Indian remedies [5]. Lead, mercury, cadmium, or arsenic are added in the belief they could enhance efficacy, with lead as a regular constituent of traditional Indian remedies [5]. ...
Purpose of the Review
To present highlights of recent liver injury from herbs and “dietary supplements,” based on a literature review from 2015 to 2017.
Recent findings
Challenging are quality issues of herb and dietary supplements (HDS) products, influenced by the circadian clock system in plants that controls many important metabolic pathways including photosynthesis and molecular processes of gene expression. Important also is plant stress, caused by pathogen attacks, heavy UV radiation, draft, soil contamination by salts or heavy metals, involving oxidative stress through generation of free radicals including reactive oxygen species (ROS), damaging the plant’s integrity. Finally, expectations are high if physicians publish case reports of HDS liver injury using the Roussel Uclaf Causality Assessment Method (RUCAM), but intentional overscoring of causality gradings must be resisted. In critical situations, reevaluation of original case data was a good approach clarifying divergencies.
Summary
Plant stress impairs the quality of herbs, requiring better understanding of plant physiology, and clinical liver injury cases need better causality assessment using RUCAM.
... Although the causality of the case reports was questioned very early in the debate [7,8], a de facto ban of kava preparations was issued in 2002 for all of Europe. The debate on the potential liver toxicity of kava extracts in Germany continued for many years without new evidence supporting a liver risk, and only recently reached a conclusion when the German Upper Administrative Court ruled that the ban of kava preparations was not justified due to lack of proof of safety issues with noble kava [9]. This may change, however, if two day kava is used in kava extract preparations, given that the acetonic extract of, most likely, today kava, had a high degree of probability of causality [9,10], which is why current German regulations allow noble kava only. ...
... The debate on the potential liver toxicity of kava extracts in Germany continued for many years without new evidence supporting a liver risk, and only recently reached a conclusion when the German Upper Administrative Court ruled that the ban of kava preparations was not justified due to lack of proof of safety issues with noble kava [9]. This may change, however, if two day kava is used in kava extract preparations, given that the acetonic extract of, most likely, today kava, had a high degree of probability of causality [9,10], which is why current German regulations allow noble kava only. ...
... The high-dose medication corresponded to the German authorized medicinal product Kavasedon (Harras Pharma Curarina, Munich, Germany). The plant material used in the study medication extract was identified as a typical noble kava [9] variety from Vanuatu. ...
Aim
Kava, an aqueous drink from the roots and peeled rootstock of the plant Piper methysticum G.Forst., is renowned in Melanesia, Polynesia and Micronesia for its relaxant effect. Modern extract preparations with defined contents of kavalactones – the major active constituents – are well established as herbal medicinal products on the European market. The aim of this trial was to present data on the clinical efficacy of an ethanolic kava extract.
Methods
In the present double‐blind clinical trial, the differences in clinical outcome between a low dose of ethanolic kava extract (equivalent to 20 mg kavalactones daily) and a respective high dose (equivalent to 200 mg kavalactones daily) were investigated. Patients with anxiety disorders were randomized into the two groups, resulting in 33 patients in the high‐dose group and 36 patients in the low‐dose group. The study duration was 4 weeks; the primary parameter was the Hamilton anxiety (HAMA) score. Global efficacy was rated by the physician at the end of the study. Safety of application was based on the documentation of adverse events.
Results
The high‐dose group was statistically significantly superior to the low‐dose group on HAMA total score and its subscores for psychological and physical manifestations of anxiety (P < 0.001), with a total improvement of −41.5% versus −13.6% relative to baseline HAMA total score on day 28. No adverse events occurred.
Conclusion
Kava preparations have a dose‐dependent anxiolytic effect.
... Kava hepatotoxicity is primarily an idiosyncratic liver injury of the metabolic subtype in most cases, but it may also have features of an intrinsic injury type (Table 5) [80,81]. This dualism of typology is the result of various analyses [80][81][82][83][84][85][86][87][88][89][90][91][92][93]. In most kava products, toxic ingredients were likely absent, and their hepatotoxicity is based on idiosyncrasy in few susceptible individuals (Table 5). ...
... In most kava products, toxic ingredients were likely absent, and their hepatotoxicity is based on idiosyncrasy in few susceptible individuals (Table 5). In few other kava products, toxic ingredients presumably are present, causing intrinsic hepatotoxicity in those few individuals who took these products [80][81][82][83][84][85][86][87][88][89][90][91][92][93]. The overall rarity of kava hepatotoxicity was also considered in a recent court trial and evaluated as a positive constellation of benefit and risk [93], opposing previous regulatory assumptions to the contrary [94]. ...
... Data are derived from a previous report [80,81] and consider other analyses and publications [82][83][84][85][86][87][88][89][90][91][92]. Abbreviations: ALP, Alkaline phosphatase; ALT, Alanine aminotransferase; RUCAM, Roussel Uclaf Causality Assessment Method. ...
Herb induced liver injury (HILI) and drug induced liver injury (DILI) share the common characteristic of chemical compounds as their causative agents, which were either produced by the plant or synthetic processes. Both, natural and synthetic chemicals are foreign products to the body and need metabolic degradation to be eliminated. During this process, hepatotoxic metabolites may be generated causing liver injury in susceptible patients. There is uncertainty, whether risk factors such as high lipophilicity or high daily and cumulative doses play a pathogenetic role for HILI, as these are under discussion for DILI. It is also often unclear, whether a HILI case has an idiosyncratic or an intrinsic background. Treatment with herbs of Western medicine or traditional Chinese medicine (TCM) rarely causes elevated liver tests (LT). However, HILI can develop to acute liver failure requiring liver transplantation in single cases. HILI is a diagnosis of exclusion, because clinical features of HILI are not specific as they are also found in many other liver diseases unrelated to herbal use. In strikingly increased liver tests signifying severe liver injury, herbal use has to be stopped. To establish HILI as the cause of liver damage, RUCAM (Roussel Uclaf Causality Assessment Method) is a useful tool. Diagnostic problems may emerge when alternative causes were not carefully excluded and the correct therapy is withheld. Future strategies should focus on RUCAM based causality assessment in suspected HILI cases and more regulatory efforts to provide all herbal medicines and herbal dietary supplements used as medicine with strict regulatory surveillance, considering them as herbal drugs and ascertaining an appropriate risk benefit balance.
... Detailed above, these confounders raise the question whether the CDC conclusions were based on valid evidence or rather on speculations. Of note, other regulators have been confronted with confounding variables in HILI cases before, both in the US [65,66,90] and Germany [106][107][108][109][110][111][112][113]. In most of these instances, confounders led to a downgrading to excluded or unlikely causality levels in virtually all examined cases [66,90,[107][108][109][110][111][112][113], in the case of kava supported by a German court decision [109]. ...
... Of note, other regulators have been confronted with confounding variables in HILI cases before, both in the US [65,66,90] and Germany [106][107][108][109][110][111][112][113]. In most of these instances, confounders led to a downgrading to excluded or unlikely causality levels in virtually all examined cases [66,90,[107][108][109][110][111][112][113], in the case of kava supported by a German court decision [109]. There is no question that HILI is a major clinical and regulatory challenge [113], a view supported in a recent review article with detailed information of this interesting field and encouraging suggestions for better models of pre-emptive testing of potential hepatotoxic properties of herbs [114]. ...
... Of note, other regulators have been confronted with confounding variables in HILI cases before, both in the US [65,66,90] and Germany [106][107][108][109][110][111][112][113]. In most of these instances, confounders led to a downgrading to excluded or unlikely causality levels in virtually all examined cases [66,90,[107][108][109][110][111][112][113], in the case of kava supported by a German court decision [109]. There is no question that HILI is a major clinical and regulatory challenge [113], a view supported in a recent review article with detailed information of this interesting field and encouraging suggestions for better models of pre-emptive testing of potential hepatotoxic properties of herbs [114]. ...
In 2013, physicians at the Honolulu Queen's Medical Center (QMC) noticed that seven liver disease patients reported the use of OxyELITE Pro (OEP), a widely consumed dietary supplement (DS). Assuming a temporal association between OEP use and disease, they argued that OEP was the cause of this mysterious cluster. Subsequent reexamination, however, has revealed that this QMC cohort is heterogeneous and not a cluster with a single agent causing a single disease. It is heterogeneous because patients used multiple DS's and drugs and because patients appeared to have suffered from multiple liver diseases: liver cirrhosis, liver failure by acetaminophen, hepatotoxicity by non-steroidal antiinflammatory drugs (NSAIDs), resolving acute viral hepatitis by hepatitis B virus (HBV), herpes simplex virus (HSV), and varicella zoster virus (VZV), and suspected hepatitis E virus (HEV). Failing to exclude these confounders and to consider more viable diagnoses, the QMC physicians may have missed specific treatment options in some of their patients. The QMC physicians unjustifiably upgraded their Roussel Uclaf Causality Assessment Method (RUCAM) causality scores so that all patients would appear to be "probable" for OEP. However, subsequent RUCAM reassessments by our group demonstrated a lack of causality for OEP in the evaluated QMC cases. The QMC's questionable approaches explain the extraordinary accumulation of suspected OEP cases at the QMC in Hawaii as single place, whereas similar cohorts were not published by any larger US liver center, substantiating that the problem is with the QMC. In this review article, we present and discuss new case data and critically evaluate upcoming developments of problematic regulatory assessments by the US Centers for Disease Control and Prevention (CDC), the Hawaii Department of Health (HDOH), and the Food and Drug Administration (FDA), as based on invalid QMC conclusions, clarifying now also basic facts and facilitating constructive discussions.
... The second type of study uses conceptual frameworks to explain how broader exogenous processes, particularly economic change, may act as causes of vulnerability (top-down). These studies often navigate at the regional or national level but only rarely show how the described processes specifically shape vulnerabilities at the local level (e.g., Leichenko and O'Brien, 2002;O'Brien et al., 2004;Parks and Roberts, 2006;Kuchta et al., 2015). ...
... For example, the German court that reversed the kava import decision can be considered a sending system because its decision opened up new markets. If we would have placed the focus on the lobbying activities of South Pacific kava-producing countries and marketing authorization holders that prompted the court to reassess the ban and ultimately to revise the ruling (Kuchta et al., 2015), the analysis would have been reversed. This may not be of great importance for the community itself, but it is for the development and characterization of a causal relationship. ...
Food insecurity is a pressing problem in many regions across the world. Drivers of food insecurity are becoming increasingly embedded in sociocultural and economic processes that transcendent multiple spatial and temporal scales. This is due to the increasingly globalized interconnections of places and people. Understanding this complexity is essential to devise locally relevant and effective adaptation strategies to tackle existing vulnerabilities causing food insecurity. This article analytically addresses the complexity in cross-scale dynamics by combining a case study from northern Vanuatu with a conceptual analysis of the broader socioeconomic dynamics within the telecoupling framework. Our aim is to identify drivers of vulnerability that span multiple temporal and spatial scales and contribute to food insecurity in a given location while exploring the relevance and applicability of the framework for the holistic assessment of vulnerability to food insecurity. The transdisciplinary approach used in this work involved local community members and local agriculture extension officers at all stages of the study process. For this, we used complementary research methods, such as workshops, participant observations, and in-depth interviews. The results showed that potential vulnerability to food insecurity in northern Vanuatu is likely to be related to individual choices aimed at maximizing income, enabled by economic development and driven by socio-cultural changes. These choices and their consequences are perceived in many cases to be responsible for lower subsistence food production and the overuse of natural food resources. However, economic changes in particular can also enable additional livelihoods that complement existing (subsistence-based) strategies, leading to a reduction in one-sided dependencies and thus to an overall increase in the resilience of local livelihoods. We find the telecoupling approach to be a useful tool to holistically capture a local vulnerability context. However, we also encountered challenges in describing telecouplings that operate over longer time scales.
... A recent review of several clinical studies suggests that kava is superior to placebo in reducing anxiety symptoms [102]. As the use and popularity of kava grew, there were reports of kava-associated hepatotoxicity, leading to initial restrictions in its use in some countries [103,104]. Despite the general concern about its safety, kava is still popularly consumed for CNS benefits. ...
