This review critically analyzes the clinical data of patients with suspected kava hepatotoxicity and suggests recommendations for minimizing risk. Kava is a plant (Piper methysticum) of the pepper ...family Piperaceae, and its rhizome is used for traditional aqueous extracts in the South Pacific Islands and for commercial ethanolic and acetonic medicinal products as anxiolytic herbs in Western countries. A regulatory ban for ethanolic and acetonic kava extracts was issued in 2002 for Germany on the basis of reports connecting liver disease with the use of kava, but the regulatory causality assessment was a matter of international discussions. Based on one positive reexposure test with the kava drug, it was indeed confirmed that kava is potentially hepatotoxic. In subsequent studies using a structured, quantitative and hepatotoxicity specific causality assessment method in 14 patients with liver disease described worldwide, causality for kava +/- comedicated drugs and dietary supplements including herbal ones was highly probable (n = 1), probable (n = 4) or possible (n = 9) regarding aqueous extracts (n = 3), ethanolic extracts (n = 5), acetonic extracts (n = 4), and mixtures containing kava (n = 2). Risk factors included overdose, prolonged treatment, and comedication with synthetic drugs and dietary supplements comprizing herbal ones in most of the 14 patients. Hepatotoxicity occurred independently of the used solvent, suggesting poor kava raw material quality as additional causative factor. In conclusion, in a few individuals kava may be hepatotoxic due to overdose, prolonged treatment, comedication, and probably triggered by an unacceptable quality of the kava raw material; standardization is now required, minimizing thereby hepatotoxic risks.
In Pohnpei Island,
sakau
(kava) is a symbol of the traditional culture. Although the use of
sakau
was once limited to people of high rank and used only during ceremonial occasions, it is now consumed ...in bars and sold in bottles around the island. Recently, negative medical and environmental effects correlated with the increase sale of
sakau
have attracted scholarly attention. However, the current use of
sakau
is not fully understood. This study aims to describe the current use of
sakau
and consider by whom, on what occasions, and for what purpose
sakau
is consumed, and whether it continues to play a traditional role. Fieldwork was conducted from July to September 2019 in Kolonia (where people of Pohnpeian ethnicity live) and Mand (where non-Pohnpeians live). The latter was included to investigate whether
sakau
was consumed by people of ethnic groups that have never used it traditionally. Data were collected via interviews using a questionnaire, direct observation, and casual conversations. A total of 89 people (41 in Kolonia; 48 in Mand) participated in the study. Most (71% of those in Kolonia and 58% of those in Mand) reported they drank
sakau
at some point in their lives. Although the frequency of
sakau
consumption was significantly lower in Mand (
P=.027
), it was consumed regardless of their original culture. Commonly reported reasons for drinking
sakau
included treating anxiety and socializing. The use of
sakau
in Pohnpeian society continues in traditional contexts, such as feasts, marriage proposals, and forgiveness. Additionally, increased consumption has been profitable for people engaged in businesses related to
sakau
.
Monoamine oxidases (MAOs) are key metabolic enzymes for neurotransmitter and dietary amines and are targets for the treatment of neuropsychiatric and neurodegenerative disorders. This study examined ...the MAO inhibition potential of kavain and other kavalactones from the roots of kava (
), a plant that has been used for its anxiolytic properties. (±)-Kavain was found to be a good potency
inhibitor of human MAO-B with an IC
of 5.34 µM. (±)-Kavain is a weaker MAO-A inhibitor with an IC
of 19.0 µM. Under the same experimental conditions, the reference MAO inhibitor, curcumin, displays IC
values of 5.01 µM and 2.55 µM for the inhibition of MAO-A and MAO-B, respectively. It was further established that (±)-kavain interacts reversibly and competitively with MAO-A and MAO-B with enzyme-inhibitor dissociation constants (K
) of 7.72 and 5.10 µM, respectively. Curcumin in turn, displays a K
value of 3.08 µM for the inhibition of MAO-A. Based on these findings, other kavalactones (dihydrokavain, methysticin, dihydromethysticin, yangonin, and desmethoxyyangonin) were also evaluated as MAO inhibitors in