... A study in 18 health volunteers did not show any clinically relevant interaction between kava and bromazepam [104]. Two case reports, however, suggested that kava use with prescription neuropsychiatric medications may not always be safe. ...
The management of neuropsychiatric disorders relies heavily on pharmacotherapy. The use of herbal products as complimentary medicine, often concomitantly, is common among patients taking prescription neuropsychiatric drugs. Herb-drug interaction, a clinical consequence of this practice, may jeopardize the success of pharmacotherapy in neuropsychiatry. Besides the well-known ability of phytochemicals to inhibit and/or induce drug-metabolizing enzymes and transport proteins, several phytoconstituents are capable of exerting pharmacological effects on the central nervous system. The consequent pharmacokinetic and pharmacodynamic interactions with orthodox medications often result in deleterious clinical consequences. This study reviewed the relevant literature and identified 13 commonly used herbal products – celery, echinacea, ginkgo, ginseng, hydroxycut, kava, kratom, moringa, piperine, rhodiola, St John’s wort, terminalia/commiphora ayurvedic mixture and valerian – which have shown clinically relevant interactions with prescription drugs used in the management of neuropsychiatric disorders. The clinical focus is aimed to provide easily accessible information that will be of interest to clinicians, researchers, and the drug-consuming public.
... the ban was inappropriate [3]. However, a concern regarding kava stems not only from Germany, but is worldwide (e.g., FDA issued warnings). ...
... The IARC Working Group also noted that the influences on composition may hinder the comparison of toxicological studies when the applied kava material is not specified exactly [4]. When the German Health Authorities decided to ban kava in 2003, the control quality system used at that time was not efficient and individual KLs and FKs were not quantitated in the extracts [3]. It is therefore possible that two-day and/or wichmannii varieties were imported into Germany and extracted. ...
Kava (Piper methysticum) is increasingly traded internationally and there is need for a rapid method to analyze kava raw material before export. The objectives of the present study were: (i) to develop a simple and robust protocol for high throughput simultaneous quantification of kavalactones (KLs) and flavokavins (FKs) in kava and (ii) to assess its potential for quality control. Methysticin; dihydromethysticin; kavain; desmethoxyyangonin; dihydrokavain; yangonin; and flavokavin A, B and C were quantified using HPTLC in acetonic extracts of 174 kava varieties. UHPLC analysis was conducted on a subset of six varieties representing the genetic variation of the species. The genetically distinct groups of nobles, two-day and wichmannii varieties were clearly differentiated and multivariate analyses of UHPLC and HPTLC data were congruent. Noble varieties have significantly low FKs/KLs (0.13) and high kavain/flavokavin B (K/FKB = 7.31). Two-day and wichmannii varieties are characterized by high FKs/KLs (0.36, 0.21) and low K/FKB (1.5, 1.7). A high-throughput HPTLC protocol was developed with a total analytical time of 50 min for 20 samples and only 10 mL of mobile phase. The use of acetone, sonication and two different detection wavelengths improves the accuracy compared to previous HPLC studies and confirms that kava varieties exhibit distinct chemotypes clearly differentiated by their FKs/KLs profiles. These results will strengthen the use of Codex Alimentarius regional standards.
... 12 The restriction on Kava has since been lifted in many jurisdictions in Europe, including Germany. 13 Several reviews have confirmed the efficacy of Kava for treating anxiety. A Cochrane systematic review by Pittler and Ernst of 12 double-blind randomized controlled trials (RCTs, n = 700) found Kava extract to be a safe and effective symptomatic treatment for anxiety. ...
... This 4-week trial, with the Kava group treated with a standardized Kava extract (KavaPure Ò ), reported negative results in both primary (changes in HAM-A scores) and secondary measures (changes in Hospital Anxiety and Depression Scale, HADS; changes in Self Assessment of Resilience and Anxiety, SARA), suggesting that Kava was not superior to placebo in the treatment of GAD. 20 Two additional trials were reported in Connor et al. 22 The first study (Study I) was similar in study design compared to Connor and Davidson, 20 but differed in the entry criteria, accepting patients with milder anxiety symptoms (baseline HAM-A score of [12][13][14][15][16][17][18][19][20]. The second study (Study II) differed from Connor and Davidson 20 in terms of the duration of GAD at study entry ( ‡6 months), the duration of study (8 weeks), the Kava tablets used (''WS 1490''), and a third arm of active treatment with venlafaxine-XR. ...
Background:
Generalized anxiety disorder (GAD) is a chronic and debilitating condition characterized by persistent and overpowering anxiety. Treatment of GAD with antidepressants and benzodiazepines is only moderately effective and not free from side effects. Kava (Piper methysticum) has been explored as a potential phytotherapeutic option for GAD.
Objectives:
To perform a systematic review and meta-analysis of the available evidence on Kava as a treatment for GAD.
Methods:
Systematic search of English-language publications from major databases for clinical trials reporting the effects of Kava for the treatment of GAD.
Results:
Twelve articles were included in this review. Evidence supporting Kava as an effective treatment for GAD was found in two placebo-controlled trials and a reference-controlled trial. One negative trial demonstrated that Kava was not more effective than placebo. Meta-analyses of the results of three placebo-controlled trials (n = 130) favored Kava for GAD treatment with effect sizes between 0.59 and 0.99 (standard mean difference) without reaching statistical significance. Kava is an appealing treatment option to GAD patients who are more attune to natural remedies or lifestyle approaches to reduce stress. Positive patient experiences and improvement of vagal cardiac control due to Kava treatment were also reported in the literature. Kava is safe and well tolerated for short-term (4-8 weeks) therapeutic use at a dosage of 120-280 mg per day of Kavalactones, regardless of dosage schedule.
Conclusions:
Current evidence, although promising, is insufficient to confirm the effect of Kava for GAD treatment beyond placebo. New evidence is expected from a large, multisite ongoing trial.
... [5,6] However, there was lack of evidence that supported the alleged dangers related to kavalactones. With German court lifting ban on kava in 2014, [7] the research on kavalactones might flourish again. Herein, we will summarize the kavalactones from the plants and their bioactivities. ...
... Eighteen kavalactones (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18), which were identified from kava roots, have already been covered in the review by Bilia et al, [8] namely 11-hydroxy-12-methoxydihydrokavain (1), 7,8dihydrokavain (2), dihydromethysticin (3), 5,6,7, 8-tetrahydroyangonin (4), 11,12-dimethoxy-5,6-dihydrokavain (5), 7,8-dihydro-5-hydroxykavain (6), kavain (7), methysticin (8), 5,6-dihydroyangonin (9), hydroxykavain (10), 5,6-dehydromethysticin (11), 7,8-dihydroyangonin (12), desmethoxyyangonin (13), yangonin (14), 11-methoxyangonin (15), 10-methoxyangonin (16), 11-hydroxyangonin (17), and 11-methoxy-12-hydroxydehydrokavain (18). Among these kavalactones, compounds 2, 3, 7, 8, 13, 14 are the most abundant in the roots of P. methysticum. ...
... Currently, in the USA kava extracts can be found in markets and on the internet. Conversely, in Germany, although the court ruling ban the use of kava in 2014 was an invalid instrument, it can now be used on the order of a referring physician.[50].V. PRECLINICAL STUDIES ON PIPER CUBEBAV. Acute toxicityMale Wistar albino rats were divided into test groups comprising of six animals in each group. ...
Culinary herbs and spices (CHS) are known for their prominent role in the kitchen as Spices/condiments. These herbs gained a significant position in ancient Indian Ayurveda because of their diversified therapeutic properties. Several exploratory findings have proven their potential in the therapeutic management of critical medical conditions like diabetes, hypertension, inflammatory reactions, and cancer. Piper cubeba (PC) known as Tailed pepper is having more commonly immense therapeutic properties, yet remains underrated. The Essential oils present in PC, embody several characteristics useful in the therapeutic management of respiratory problems like bronchitis, congestion, throat infections, and acting as a diuretic and also help to reduce indigestion. Essential oils prominently consist of sabinene, β-elemene, β-caryophyllene, epi-cubebol, cubebol, trans-sabinene hydrate, epicubebol, γ-cadinene and cubebol, alkaloids such as piperine, glycosides, tannins, flavonoid, anthraquinones, saponins, carbohydrates, tannins, and coumarins are the main components of the berry oil. These photo-constituents are also beneficial for various non-communicable chronic diseases as they serve anti-oxidant, anti-microbial, and anti-inflammatory properties. It is reported that PC has the highest phenol content mainly due to the presence of polyphenols, therefore it also has greater antimutagenic activity. It is remarkably, responsible for the reduction in the lipid peroxidation inside, the liver and reinstatement, behaviors for defense antioxidant enzymes NP-SH (Non-protein thiol) and CAT (Catalase) towards normal levels. The hepatic-protective effect of ethanol extract PC is attributed to the down-regulation of pro-inflammatory cytokines, for example, TNF-α (Tumour necrosis factor) and IL-6 (Interleukin) and mRNA (messenger ribonucleic acid) expression 1 ofiNOS (inducible nitric oxide synthase) and HO-1 (Heme oxygenase) gene, and up-regulationoftheIL-10.
... Preliminary data from a previous human study did not report any significant adverse events due to the consumption of kava supplementation [18]. Because there is a potential for kava to affect the function of the liver through drug-herb interaction (< 0.3 cases per million dosages) [20][21][22][23][24][25][26][27][28], we will exclude any subjects with liver conditions and will monitor liver function during and after participants are receiving the intervention. AB-free kava (a kava preparation free of flavokavains A and B, the potential hepatotoxic ingredients in kava [29]) will be used in the study as well, which is expected to have an improved safety profile. ...
Background
Tobacco use is the leading cause of many preventable diseases, resulting in premature death or disease. Given that the majority of adult who smoke want to stop, this health burden could be significantly reduced if the success rate of tobacco cessation can be improved. In addition, most adults planning to quit were interested in trying complementary approaches to facilitating tobacco cessation, which is currently lacking. Therefore, there is an unmet and urgent need for novel interventions to improve the success of tobacco cessation. If such an intervention can reduce tobacco-associated lung carcinogenesis, that will be more desirable. The goal of this project is to develop a safe and effective kava-based intervention to enable tobacco cessation and reduce lung cancer risk, which will improve the health of smokers.
Methods
A randomized controlled trial will enroll 80 adults who currently smoke at least 10 cigarettes daily and randomize 1:1 into the placebo and AB-free kava arms, being exposed for 4 weeks, with a total of six visits (weeks 0, 1, 2, 4, 8, and 12) to evaluate the compliance and potential issues of AB-free kava use among the participants, explore the potential effect of the AB-free kava intervention on tobacco dependence, tobacco use, and lung carcinogenesis biomarkers. Participants will be enrolled during their primary care clinic visit.
Discussion
Primary care settings play a critical role in tobacco-related disease screening, counseling, and early intervention, as the majority of adults who smoke visit their physicians annually. Building upon our promising pilot human trial results in conjunction with ample compelling lab animal results, and consistent with evidence of kava’s benefits from epidemiological data, this trial will evaluate the compliance of AB-free kava among adults who currently smoke with no intention to quit. The other exploratory aims include (1) whether AB-free kava intervention can reduce tobacco use and tobacco dependence; (2) whether AB-free kava use suppresses tobacco-induced carcinogenesis; and (3) the potential of the mechanism-based noninvasive biomarkers in precision AB-free kava intervention. The positive results from this study are expected to provide a great opportunity to effectively reduce smoking rates and tobacco-related diseases.
Trial registration
ClinicalTrials.gov with the identifier: NCT05081882. Registered on October 18, 2021.
... In addition, the U.S. Food and Drug Administration (FDA) decided to investigate if these products were indeed responsible for public health problems, and after reviewing the available cases, decided to issue a statement on the products containing kava, albeit not banning them [3]. Later, in 2014, two German administrative courts concluded that the relationship between kava ingestion and liver damage was not well established in most cases [13]. ...
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.
... These extracts have concentrated kavalactone content of between 30 and 70% (Food and Agriculture Organization of United Nations, 2016). The ethanolic extracts contain even higher amounts of kavalactones and flavokavains, potentially leading to some adverse effects when consumed at higher doses (Food and Agriculture Organization of United Nations, 2016; Kuchta et al., 2015). Some kava preparations may induce hepatotoxicity in rare cases (thought to be caused by the presence of flavokavains A and B), leading the Food and Drug Administration (FDA) to issue a public health advisory and suspended clinical studies of kava in 2002 following a few cases of liver toxicity with a few resulting in death, reported in the US, Germany, and Switzerland (Centers for Disease Control and Prevention, 2002). ...
Ethnopharmacological relevance
Piper methysticum G. Forst. (Piperaceae), commonly known as kava, has been used as a traditional beverage for centuries for its relaxing properties. Kavalactones are considered to be the major constituents responsible for kava's beneficial effects. Despite the extensive use of kava, clinical pharmacokinetic data is not available in the literature; therefore, the findings of this study will be critical for the dosage calculations for future clinical evaluation of kava.
Aim of the study
The aim of the current study is to examine the clinical pharmacokinetics of six major kavalactones following dosage of flavokavain A/B-free standardized kava extract capsules in healthy volunteers using two dosage regimens.
Materials and methods
A sensitive, reliable, and specific ultra-high pressure liquid chromatography-mass spectrometry (UPLC-MS/MS) method was developed and validated for the simultaneous quantification of six major kavalactones (kavain, dihydrokavain, methysticin, dihydromethysticin, yangonin, and desmethoxyyangonin) and two flavokavains (A and B) in human plasma. Pharmacokinetic profiles were assessed in ten healthy volunteers after oral doses of standardized kava product, and plasma samples were analyzed for six kavalactones and two flavokavains using the validated UPLC-MS/MS method. Concentration-time data was subjected to pharmacokinetic analysis.
Results
The systemic exposure of the kavalactones was found to be in the following order: dihydrokavain > dihydromethysticin > kavain > methysticin > yangonin. Desmethoxyyangonin was observed only at a couple of time points, while flavokavain A and flavokavain B were not present in any of the plasma samples. Fast absorption of five kavalactones was observed with time to reach the maximum plasma concentration of 1–3 h. A dose proportionality in pharmacokinetics was observed from 75-225 mg of kavalactone doses. In the multiple-dose study, a significant reduction in the extent of absorption of kavalactones with food was observed.
Conclusion
Single and multiple-dose clinical pharmacokinetic studies for kava were performed in healthy volunteers, and higher exposure to the kavalactones was observed after single-dosing (225 mg), while a longer duration of exposure was observed after three times a day (3 x 75 mg) dosing.
... Finally, via a recent court decision against the German regulatory ban of kava (Piper methysticum) and in support of case analyses mainly from the group of the first author (R Teschke), the controversy has now hopefully been settled. According to a comprehensive report published 2015, the administrative court of Cologne in Germany ruled that the available data do not support the alleged liver injury of kava, the herbal anxiolytic drug and traditional herb in Oceania (113). Overall, the number of cases seemed insignificant for the court when compared with the known exposure data of 450 million daily doses in ten years. ...
Herbal products including herbal medicines are worldwide used in large amounts for treating minor ailments and for disease prevention. However, efficacy of most herbal products has rarely been well documented through randomized controlled trials in line with evidence-based medicine concepts, which could be used to estimate the benefit/risk ratio. Instead, much better documented are adverse reactions such as liver injury associated with the consumption of some herbal products, so called herb-induced liver injury (HILI), which represents a clinical challenge. In order to establish HILI as valid diagnosis, the use of a diagnostic algorithms such as Roussel Uclaf Causality Assessment Method (RUCAM) is widely recommended, although physicians in some countries are reluctant to use RUCAM for their HILI cases. This review on worldwide HILI and RUCAM, developed as part of the artificial intelligence ideas, reveals that China is the leading country with 24 publications on HILI cases that were all assessed for causality using RUCAM, followed by Korea with 15 reports, Germany with 9 reports, the US with 7 reports, and Spain with 6 reports, whereas the remaining countries provided less than 4 reports. The total number of assessed HILI cases is 12,068 worldwide derived from 80 publications but in each report HILI case numbers were variable in a range from 1 up to 6,971. This figure compares with 46,266 cases of drug-induced liver injury (DILI) published worldwide from 2014 to early 2019 also assessed for causality by RUCAM. The original version of RUCAM was validated and established in 1993 and updated in 2016 that should be used in future HILI cases. RUCAM is an objective, structured, and validated method, specifically designed for liver injury. It is a scoring system including case data elements to be assessed and scored individually to provide a final score in five causality gradings. Among the 11,404/12,068 HILI (94.5%) cases assessable for evaluation, causality gradings were highly probable in 4.2%, probable in 15.5%, possible in 70.3%, and unlikely or excluded in 10.0%. To improve the future reporting of RUCAM based HILI cases, recommendations include the strict adherence to instructions outlined in the updated RUCAM and, in particular, to follow prospective data collection on the cases to ensure completeness of case data. In conclusion, RUCAM can well be used to assess causality in suspected HILI cases, and additional efforts are now required to increase the quality of the reported cases.
... Hepatotoxic effects of Kava-Kava have been reported, which are directly related to the raw material parts used, including mainly aerial parts (leaves and bark) of P. methysticum. [81][82][83] The consumption of kava-kava has been shown to impair the ability to drive vehicles. [84] P. methysticum is listed in the WHO, EMA, and ESCOP monographs. ...
... Hepatotoxic effects of Kava-Kava have been reported, which are directly related to the raw material parts used, including mainly aerial parts (leaves and bark) of P. methysticum. [81][82][83] The consumption of kava-kava has been shown to impair the ability to drive vehicles. [84] P. methysticum is listed in the WHO, EMA, and ESCOP monographs. ...
This review focuses on four new product categories of food supplements: pre‐workout, fat burner/thermogenic, brain/cognitive booster, and hormone/testosterone booster. Many food supplements have been shown to be contaminated with unauthorized substances. In some cases, the ingredients in the new categories of dietary supplements were medicinal products or new synthetic compounds added without performing clinical trials. Some of the new ingredients in dietary supplements are plant materials that are registered in the pharmacopoeia as herbal medicines. In other cases, dietary supplements may contain plant materials that have no history of human use and are often used as materials to “camouflage” stimulants. In the European Union, new ingredients of dietary supplements, according to European Food Safety Authority or unauthorized novel food. Furthermore, selected ingredients in dietary supplements may be prohibited in sports and are recognized as doping agents by World Anti‐Doping Agency.
... 8 An important issue is the differentiation between so-called "two-day kava" and "noble kava" varieties. Kava noble cultivars have a high percentage of KAV over MET and DHM, associated to low levels of flavokavin B (FKB), 9 and previous studies demonstrated that FKB has been considered as a possible cause for hepatotoxicity. 10, 11 Lebot et al. analysed flavokavain B in kava extracts from different cultivars and showed that the ratio flavokavain B/kavalactones was higher in two-day kava compared to noble varieties, so that FKB could be used as a marker for the determination of kava safety. ...
Introduction
Dried extracts of Piper methysticum G. Forst, also known as kava, has been widely used due to its anxiolytic and sedative properties. In order to assure the quality of these extracts, it is essential to accurately quantify kavalactones, known as the active principle.
Objectives
To develop and validate an analytical method for the simultaneous quantification of six major kavalactones (kavain, dihydrokavain, methysticin, dihydromethysticin, yangonin and demethoxyyangonin) in kava extracts, comparing multi‐standards and single standard validation approaches.
Material and methods
Separation was performed using a C18 column, water/methanol/acetonitrile/2‐propanol (66:07:09:18 v/v/v/v) and detection at 245 and 350 nm. A full method validation was performed, employing analytical standards for each compound. Commercial kava dried extracts were assayed and the results obtained using the method validated for six kavalactone standards were compared with those obtained when only kavain was used as standard.
Results
Baseline resolution for all kavalactones was obtained in short run time (15 min). Although the total kavalactone content varied between samples, a similar distribution profile was observed. When the method validated with all six analytical standards was compared to the calibration using only kavain standard, kavalactone contents were considerably different (from 7.57 to 36.53%).
Conclusion
The obtained results demonstrate the importance of a validated method using individual kavalactone standards for the effective quality control of kava extracts. In a next step, the method needs to be adapted to also include flavokavin B (FKB), as an important authentication marker to distinguish between the accepted variety “noble Kava” and the toxic “two‐day Kava”.
... The first harvests of two-day kava coincided with the occurrence of the case reports (Kuchta et al., 2015;Schmidt, 2007;. Even though two-day kava may thus have been the reason for the sudden change in kava safety, the causative phytochemical ingredient is still not known. ...
Ethnopharmacological relevance
Kava (Piper methysticum G. Forst. f.) is by far the most important plant used in the islands of Melanesia, Polynesia and Micronesia for its relaxing effects. Kava drinking is a pillar of South Pacific societies and is also the foundation of their economies. Preparations of kava extract as herbal medicinal drugs were banned in Germany in 2002 and again in 2019, with dramatic consequences for the South Pacific economies. In 2002, the major regulatory argument for the ban of kava was safety issues. In 2019, the assessment report of the European Medicines Agency's Herbal Medicinal Product Committee (HMPC) justified a negative benefit-to-risk ratio by a supposed lack of efficacy of ethanolic extracts for an indication of which kava extract preparations never had an approval. In this HMPC report the efficacy in the approved indications ‘nervous anxiety, tension and restlessness’ was attributed to the extract branded as ‘WS 1490’, which was assumed to have been prepared with acetone as an extraction solvent. In addition to this change of indication and the attribution of efficacy to acetone kava extract alone, the German health authorities and the HMPC still refuse to discuss quality issues as a likely factor impacting drug safety. The first case reports of liver toxicity were observed with an acetone extract in a timely relationship with the introduction of ‘two-day kava’ instead of ‘noble kava’ as used in ethanolic kava extracts.
Aim of the study
The correlation between clinical benefits and the type of extract preparation was examined.
Methods
In order to identify the types of kava material and extracts used in clinical trials, the respective publications were compared with regulatory databases and protocols of a German regulatory advisory board.
Results and conclusions
The comparison reveals inconsistencies in the regulatory decisions. In all studies with WS 1490, the evidence points to the use of an ethanolic extract. The efficacy of kava extract for the approved indication was clearly demonstrated. The HMPC report and the recent renewed German regulatory ban of kava therefore require major revision, which should include the impact of the use of “two-day kava” on drug safety. Such a revision could contribute to restoring the reputation of “noble kava” on the international markets.
... 'Awa is non-psychoactive and non-stimulant, providing instead sensations of well-being, calm and is a mild soporific. It has a low side effect profile, with 1999-2001 reports of hepatotoxicity being now overwritten, and chronic use associated with a reversible icthyoform dermopathy in some Pacific populations (Kuchta et al., 2015;Showman et al., 2015). There is good clinical evidence that it is an anti-anxiolytic which is consistent with its use in traditional contexts (Sarris et al., 2013) and it may have potential for facilitation of tobacco cessation . ...
Ethnopharmacological relevance
Traditional pharmacopeias have been developed by multiple cultures and evaluated for efficacy and safety through both historical/empirical iteration and more recently through controlled studies using Western scientific paradigms and an increasing emphasis on data science methodologies for network pharmacology. Traditional medicines represent likely sources of relatively inexpensive drugs for symptomatic management as well as potential libraries of new therapeutic approaches. Leveraging this potential requires hard evidence for efficacy that separates science from pseudoscience.
Materials and methods
We performed a review of non-Western medical systems and developed case studies that illustrate the epistemological and practical translative barriers that hamper their transition to integration with Western approaches. We developed a new data analytics approach, in silico convergence analysis, to deconvolve modes of action, and potentially predict desirable components of TM-derived formulations based on computational consensus analysis across cultures and medical systems.
Results
Abstraction, simplification and altered dose and delivery modalities were identified as factors that influence actual and perceived efficacy once a medicine is moved from a non-Western to Western setting. Case studies on these factors highlighted issues with translation between non-Western and Western epistemologies, including those where epistemological and medicinal systems drive markets that can be epicenters for zoonoses such as the novel Coronavirus. The proposed novel data science approach demonstrated the ability to identify and predict desirable medicinal components for a test indication, pain.
Conclusions
Relegation of traditional therapies to the relatively unregulated nutraceutical industry may lead healthcare providers and patients to underestimate the therapeutic potential of these medicines. We suggest three areas of emphasis for this field: First, vertical integration and embedding of traditional medicines into healthcare systems would subject them to appropriate regulation and evidence-based practice, as viable integrative implementation mode. Second, we offer a new Bradford-Hill-like framework for setting research priorities and evaluating efficacy, with the goal of rescuing potentially valuable therapies from the nutraceutical market and discrediting those that are pseudoscience. Third, data analytics pipelines offer new capacity to generate new types of TMS-inspired medicines that are rationally-designed based on integrated knowledge across cultures, and also provide an evaluative framework against which to test claims of fidelity and efficacy to TMS made for nutraceuticals.
... b The following medications taken for their respective disease/conditions were also reported, however, each only by less than 2% of all participants reporting to take 2002). In the advisories, it was warned that St. John's Wort may interfere with medications taken for HIV infection, heart conditions, blood clots, asthma, depression and migraines [38] and kava kava was banned in August 2002 over concerns of hepatotoxicity [39], as well as uncertainty of how to extrapolate evidence from various populations and forms of consumption (e.g. as a tea, standardized extract, traditional preparations) [40]. Ultimately, the ban on kava kava was lifted in Canada and in other jurisdictions, with the provision of label warnings regarding the potential for drug-herb interactions, and directions to consult a health care provider if pregnant, lactating, or suffering from liver disease or epilepsy. ...
... While being potentially efficacious for anxiety, the World Health Organization-commissioned report in 2006 assessing Kava products called for clinical trials using waterbased extractions in order to firmly establish Kava's efficacy and safety, due to concerns at the time about liver toxicity related to ethanolic and acetonic extracts (Coulter, 2007). Subsequently, it should be noted that negative effects on the liver were not substantiated by the German Regulatory Authority (Kuchta et al., 2015). ...
Objective:
Previous randomised, double-blind, placebo-controlled studies have shown that Kava (a South Pacific medicinal plant) reduced anxiety during short-term administration. The objective of this randomised, double-blind, placebo-controlled study was to perform a larger, longer-term trial assessing the efficacy and safety of Kava in the treatment of generalised anxiety disorder and to determine whether gamma-aminobutyric acid transporter (SLC6A1) single-nucleotide polymorphisms were moderators of response.
Methods:
The trial was a phase III, multi-site, two-arm, 16-week, randomised, double-blind, placebo-controlled study investigating an aqueous extract of dried Kava root administered twice per day in tablet form (standardised to 120 mg of kavalactones twice/day) in 171 currently non-medicated anxious participants with diagnosed generalised anxiety disorder. The trial took place in Australia.
Results:
An analysis of 171 participants revealed a non-significant difference in anxiety reduction between the Kava and placebo groups (a relative reduction favouring placebo of 1.37 points; p = 0.25). At the conclusion of the controlled phase, 17.4% of the Kava group were classified as remitted (Hamilton Anxiety Rating Scale score < 7) compared to 23.8% of the placebo group (p = 0.46). No SLC6A1 polymorphisms were associated with treatment response, while carriers of the rs2601126 T allele preferentially respond to placebo (p = 0.006). Kava was well tolerated aside from poorer memory (Kava = 36 vs placebo = 23; p = 0.044) and tremor/shakiness (Kava = 36 vs placebo = 23; p = 0.024) occurring more frequently in the Kava group. Liver function test abnormalities were significantly more frequent in the Kava group, although no participant met criteria for herb-induced hepatic injury.
Conclusion:
While research has generally supported Kava in non-clinical populations (potentially for more 'situational' anxiety as a short-term anxiolytic), this particular extract was not effective for diagnosed generalised anxiety disorder.
... It has been speculated that during the kava boom (1998)(1999)(2000), exporters may have compensated for the shortage of preferred parts for export (dry roots/peeled rhizome) by using aerial parts of the shrub, including the leaves, to cope with demand (Lim et al., 2007). This hypothesis was refuted in the case of kava imports to Germany (Kuchta et al., 2015;Lechtenberg et al., 2018), however, it may still apply to some kava exports from Vanuatu. The development of reliable, rapid and cost-effective techniques that can be applied to verify the plant part of powdered raw material during quality control, prior to export, would make a valuable contribution to ensuring the safety of kava products. ...
Piper methysticum Forst., commonly referred to as kava, has been used medicinally and recreationally by inhabitants of the South Pacific Islands for centuries. Kavalactones present in roots and aerial parts are regarded as the bioactive compounds responsible for the relaxant effects, and for mitigating anxiety and stress-related conditions. The development of pharmaceutical products containing root extracts led to a boom in kava sales in Europe in 1998. However, reported cases of toxicity led to the subsequent banning of kava products in several countries. This study was initiated to develop rapid, robust and alternative spectroscopic methods for quality control that can be implemented at the point of export, to authenticate the use of kava roots as legislated by the Vanuatu Amended Kava Act no. 6 (2015). Roots, peeled stems, and stump peelings samples (n = 47) were sourced from Fiji, Hawaii, Samoa, the Solomon Islands and Tonga. The sample extracts were analysed using ultra performance liquid chromatography coupled to a photodiode array detector and mass spectrometer (UHPLC-PDA/MS), while powdered material was analysed using spectroscopic techniques. These included single-point (near-infrared (NIR) and mid-infrared (MIR) spectroscopy), as well as an imaging (hyperspectral imaging). Principal component analysis of both the raw UPLC-MS and the quantitative UPLC-PDA data revealed chemical differences between the root and non-root samples. Kavain, methysticin and yangonin were identified as the compounds largely responsible for the chemical differences between the plant parts. Discriminant analysis models (OPLS-DA and PLS-DA) were developed for all the techniques, to reliably discriminate kava roots from non-roots. All the discriminant models indicated a good prediction ability (Q²XCum ≥ 60 %) and were successfully used to accurately identify external roots and non-root samples. However, hyperspectral imaging yielded superior results, with a prediction ability above 90 %. This technique can be automated and is capable of continuously scanning multiple samples, making it ideal for quality control.
... The final ruling by the Court was that it was unlikely kava had caused the reported deaths, and that liver damage from kava was so rare it was negligible. The Court rejected claims of liver damage caused by kava, and specified that these assertions were a gross misrepresentation of the possible effects (Kuchta et al., 2015;Schmidt, 2014). ...
What seemed impossible 50 years ago is today becoming a reality as ‘soft drugs’ such as cannabis are being decriminalized and accepted for their calming effects as well as their legitimate medicinal properties. Several countries have now made the possession of cannabis legal, with others considering this, while the coffee shops in the Netherlands have been supplying cannabis in different forms for many years. It is now the turn of kava to be re-evaluated, to see whether there are properties in this plant that might be readily substituted for more conventional and harmful drugs, for instance tobacco and alcohol. However, as highlighted by Norton and Ruze (1994), kava like cannabis, has an enduring reputation that still makes it difficult for many to accept. Kava has been mythologized as an illicit alcohol, highly addictive, and causing physical harm. When examining the history of kava use in traditional contexts and considering the evidence now available, it is possible to demythologize this characterization. Looking at the potential benefits, it is time to re-brand kava, not only on the grounds as a relaxant, but in possessing life enhancing medicinal properties and as an alternative to alcohol, understanding that will be beneficial to policy makers, doctors and pharmacists.
... Kava abuse has been a concern in other countries. Kava products were, until recently, banned in the United Kingdom and Germany due to cases of hepatotoxicity (5). This hepatotoxicity may be caused by overconsumption or improper preparation of kava (6,7). ...
Kava is an Oceanic plant in which the root is consumed as a beverage and is becoming increasingly popular. The effects of kava consumption may include sedation, euphoria, and impairment of motor coordination. This article demonstrates kava impairment through four cases of self‐reported kava use supported with Drug Recognition Expert (DRE) evaluations of each subject. Subject's urines screened negative for common drugs of abuse by immunoassay analysis. Urine from cases 3 and 4 were analyzed by liquid chromatography–tandem mass spectrometry, and gas chromatography–mass spectrometry, which yielded the presence of kavalactones. Subjects exhibited poor driving behavior and signs of intoxication. Indicators of impairment from multiple drug categories, central nervous system (CNS) depressants, CNS stimulants, and cannabis were observed, which may be consistent with the presence of multiple kavalactones and their diverse array of mechanisms of action. The consumption of kava can hinder one's ability to operate a vehicle safely.
... 15 The culprit of kava hepatotoxicity remains a mystery and under debate. 16,17 Even though the kava ban has been lifted in Germany in 2015, 18 kava hepatotoxicity remains a major concern in the United States and other countries. 19,20 Therefore, more studies are required to understand the risk factors and underlying mechanisms that lead to kava hepatotoxicity. ...
Kavain is an active and major component in Piper methysticum Forst. (kava), which is a widely used dietary supplement for the treatment of anxiety, insomnia, and stress. However, kava-containing products can cause liver toxicity and its underlying mechanisms are understudied. Cytochrome P450s (CYPs)-mediated bioactivation and biotransformation are highly associated with drug toxicity. In the current study, we profiled the metabolic pathways of kavain in mouse liver, urine, and feces. Overall, 28 kavain metabolites were identified, including 17 new ones. The metabolic pathways of kavain include glutathione (GSH) conjugation, oxidation, dehydrogenation, O-demethylation, sulfation, and glucuronidation. The identification of kavain-GSH adducts suggests the formation of reactive metabolites of kavain in the liver. We further illustrated that CYP2C19, a highly polymorphic and inducible enzyme, was the major enzyme contributing to kavain biotransformation and bioactivation. Our data can be used to guide the safe use of kava products by preventing potential herb-drug interactions and hepatotoxicity.
... Other confounding factors specifically related to kava include lack of quality control at the producer level (inappropriate cultivar, plant quality, plant parts used, and mold contamination), and production level (kavalactone content and profile, solvent use, metal contaminants and toxin testing) (Teschke et al., 2011). The German ban on kava was finally overturned in 2014 due to lack of conclusive evidence associating kava with liver toxicity (Kuchta et al., 2015). ...
Ethnopharmacological relevance
Kava and kava extracts have shown great potential as a way to minimize anxiety-associated symptoms and to help alleviate pain. Hepatoxicity has been associated with the consumption of kava products. The chemical compounds, kavalactones (KL) and flavokavains (FK) have been implicated in kava’s psychotropic and possible hepatotoxic properties.
Aim of the study
To investigate the kavalactone and flavokavain content and in vitro toxicity of KAVOA™, a supercritical carbon dioxide extraction (SFE) of kava.
Materials and methods
Kavalactone and flavokavain content of SFE kava and noble kava root were determined following extraction in acetone, cell culture media, and water using ultra high-performance liquid chromatography (UHPLC). Using water extractions of the kava products, the cell viability and toxicity on the human hepatocellular carcinoma cell line (HepG2) were determined using luminescent and fluorescent assays, respectively. The half maximal inhibitory concentration (IC50) of the SFE kava and noble kava root, extracted in cell culture media, were determined utilizing a luminescent cell viability assay.
Results
Quantification of the KAVOA™, a SFE extract of kava and kava root showed similar profiles of kavalactone and flavokavain content. Water extracted SFE and root kava did not show a negative impact on cell viability and toxicity when compared to the vehicle control treated cells. IC50 values were determined for the SFE kava and kava root extracted in cell culture media in respect to cell viability, 78.63 and 47.65 µg/mL, respectively.
Conclusions
KAVOA™, a supercritical carbon dioxide extract of kava displays a similar kavalactone profile to a noble variety of kava. In relation to total kavalactone content, KAVOA™ also has a lower content of the cytotoxic compound FKB. Aqueous extractions of KAVOA™ and noble kava root had no significant negative impact on cell viability and toxicity on HepG2 cells when compared to vehicle controlled treated cells. Results indicate KAVOA™ demonstrates a similar in vitro safety profile to that of noble kava root when experiments are normalized to kavalactone content.
... cal trials [2,7]. In 2015, the German kava ban was lifted by court [10]. Kava has regained its legal status in most countries; however, its trade, consumption, and distribution are strictly regulated and monitored [2]. ...
Piper methysticum (Kava) is a plant whose roots are used in the preparation of traditional beverages with spiritual, medicinal, and social importance for the Pacific Islanders. Kava is also sold as a herbal supplement or recreational beverage consumed for its mild inebriating effect in Europe and North America. With an ongoing interest in the safety and quality of kava products, it is necessary to develop a validated method for determination of kava chemical composition to ensure confidence in quality assessment. Thus, an high-performance liquid chromatography with ultraviolet detection (HPLC-UV) method was developed, optimized, and validated for determining six major kavalactones and three flavokavains in kava raw materials and finished products based on AOAC single-laboratory validation guidelines. This is the first fully validated analytical method for measuring kavalactones and flavokavains in a single run. The separation of the analytes was achieved in 10 min with an Agilent Poroshell C18 column using gradient separation. The sample was extracted with methanol first and then acetone. The signals were detected at 240 nm and 355 nm. The limit of quantification was under 1.2 µg/mL (0.3 mg/g) for kavalactones and under 0.35 µg/mL (0.01 mg/g) for flavokavains. The Horwitz ratio values described ranged from 0.3 to 1.82. The spike recovery experiments showed an accuracy between 92 and 105% for all analytes. The results of the study demonstrate that the method is fit for the purpose of determining methysticin, dihydromethysticin, kavain, dihydrokavain, yangonin, desmethoxyyangonin, flavokavain A, flavokavain B, and flavokavain C in kava raw material and finished products (dry-filled capsule, liquid phytocaps, and tincture).
... Beyond potential benefits, reports of rare but sometimes severe hepatotoxic cases among kava users in the late 1990s have brought the public attention to its safety [2], resulting in the ban of kava in Germany between 2001-2014 [17]. The US Food and Drug Administration (FDA) also advised consumers of its hepatotoxic risk in 2002. ...
Kava is regaining its popularity with detailed characterizations warranted. We developed an ultraperformance liquid chromatography high-resolution tandem mass spectrometry (UPLC-MS/MS) method for major kavalactones (kavain, dihydrokavain, methysticin, dihydromethysticin and desmethoxyyangonin) with excellent selectivity and specificity. The method has been validated for different matrices following the Food and Drug Administration guidance of analytical procedures and methods validation. The scope of this method has been demonstrated by quantifying these kavalactones in two kava products, characterizing their tissue distribution and pharmacokinetics in mice, and detecting their presence in human urines and plasmas upon kava intake. As expected, the abundances of these kavalactones differed significantly in kava products. All of them exhibited a large volume of distribution with extensive tissue affinity and adequate mean residence time (MRT) in mice. This method also successfully quantified these kavalactones in human body fluids upon kava consumption at the recommended human dose. This UPLC-MS/MS method therefore can be used to characterize kava products and its pharmacokinetics in animals and in humans.
... 14 Ultimately, these bans have been lifted in most places, as evidence became overwhelming that kava is not inherently hepatotoxic, that the cases represented idiosyncratic harm at most, and that any adverse liver-related outcome was extremely rare. 15,16 Kava may not be intrinsically hepatotoxic but, out of an abundance of caution, should be avoided in combination with known hepatotoxins (e.g., excessive alcohol, acetaminophen, metronidazole) or in patients with severe liver disease until more information is available. ...
The many herbal options for patients with anxiety are discussed, focusing initially on Piper methysticum (kava) as one of the most well-researched options in this setting. The unstudied, but clinically as effective (and much more palatable), Pedicularis spp. (lousewort) are also discussed. Other nervine herbs including Lavandula angustifolia (true lavender), L. latifolia (spike or Portuguese lavender), Lavandula x intermedia (lavandin, Dutch lavender), L. stoechas (Spanish lavender), Matricaria chamomilla (chamomile), and Passiflora incarnata (passionflower) are reviewed (and a table of other nervines is provided). Three formulas, including mixtures of nervines, Ze 185, Euphytose, and Yì Qì Yng Xīn (Replenish Qi and Nourish the Heart), are discussed. Miscellaneous anxiolytics such as Crocus sativus (saffron), L-theanine from Camellia sinensis (green tea), and the three calming adaptogens Rhodiola rosea (roseroot), Centella asiatica (gotu kola), and Withania somnifera (ashwagandha) are then detailed. Herbal anxiolytics offer great promise to relieve anxiety safely.
... Given kava's widespread history within Oceania, the market for kava was inadvertently decimated in 2002 when kava-containing substances were banned by the European Union (EU) for controversial hepatotoxicity issues (Baker, 2008(Baker, , 2011Teschke, Schwarzenboeck, & Hennermann, 2008;Pollock, 2009;Teschke, Qiu, &Lebot, 2011;and Kuchta, Schmidt, & Nahrstedt, 2015). The ban on kava would be overturned nearly eight years later in 2015. ...
This study investigated ethnobotanical knowledge variation in Hawai’i and Vanuatu, two regions in opposite ends of the Oceanic archipelago known for its distinctive yet interrelated cosmologies that have shaped kava culture and epistemology. The theory of perceptual salience suggests that the more exposure one has to a certain environment, the more one will know about that environment. In this study, this theory was applied in both Hawai’i and Vanuatu to understand the drivers of kava consumption and how exposure to an environment where diverse varieties of kava are grown influences knowledge of kava and selection of varieties for consumption. Data were obtained by free-listing of kava cultivars and through semi-structured surveys. Perceptual salience was determined by location, frequency of cultivars cited, tudey cultivars, and rate of consumption. This study also explored how the dynamics of gender and age affect how much a person knows about kava. The results show that there is no significant relationship between varietal diversity and varietal knowledge. This lack of significant influence of exposure on individual knowledge is due to the high variation in varietal knowledge in Hawai’i. However, there was a significant relationship between the predictors of knowledge, age and region. Specifically, varietal knowledge has more to do with exposure over time, rather than how much exposure one has had to varieties of kava. This study provides insight into how varietal diversity alone is not enough to influence people’s knowledge. It also shows how the length of exposure to a given environment better defines how environmental structures affect people's knowledge. This study provides further insight into future pathways as kava enters the global market, which varieties require more attention to ensure their survival, and how exposure to kava varieties over time influences consumption patterns.
... This, and the fact that traded plant material consists of powdered, dry underground organs, make attribution of commercially sold material to a specific cultivar, or even a group of cultivars, impossible. This uncertainty and misidentification may have been the cause of the reported liver problems (Kuchta et al., 2015;Martin et al., 2014;Teschke et al., 2011). ...
The present study aimed at evaluating the potential of diethyl ether extracts UV/visible (UV/vis) absorbance for assessing the suitability of commercial lots of kava (Piper methysticum). The UV/vis absorption spectra of diethyl ether root extracts of 15 cultivars clustered them into three groups in parallel to their known genetic relatedness and their chemical composition determined by GC–MS and LC–MS analyses. Absorption peaks at 250 nm and 290 nm respectively corresponded to kavain, the most health-promoting kavalactone, and dihydromethysticin a non-desirable kavalactone. The absorbance peak at 340–350 nm reflected the yellow coloration of the extract, which was mainly due to the undesirable flavokavins, desmethoxyyangonin and yangonin. Ratios of absorbance values at 250 nm and 290 nm significantly differentiated all three groups of cultivars, namely ‘noble’ which provide health benefits from ‘two-day’ and ‘wichmannii’ that are health damaging. These results provide a robust and rapid colorimetric test for routine control of a critical aspect of the quality of kava batches.
... The ban of re- spective products in Europe 2002 was surprising, because their assumed hepatotoxicity could not be confirmed convincingly. Several possible explanations for reported liver damage after kava consumption were postulated, ranging from human genetic vari- ability and the use of inappropriate solvents for extraction to plant adulteration [3]. As a consequence, in February 2015, the German upper administrative court confirmed a previous decision that a ban of kava is not justified because of indecisive data on its toxic- ity or efficacy. ...
A fast and validated supercritical fluid chromatography method for the quantitative determination of major lactones in Piper methysticum, a plant used against nervous anxiety, stress, and restlessness, was developed. The baseline separation of dihydrokavain, demethoxyyangonin, kavain, yangonin, dihydromethysticin, and methysticin was possible in less than 4 min on an Aquity UPC(2) BEH 1.7 µm column, in combination with a mobile phase comprising CO2 and methanol with diethylamine. The column temperature had a great impact on the results because only at 70 °C could kavain and yangonin be fully resolved. With correlation coefficients above 0.998, recovery rates between 95.9 and 104.1 % as well as limit of detection values below 1.5 ng on-column, the procedure fulfilled all validation requirements and was well suited for the quantitative analysis of commercial products containing P. methysticum root powder and/or extract. All of them contained the target analytes, however, the absolute content of lactones was quite variable. Accordingly, depending on the product, the total daily intake of lactones varied from 56 to 312 mg. Concerning speed, selectivity, and environmental friendly operation, this supercritical fluid chromatography approach surpasses all previously reported ones.
... Studies attribute toxic effects to organic solvents used for extraction or to contamination, impurities, handling and storage, age of plant, quality of cultivars ( Triolet et al., 2012;Martin et al., 2014 ) or using the wrong plant part, such as the leaf or stem. A kava ban instituted by Germany in 2002 was lifted in June 2014 ( Kuchta et al., 2015 ). ...
Background:
Epidemiological studies indicate there is low incidence of colon cancer in the South Pacific islands, including Fiji, West Samoa, and Vanuatu. Cancer incidence has been shown to be inversely associated with kava (Piper methysticum G. Forst.) ingestion. Hypothesis/Purpose: Kava prepared traditionally will inhibit the growth of human cancer cells. This investigation entails preparation and analysis of kava extracts and study of the growth inhibitory activity of the extracts, alone and combined with hibiscus.
Study design:
We will prepare kava as in Micronesia - as a water extract, high in particulate content, alone or combined with sea hibiscus (Hibiscus tiliaceus L.) - and examine the components and growth inhibitory activity.
Methods:
We obtained ground kava prepared in the traditional way from lateral roots and sea hibiscus mucilage and sap from different sources in Micronesia, and prepared water extracts (unfiltered, as well as filtered, since in traditional use the kava beverage contains a high particulate content) and partitions. We used the MTT assay to determine the growth inhibitory activity of the preparations on colon and breast cancer cells and nonmalignant intestinal epithelial cells. LC-MS analysis was used to examine the components of the kava and sea hibiscus extracts and partitions.
Results:
Traditional preparations of kava inhibit the growth of breast and colon cancer cells. Among the kava preparations, the order of decreasing activity was Fiji(2), Fiji(1), Hawaii; the unfiltered preparations from Fiji were more active than the filtered. Phytochemical analysis indicated that filtering reduced most kavalactone and chalcone content. For example, for Fiji(2), the ratio of dihydromethysticin in filtered/unfiltered kava was 0.01. Thus, for the extracts from Fiji, growth inhibitory activity correlates with the content of these compounds. Unfiltered and filtered kava from Fiji(1) were more active on malignant than nonmalignant intestinal epithelial cells. Since kava is prepared in Micronesia by squeezing the extract through sea hibiscus bark, we assayed the growth inhibitory activity of combinations of kava and sea hibiscus sap and found that sea hibiscus enhanced the growth inhibitory effect of kava.
Conclusion:
Our results show that traditional kava, alone or combined with sea hibiscus, displays activity against human cancer cells and indicate it will be worthwhile to develop and further analyze these preparations to prevent and treat colon and other cancers. Our findings suggest it is important to examine the activity of plants in the form that people consume them.
... In addition to its chemopreventive potential, kava usage has been linked to hepatotoxicity in humans. 35 Here we characterized the impact of dietary DHM on CYP1A1/2 to further explore its safety. We focused on CYP1A1/2 in this study mainly because these two CYP isozymes are dominantly regulated by AhR 36 and Li et al. has demonstrated CYP1A1 activation by DHM in an AhR-dependent manner in vitro. ...
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a key carcinogen responsible for tobacco smoke-induced lung carcinogenesis. Among DNA damages caused by NNK and its metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), O6-methylguanine (O6-mG) is likely the most carcinogenic in A/J mice. Results of our previous studies showed that O6-mG and other NNAL-derived DNA damages were preferentially reduced in the lung of female A/J mice upon the dietary treatment with dihydromethysticin (DHM), a promising lung cancer chemopreventive agent from kava. Such a differential blockage may be mediated via increased NNAL glucuronidation and thereof leading to its detoxification. The potential of the aryl hydrocarbon receptor (AhR) as an up-stream target of DHM mediating these events was evaluated herein using Ahr+/- and Ahr-/- C57BL/6 female mice because DHM was reported as an AhR agonist. DHM (0.05, 0.2 and 1.0 mg/g of diet) and dihydrokavain (DHK, an inactive analog, 1.0 mg/g of diet) were given to mice for seven days, followed by a single i.p. dose of NNK at 100 mg/kg of bodyweight. The effects of DHM on the amount of O6-mG in the lung, on the urinary ratio of glucuronidated NNAL (NNAL-Gluc) and free NNAL, and on CYP1A1/2 activity in the liver microsomes were analyzed. As observed in A/J mice, DHM treatment significantly and dose-dependently reduced O6-mG in the target lung tissue, but there were no significant differences in O6-mG reduction between mice from Ahr+/- and Ahr-/- backgrounds. Similarly, in both strains, DHM at 1 mg/g of diet significantly increased the urinary ratio of NNAL-Gluc to free NNAL and CYP1A1/2 enzymatic activity in liver with no changes detected at lower DHM dosages. Since none of these effects of DHM were dependent of Ahr status, AhR clearly is not the up-stream target for DHM.
... Its manifestation is suggested to be in relationship with a lack of compliance to recommended dose/overdosing or with a co-ingestion of herbal supplements or other substances or as a consequence of non-standardization of the kava products [178]. Furthermore, the ban imposed in Germany on the herbal supplement kava was overturned in 2014, after the decisions of two administrative German Courts [179][180][181]. ...
The 3Ks (kava, kratom and khat) are herbals that can potentially induce liver injuries. On the one hand, growing controversial data have been reported about the hepatotoxicity of kratom, while, on the other hand, even though kava and khat hepatotoxicity has been investigated, the hepatotoxic effects are still not clear. Chronic recreational use of kratom has been associated with rare instances of acute liver injury. Several studies and case reports have suggested that khat is hepatotoxic, leading to deranged liver enzymes and also histopathological evidence of acute hepatocellular degeneration. Numerous reports of severe hepatotoxicity potentially induced by kava have also been highlighted, both in the USA and Europe. The aim of this review is to focus on the different patterns and the mechanisms of hepatotoxicity induced by "the 3Ks", while trying to clarify the numerous aspects that still need to be addressed.
Drug (ab)use among young people is a serious issue, negatively impacting their well-being and prospects. The emergence of new psychoactive substances (NPS) further complicates the situation as they are easily accessible (e.g., online), but users are at high risk of intoxication as their chemical identity is often unknown and toxicity poorly understood. While surveys and drug testing are traditionally used in educational institutions to comprehend drug use trends and establish effective prevention programs, they are not without their limitations. Accordingly, we investigated the occurrence of NPS in educational institutions through wastewater analysis and critically evaluated the viability of the approach. The study included eight wastewater samples from primary schools (ages 6-15 years), six from secondary schools (ages 15-19 years), three from institutions for both secondary and higher education (ages 15+), and six from higher educational institutions (ages 19+). Samples were obtained mid-week and evaluated in two Slovenian municipalities; the capital Ljubljana and a smaller one (M1). Samples were screened using liquid chromatography-ion mobility-high-resolution mass spectrometry (LC-IMS-HRMS), and NPS identified at three levels of confidence (Level 1: unequivocal, Level 2: probable, Level 3: tentative) from a suspect list containing over 5600 entries. NPS were identified in all types of educational institutions. Most were synthetic stimulants, with 3-MMC, ephedrine, 4-chloro-α-PPP, and ethcathinone being unequivocally identified. Also, NPS were present in wastewater from all educational institution types revealing potential spatial but no inter-institutional trends. Although specific groups cannot be targeted, the study, as a proof-of-concept, demonstrates that a suspect screening of wastewater employing LC-IMS-HRMS can be used as a radar for NPS in educational institutions and potentially replace invasive drug testing.
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.].
Ethnopharmacological relevance:
Piper methysticum G. Forst, popularly known as kava, is a traditional medicinal plant native from South Pacific islands and widely used to treat anxiety, depression and stress. The psychoactive properties are related to the kavalactones, mainly kavain.
Aim of the study:
To evaluate the biopharmaceutical properties of synthetic kavain and when present in kava dried extracts by means of equilibrium solubility and intestinal permeability studies in the Caco-2 cell model.
Materials and methods:
The equilibrium solubility of kavain was performed using a shake flask incubator at 37 °C in different media at physiological pH range (1.2-6.8). The intestinal permeability of kavain evaluated in Caco-2 cells in the presence and absence of the P-glycoprotein inhibitor verapamil. Kavain concentrations were determined by reversed phase high performance liquid chromatography (HPLC).
Results:
HPLC methods were developed and fully validated for kavain quantitation. Kavain demonstrated low solubility and the pH of the aqueous media did not affect its solubility. Kavain was found to be highly permeable and efflux of kavain mediated by P-glycoprotein was not significant during intestinal permeation.
Conclusion:
The results of biopharmaceutical studies provided useful information for predicting availability of kavain from the gastrointestinal tract and this compound was ranked as BCS Class II, exhibiting dissolution rate-limited absorption.
Zusammenfassung
Arzneimittel auf der Basis von Extrakten aus den Wurzeln der Kavapflanze (Piper methysticum) waren in Deutschland bis zum Widerruf der Zulassungen am 14. Juni 2002 sehr beliebte Mittel gegen nervöse Angst-, Spannungs- und Unruhezustände. Kava ist eine der am besten untersuchten Arzneipflanzen, sowohl aus pharmakologischer Sicht als auch durch klinische Evidenz und Jahrhunderte traditioneller Erfahrung der sicheren Anwendung im Südpazifik. Noch bleibt Hoffnung, dass die behördliche Entscheidung revidiert werden kann.
Kavain, kavalactone, present in Piper methysticum exhibits anticonvulsive, analgesic, anxiolytic, antiepileptic, antithrombotic, anti-inflammatory and antioxidant properties. Given its importance, the aim of the present study was to assess (1) the mutagenic and carcinogenicity of kavain administered alone and (2) the antimutagenic and anticarcinogenic potential when administered simultaneously with the chemotherapeutic drug doxorubicin (DXR) using the Somatic Mutation and Recombination Test (SMART) and Epithelial Tumor Test (ETT) using Drosophila melanogaster as a model system. Third-stage larvae from a standard (ST) and high metabolic bioactivation (HB) crosses were treated with different kavain concentrations (32, 64 or 128 μg/ml), alone or in conjunction with DXR (0.125 mg/ml). In ST descendants, kavain produced no significant mutagenic or recombinogenic effects. In the HB cross, mutagenic activity was observed at kavain concentrations of 64 and 128 μg/ml. In the DXR and kavain co-treatment, a modulating effect of the DXR-mediated mutagenic response dependent upon the concentration was detected in both crosses. In ETT, no marked carcinogenic or anticarcinogenic activity was noted for kavain. However, when kavain was combined with DXR synergistic induction of tumors by the chemotherapeutic drug occurred indicating that kavain enhanced the carcinogenic action of DXR.
Kava, the rhizomes and roots of Piper methysticum Forst, is a popular edible medicinal herb traditionally used to prepare beverages for anxiety reduction. Since the German kava ban has been lifted by the court, the quality evaluation is particularly important for its application, especially the flavokawains which were believed the responsibilities for the hepatotoxicity. Now, by employing two different standard references and four different methods to calculate the relative correction factors, eight different quantitative analysis of multi-components by single-marker methods have been developed for the simultaneous determination of eight major kavalactones and flavokawains in kava. The low standard method difference on quantitative measurement of the compounds among the external standard method and ours confirmed the reliable of the mentioned methods. A radar plot clearly illustrated that the contents of dihydrokavain and kavain were higher, whereas flavokawains A and B were lower in different kava samples. Only one of eight samples did not detected flavokawains which maybe related to hepatotoxicity. Summarily, by using different agents as internal standard reference, the developed methods were believed as a powerful analytical tool not only for the qualitative and quantitative of kava constituents but also for the other multi-components when authentic standard substances were unavailable. This article is protected by copyright. All rights reserved.
Tobacco smoking is the primary risk factor for lung cancer, driven by the addictive nature of nicotine and the indisputable carcinogenicity of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) as well as other compounds. The integration of lung cancer chemoprevention with smoking cessation is one potential approach to reduce this risk and mitigate lung cancer mortality. Experimental data from our group suggest that kava, commonly consumed in the South Pacific Islands as a beverage to promote relaxation, may reduce lung cancer risk by enhancing NNK detoxification and reducing NNK-derived DNA damage. Building upon these observations, we conducted a pilot clinical trial to evaluate the effects of a 7-day course of kava on NNK metabolism in active smokers. The primary objective was to compare urinary total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL plus its glucuronides, major metabolites of NNK) before and after kava administration as an indicator of NNK detoxification. Secondary objectives included determining kava's safety, its effects on DNA damage, tobacco use, and cortisol (a biomarker of stress). Kava increased urinary excretion of total NNAL and reduced urinary 3-methyladenine (3-mA) in participants, suggestive of its ability to reduce the carcinogenicity of NNK. Kava also reduced urinary total nicotine equivalents (TNE), indicative of its potential to facilitate tobacco cessation. Plasma cortisol and urinary total cortisol equivalents (TCE) were reduced upon kava use, which may contribute to reductions in tobacco use. These results demonstrate the potential of kava intake to reduce lung cancer risk among smokers.
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.
Extracts of the pepper plant kava (Piper methysticum) are effective in alleviating anxiety in clinical trials. Despite the long-standing therapeutic interest in kava, the molecular target(s) of the pharmacologically active constituents, kavalactones have not been established. γ-Aminobutyric acid type A receptors (GABAARs) are assumed to be the in vivo molecular target of kavalactones based on data from binding assays, but evidence in support of a direct interaction between kavalactones and GABAARs is scarce and equivocal. In this study, we characterised the functional properties of the major anxiolytic kavalactone, kavain at human recombinant α1β2, β2γ2L, αxβ2γ2L (x = 1, 2, 3 and 5), α1βxγ2L (x = 1, 2 and 3) and α4β2δ GABAARs expressed in Xenopus oocytes using the two-electrode voltage clamp technique. We found that kavain positively modulated all receptors regardless of the subunit composition, but the degree of enhancement was greater at α4β2δ than at α1β2γ2L GABAARs. The modulatory effect of kavain was unaffected by flumazenil, indicating that kavain did not enhance GABAARs via the classical benzodiazepine binding site. The β3N265M point mutation which has been previously shown to profoundly decrease anaesthetic sensitivity, also diminished kavain-mediated potentiation. To our knowledge, this study is the first report of the functional characteristics of a single kavalactone at distinct GABAAR subtypes, and presents the first experimental evidence in support of a direct interaction between a kavalactone and GABAARs.
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
The diagnosis of herbal hepatotoxicity or herb induced liver injury (HILI) represents a particular clinical and regulatory challenge with major pitfalls for the causality evaluation. At the day HILI is suspected in a patient, physicians should start assessing the quality of the used herbal product, optimizing the clinical data for completeness, and applying the Council for International Organizations of Medical Sciences (CIOMS) scale for initial causality assessment. This scale is structured, quantitative, liver specific, and validated for hepatotoxicity cases. Its items provide individual scores, which together yield causality levels of highly probable, probable, possible, unlikely, and excluded. After completion by additional information including raw data, this scale with all items should be reported to regulatory agencies and manufacturers for further evaluation. The CIOMS scale is preferred as tool for assessing causality in hepatotoxicity cases, compared to numerous other causality assessment methods, which are inferior on various grounds. Among these disputed methods are the Maria and Victorino scale, an insufficiently qualified, shortened version of the CIOMS scale, as well as various liver unspecific methods such as the ad hoc causality approach, the Naranjo scale, the World Health Organization (WHO) method, and the Karch and Lasagna method. An expert panel is required for the Drug Induced Liver Injury Network method, the WHO method, and other approaches based on expert opinion, which provide retrospective analyses with a long delay and thereby prevent a timely assessment of the illness in question by the physician. In conclusion, HILI causality assessment is challenging and is best achieved by the liver specific CIOMS scale, avoiding pitfalls commonly observed with other approaches.
Men living in Fiji and drinking kava have low incidence of prostate cancer (PCa). However, the PCa incidence among Fijian men who had migrated to Australia, increased by 5.1-fold. We therefore examined the potential effects of kava root extracts and its active components (kavalactones and flavokawains) on PCa growth and androgen receptor (AR) expression. PCa cell lines (LNCaP, LAPC-4, 22Rv1, C4-2B, DU145 and PC-3) with different AR expression, and a transformed prostate myofibroblast cell line (WPMY-1), were treated with a commercial kava extract, kavalactones (kawain, 5'6'-dehydrokawain, yangonin, methysticin) and flavokawain B. Expression of AR and its target genes (PSA and TMPRSS2) was examined. Two novel patient-derived PCa xenograft models from high grade PCa specimens were established by implanting the specimens into nude mice and passing tumor pieces through subcutaneous injection in nude mice, and then treated with kava extract and flavokawain B to examine their effects on tumor growth, AR expression and serum PSA levels. The kava extract and flavokawain B effectively down-regulated the expression of both the full-length AR and AR splice variants. The kava extract and kavalactones accelerated AR protein degradation, while flavokawain B inhibited AR mRNA transcription via decreasing Sp1 expression and the binding of Sp1 to the AR promoter. The kava root extract and flavokawain B reduce tumor growth, AR expression in tumor tissues and levels of serum PSA in the patient-derived PCa xenograft models. These results suggest a potential usefulness of a safe kava product or its active components for prevention and treatment of advanced PCa by targeting AR.
Kava (Piper methysticum Foster, Piperaceae) organic solvent-extract has been used to treat mild to moderate anxiety, insomnia, and muscle fatigue in Western countries, leading to its emergence as one of the 10 best-selling herbal preparations. However, several reports of severe hepatotoxicity in kava consumers led the U.S. Food and Drug Administration and authorities in Europe to restrict sales of kava-containing products. Herein we demonstrate that flavokawain B (FKB), a chalcone from kava root, is a potent hepatocellular toxin, inducing cell death in HepG2 (LD(50)=15.3 ± 0.2 μM) and L-02 (LD(50)=32 μM) cells. Hepatocellular toxicity of FKB is mediated by induction of oxidative stress, depletion of reduced glutathione (GSH), inhibition of IKK activity leading to NF-κB transcriptional blockade, and constitutive TNF-α-independent activation of mitogen-activated protein kinase (MAPK) signaling pathways, namely, ERK, p38, and JNK. We further demonstrate by noninvasive bioluminescence imaging that oral consumption of FKB leads to inhibition of hepatic NF-κB transcriptional activity in vivo and severe liver damage. Surprisingly, replenishment with exogenous GSH normalizes both TNF-α-dependent NF-κB as well as MAPK signaling and rescues hepatocytes from FKB-induced death. Our data identify FKB as a potent GSH-sensitive hepatotoxin, levels of which should be specifically monitored and controlled in kava-containing herb products.
Kava ( Piper methysticum Forst. f., Piperaceae), prepared as the traditional aqueous infusion, was tested in the rat for possible effects on liver function tests. Extracts were administered in daily dosages of 200 or 500 mg of the active kavalactones/kg for two or four weeks. Sera were assayed for four enzymes that are markers of liver toxicity and liver homogenates for malondialdehyde formation that indicates changes in lipid peroxidation. The data showed that none of the enzymes, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and lactate dehydrogenase, nor malondialdehyde were elevated, in fact in some cases they were significantly reduced, suggesting the lack of a toxic effect by kava on the liver.
The pyridone alkaloid pipermethystine has been considered to be responsible for alleged hepatoxicity of Kava products. Investigation of a series of retain samples of finished products from the German market and self-produced extracts from root and stem material of Piper methysticum clearly showed that pipermethystine (1) is absent from all root and retain samples and extracts, with a limit of quantification of 45 ppm. As a positive control, leaves of P. methysticum showed an amount of 0.2% of 1. Thus, if there is any hepatotoxicity, compound 1 should not be the responsible constituent in the case reports with ethanolic extracts produced in Germany.
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.
Anxiolytic kava products have been associated with rare but severe hepatotoxicity in humans. This adverse potential has never been captured in animal models and the responsible compound(s) remains to be determined. The lack of such knowledge greatly hinders the preparation of a safer kava product and limits its beneficial applications. In this study we evaluated the toxicity of kava as a single entity or in combination with acetaminophen (APAP) in C57BL/6 mice. Kava alone revealed no adverse effects for long-term usage even at a dose of 500 mg/kg bodyweight. On the contrary a three-day kava pre-treatment potentiated APAP-induced hepatotoxicity, resulted in an increase in serum ALT and AST and increased severity of liver lesions. Chalcone-based flavokawains A (FKA) and B (FKB) in kava recapitulated its hepatotoxic synergism with APAP while dihydromethysticin (DHM, a representative kavalactone and a potential lung cancer chemopreventive agent) had no such effect. These results, for the first time, demonstrate the hepatotoxic risk of kava and its chalcone-based FKA and FKB in vivo and suggest that herb-drug interaction may account for the rare hepatotoxicity associated with anxiolytic kava usage in humans.
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.
Kava (Piper methysticum) is a plant-based medicine, which has been previously shown to reduce anxiety. To date, however, no placebo-controlled trial assessing kava in the treatment of generalized anxiety disorder (GAD) has been completed. A total of 75 participants with GAD and no comorbid mood disorder were enrolled in a 6-week double-blind trial of an aqueous extract of kava (120/240 mg of kavalactones per day depending on response) versus placebo. γ-Aminobutyric acid (GABA) and noradrenaline transporter polymorphisms were also analyzed as potential pharmacogenetic markers of response. Reduction in anxiety was measured using the Hamilton Anxiety Rating Scale (HAMA) as the primary outcome. Intention-to-treat analysis was performed on 58 participants who met inclusion criteria after an initial 1 week placebo run-in phase. Results revealed a significant reduction in anxiety for the kava group compared with the placebo group with a moderate effect size (P = 0.046, Cohen d = 0.62). Among participants with moderate to severe Diagnostic and Statistical Manual of Mental Disorders-diagnosed GAD, this effect was larger (P = 0.02; d = 0.82). At conclusion of the controlled phase, 26% of the kava group were classified as remitted (HAMA ≤ 7) compared with 6% of the placebo group (P = 0.04). Within the kava group, GABA transporter polymorphisms rs2601126 (P = 0.021) and rs2697153 (P = 0.046) were associated with HAMA reduction. Kava was well tolerated, and aside from more headaches reported in the kava group (P = 0.05), no other significant differences between groups occurred for any other adverse effects, nor for liver function tests. Standardized kava may be a moderately effective short-term option for the treatment of GAD. Furthermore, specific GABA transporter polymorphisms appear to potentially modify anxiolytic response to kava.
Presently, little is known about a number issues concerning kava (Piper methysticum), including (i) whether kava has any withdrawal or addictive effects; (ii) if genetic polymorphisms of the cytochrome (CYP) P450 2D6 liver enzyme moderates any potential adverse effects; and (iii) if medicinal application of kava has any negative or beneficial effect on sexual function and experience. The study design was a 6-week, double-blind, randomized controlled trial (n = 75) involving chronic administration of kava (one tablet of kava twice per day; 120 mg of kavalactones per day, titrated in non-response to two tablets of kava twice per day; 240 mg of kavalactones) or placebo for participants with generalized anxiety disorder. Results showed no significant differences across groups for liver function tests, nor were there any significant adverse reactions that could be attributed to kava. No differences in withdrawal or addiction were found between groups. Interesting, kava significantly increased female's sexual drive compared to placebo (p = 0.040) on a sub-domain of the Arizona Sexual Experience Scale (ASEX), with no negative effects seen in males. Further, it was found that there was a highly significant correlation between ASEX reduction (improved sexual function and performance) and anxiety reduction in the whole sample. Copyright © 2013 John Wiley & Sons, Ltd.
Zusammenfassung: Die Arzneimittelzulassung folgt weltweit drei Grundprinzipien: dem Nachweis von Qualität, Wirksamkeit und Unbedenklichkeit. Im folgenden Beitrag soll im Lichte der derzeitigen Diskussion um hepatische Nebenwirkungen die Anwendbarkeit dieser drei Prinzipien auf Extrakte aus den Wurzeln der Arzneipflanze Kava (Piper methysticum) dargestellt werden.Piper methysticum (Kava) in Discussion: Proof of Quality, Efficacy and SafetySummary: Worldwide the application for a drug registration follows three basic principles: the proof of quality, efficacy and safety. In the following the applicability of these three principles on extracts from roots of the medicinal plant Kava (Piper methysticum) will be examined in the light of the current discussion of possible hepatic side effects ratio.
Background:
Kava hepatotoxicity in 20 patients from Germany has been debated worldwide following a regulatory ad hoc causality assessment and ban of kava, an anxiolytic herbal remedy obtained from the rhizome of Piper methysticum Forster.
Aims:
We assessed causality with a quantitative structured causality analysis in all 20 cases of patients with liver disease, presented by the German regulatory agency that assumed a causal relationship with the use of kava extracts.
Methods:
The quantitative scale of CIOMS (Council for International Organizations of Medical Sciences) in its updated form was employed for causality assessment and quality evaluation of the regulatory data presentation.
Results:
The regulatory information is scattered and selective, and items essential for causality assessment, such as exclusion of kava independent causes, were not, or only marginally, considered by the regulator. Quantitative causality assessment for kava was possible (n=2), unlikely (n=12), or excluded (n=6), showing no concordance with the regulatory ad hoc causality evaluation.
Conclusion:
The regulatory data regarding kava hepatotoxicity is selective and of low quality, not supportive of the regulatory proposed causality; but instead, is an explanation of the overall causality discussions of kava hepatotoxicity. We are proposing that the regulatory agency reports data in full length and reevaluates causality.
Kava (Piper methysticum) is a psychotropic plant medicine with history of cultural and medicinal use. We conducted a study comparing the acute neurocognitive, anxiolytic, and thymoleptic effects of a medicinal dose of kava to a benzodiazepine and explored for the first time specific genetic polymorphisms, which may affect the psychotropic activity of phytomedicines or benzodiazepines.
Twenty-two moderately anxious adults aged between 18 and 65 years were randomized to receive an acute dose of kava (180 mg of kavalactones), oxazepam (30 mg), and placebo 1 week apart in a crossover design trial.
After exposure to cognitive tasks, a significant interaction was revealed between conditions on State-Trait Anxiety Inventory-State anxiety (p = 0.046, partial ŋ² = 0.14). In the oxazepam condition, there was a significant reduction in anxiety (p = 0.035), whereas there was no change in anxiety in the kava condition, and there was an increase in anxiety in the placebo condition. An increase in Bond-Lader "calmness" (p = 0.002) also occurred for the oxazepam condition. Kava was found to have no negative effect on cognition, whereas a reduction in alertness (p < 0.001) occurred in the oxazepam condition. Genetic analyses provide tentative evidence that noradrenaline (SLC6A2) transporter polymorphisms may have an effect on response to kava.
Acute "medicinal level" doses of this particular kava cultivar in naive users do not provide anxiolytic activity, although the phytomedicine also appears to have no negative effects on cognition.
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
• The rhizome of the Pacific kava plant ( Piper methysticum ) contains as its active constituents numerous kavalactones known for their relaxing properties. Kavalactones are found in aqueous, acetonic and ethanolic extracts of the kava rhizomes. These kava extracts are consumed worldwide and used for recreational purposes as well as to treat general anxiety. Kava use is associated with rare hepatotoxicity.
WHAT THIS PAPER ADDS
• Kava is a Pacific herb consumed worldwide and used for recreational purposes and to treat general anxiety. Kava use is associated with rare hepatotoxicity. The previously proposed Pacific kava paradox was based on kava hepatotoxicity, not observed following use of traditional aqueous extracts in the Pacific region but restricted to use of Western acetonic and ethanolic extracts. However, cases assessed by the WHO report and additional published case reports revealed that traditional aqueous extracts used in New Caledonia, Australia, the USA and Germany may also be hepatotoxic; hence, there is no longer a basis to sustain the previously proposed Pacific kava paradox. It appears that the primary cause of toxicity may be attributed to poor quality of the raw material caused by mould hepatotoxins.
Kava, a Pacific herb consumed worldwide for medicinal, recreational and cultural purposes, has been associated with rare hepatotoxicity, and there is currently a critical need to determine this causation. The previously proposed Pacific kava paradox was based on the theory that kava hepatotoxicity was not observed following use of traditional aqueous extracts in the Pacific region, but was restricted to use of Western acetonic and ethanolic extracts. Subsequent cases analyzed by the World Health Organization and published case reports revealed that traditional aqueous extracts used in New Caledonia, Australia, the USA and Germany may also be hepatotoxic; thus, there is no longer a basis to sustain the previously proposed Pacific kava paradox. It appears that the primary cause of toxicity may reside in the time before the preparation of the various kava extracts, possibly attributed to poor quality of the raw material caused by mould hepatotoxins. Rigorous testing of kava raw material is urgently advised, in addition to Pan‐Pacific kava manufacturing quality standards.
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.
Aqueous kava root preparations have been consumed in the South Pacific as an apparently safe ceremonial and cultural drink for centuries. However, several reports of hepatotoxicity have been linked to the consumption of kava extracts in Western countries, where mainly ethanolic or acetonic extracts are used. The mechanism of toxicity has not been established, although several theories have been put forward. The composition of the major constituents, the kava lactones, varies according to preparation method and species of kava plant, and thus, the toxicity of the individual lactones has been tested in order to establish whether a single lactone or a certain composition of lactones may be responsible for the increased prevalence of kava-induced hepatotoxicity in Western countries. However, no such conclusion has been made on the basis of current data. Inhibition or induction of the major metabolizing enzymes, which might result in drug interactions, has also gained attention, but ambiguous results have been reported. On the basis of the chemical structures of kava constituents, the formation of reactive metabolites has also been suggested as an explanation of toxicity. Furthermore, skin rash is a side effect in kava consumers, which may be indicative of the formation of reactive metabolites and covalent binding to skin proteins leading to immune-mediated responses. Reactive metabolites of kava lactones have been identified in vitro as glutathione (GSH) conjugates and in vivo as mercapturates excreted in urine. Addition of GSH to kava extracts has been shown to reduce cytotoxicity in vitro, which suggests the presence of inherently reactive constituents. Only a few studies have investigated the toxicity of the minor constituents present in kava extract, such as pipermethystine and the flavokavains, where some have been shown to display higher in vitro cytotoxicity than the lactones. To date, there remains no indisputable reason for the increased prevalence of kava-induced hepatotoxicity in Western countries.
Kava hepatotoxicity is a well described disease entity, yet there is uncertainty as to the culprit(s). In particular, there is so far no clear evidence for a causative role of kavalactones and non-kavalactone constituents, such as pipermethystine and flavokavain B, identified from kava. Therefore, novel enzymatic, analytical, toxicological, ethnobotanical and clinical studies are now required. Studies should focus on the identification of further potential hepatotoxic constituents, considering in particular possible adulterants and impurities with special reference to ochratoxin A and aflatoxins (AFs) producing Aspergillus varieties, which should be urgently assessed and published. At present, Aspergillus and other fungus species producing hepatotoxic mycotoxins have not yet been examined thoroughly as possible contaminants of some kava raw materials. Its occurence may be facilitated by high humidity, poor methods for drying procedures and insufficient storage facilities during the time after harvest. Various experimental studies are recommended using aqueous, acetonic and ethanolic kava extracts derived from different plant parts, such as peeled rhizomes and peeled roots including their peelings, and considering both noble and non-noble kava cultivars. In addition, ethnobotanical studies associated with local expertise and surveillance are required to achieve a good quality of kava as the raw material. In clinical trials of patients with anxiety disorders seeking herbal anxiolytic treatment with kava extracts, long-term safety and efficacy should be tested using traditional aqueous extracts obtained from peeled rhizomes and peeled roots of a noble kava cultivar, such as Borogu, to evaluate the risk: benefit ratio. Concomitantly, more research should be conducted on the bioavailability of kavalactones and non-kavalactones derived from aqueous kava extracts. To be on the side of caution and to ensure lack of liver injury, kava consuming inhabitants of the kava producing or importing South Pacific islands should undergo assessment of their liver function values and serum aflatoxin levels. The primary aim is to achieve a good quality of kava raw material, without the risk of adulterants and impurities including ochratoxin A and AFs, which represent the sum of aflatoxin B1, B2, G1 and G2. Although it is known that kava may naturally be contaminated with AFs, there is at present no evidence that kava hepatotoxicity might be due to aflatoxicosis. However, appropriate studies have yet to be done and should be extended to other mould hepatotoxins, with the aim of publishing the obtained results. It is hoped that with the proposed qualifying measures, the safety of individuals consuming kava will substantially be improved. Copyright © 2011 John Wiley & Sons, Ltd.
Since 1998 liver injury has been assumed in some patients after the use of kava (Piper methysticum G. Forster) as an anxyolytic herbal extract, but the regulatory causality evaluation of these cases was a matter of international and scientific debate. This review critically analyzes the regulatory issues of causality assessments of patients with primarily suspected kava hepatotoxicity and suggests recommendations for minimizing regulatory risks when assessing causality in these and other related cases. The various regulatory causality approaches were based on liver unspecific assessments such as ad hoc evaluations, the WHO scale using the definitions of the WHO Collaborating Centre for International Drug Monitoring, and the Naranjo scale. Due to their liver unspecificity, however, these causality approaches are not suitable for assessing cases of primarily assumed liver related adverse reactions by drugs and herbs including kava. Major problems emerged trough the combination of regulatory inappropriate causality assessment methods with the poor data quality as presented by the regulatory agency when reassessment was done and the resulting data were heavily criticized worldwide within the scientific community. Conversely, causality of cases with primarily assumed kava hepatotoxicity is best assessed by structured, quantitative and liver specific causality algorithms such as the scale of the CIOMS (Council for International Organizations of Medical Sciences) or the main-test as its update. Future strategies should therefore focus on the implementation of structured, quantitative and liver specific causality assessment methods as regulatory standards to improve regulatory causality assessments for liver injury by drugs and herbs including kava.
Ingestion of the medicinal herb kava has been associated with hepatotoxicity. We aimed to compare two different quantitative methods of causality assessment of patients with assumed hepatotoxicity by the herb.
We assessed causality in 26 patients from Germany and Switzerland, using two structured quantitative analytical methods: the system of Maria and Victorino (MV) and that of the Council for International Organizations of Medical Sciences (CIOMS). In all 26 patients, regulatory ad hoc evaluation had suggested a causal relationship between liver disease and kava use.
Assessment with the MV scale resulted in no or low graded causality for kava in the 26 patients with liver disease. Causality was probable (n=1), possible (n=2), unlikely (n=7), and excluded (n=16). Causality for kava was more evident with the CIOMS scale: highly probable (n=1), probable (n=2), possible (n=6), unlikely (n=2) and excluded (n=15). However, the results of both quantitative causality assessments are not supportive for most of the regulatory ad hoc causality assessments of the 26 patients.
Grades of causality for suspected hepatotoxicity by kava were much lower when evaluated by structured quantitative causality assessment scales than by regulatory ad hoc judgements. The quantitative CIOMS scale is the preferable tool for causality assessment of spontaneous reports of hepatotoxcity involving kava.
Piper methysticum (Kava) has been withdrawn in European, British, and Canadian markets due to concerns over hepatotoxic reactions. The WHO recently recommended research into "aqueous" extracts of Kava.
The objective of this study was to conduct the first documented human clinical trial assessing the anxiolytic and antidepressant efficacy of an aqueous extract of Kava.
The Kava Anxiety Depression Spectrum Study was a 3-week placebo-controlled, double-blind crossover trial that recruited 60 adult participants with 1 month or more of elevated generalized anxiety. Five Kava tablets per day were prescribed containing 250 mg of kavalactones/day.
The aqueous extract of Kava reduced participants' Hamilton Anxiety Scale score in the first controlled phase by -9.9 (CI = 7.1, 12.7) vs. -0.8 (CI = -2.7, 4.3) for placebo and in the second controlled phase by -10.3 (CI = 5.8, 14.7) vs. +3.3 (CI = -6.8, 0.2). The pooled effect of Kava vs. placebo across phases was highly significant (p < 0.0001), with a substantial effect size (d = 2.24, eta(2)(p)). Pooled analyses also revealed highly significant relative reductions in Beck Anxiety Inventory and Montgomery-Asberg Depression Rating Scale scores. The aqueous extract was found to be safe, with no serious adverse effects and no clinical hepatotoxicity.
The aqueous Kava preparation produced significant anxiolytic and antidepressant activity and raised no safety concerns at the dose and duration studied. Kava appears equally effective in cases where anxiety is accompanied by depression. This should encourage further study and consideration of globally reintroducing aqueous rootstock extracts of Kava for the management of anxiety.
We report the first randomised controlled trial (RCT) using a combination of St. John's wort (SJW) and Kava for the treatment of major depressive disorder (MDD) with comorbid anxiety.
Twenty-eight adults with MDD and co-occurring anxiety were recruited for a double-blind RCT. After a placebo run-in of 2 weeks, the trial had a crossover design testing SJW and Kava against placebo over two controlled phases, each of 4 weeks. The primary analyses used intention-to-treat and completer analyses.
On both intention-to-treat (p = 0.047) and completer analyses (p = 0.003), SJW and Kava gave a significantly greater reduction in self-reported depression on the Beck Depression Inventory (BDI-II) over placebo in the first controlled phase. However, in the crossover phase, a replication of those effects in the delayed medication group did not occur. Nor were there significant effects on anxiety or quality of life.
There was some evidence of antidepressant effects using SJW and Kava in a small sample with comorbid anxiety. Possible explanations for the absence of anxiolysis may include a potential interaction with SJW, the presence of depression, or an inadequate dose of Kava.
Structured causality assessment of hepatotoxicity by drugs and dietary supplements (DDS) is a major clinical challenge, since temporal associations as the sole criteria for a valid evaluation are not acceptable. Initially, a clear intuition for an ad hoc evaluation is necessary, but only provisional, and must be followed by a diagnostic algorithm using a pretest, main test and post test. The evaluation is based on a variety of items such as latency period, course of alanine aminotransferase and alkaline phosphatase after DDS discontinuation, risk factors, co-medication, previous information on hepatotoxicity of the DDS, response to rechallenge, and exclusion of other diseases. It is essential that practising and hospital physicians as well as other key health professionals, such as pharmacists, gather all information required for a sound causality assessment, obviating major discussions by expert panels, manufacturers and health agencies in face of scanty and fragmentary data. Because pharmacogenetic alterations may trigger metabolic hepatotoxicity by a few DDS, levels in plasma and urine should be measured and may be helpful for diagnosis. Concomitant genotyping of cytochrome P450 and other enzymes may also be useful in future to minimize the risk of unwanted side-effects, including toxic liver disease elicited by DDS.
Hepatotoxicity has been previously suspected by national regulatory agencies in 26 patients in causal relationship with the treatment by kava extracts commonly used as herbal anxiolytic drugs.
A quantitative causality assessment was undertaken using the system of the Council for International Organizations of Medical Sciences, scale of objective probability scoring.
Causality was unassessable, unrelated, or excluded in 16 patients owing to lack of temporal association and causes independent of kava or comedicated drugs. Low Council for International Organizations of Medical Sciences scores additionally resulted in excluded or unlikely causality assessments (n=2), leaving a total of eight patients with various degrees of causality for kava +/- comedicated drugs. Only one out of these eight patients adhered to the regulatory recommendations regarding both daily dose (<or=120 mg kavapyrones) and duration of therapy (<or=3 months) and experienced toxic liver injury with a probable causality for kava. In six cases with kava overdose and/or increased duration of kava treatment causality for kava was possible (n=3) and for kava together with the comedicated drug(s) possible (n=2) or probable (n=1).
Kava taken as recommended is associated with rare hepatotoxicity, whereas overdose, prolonged treatment, and comedication may carry an increased risk.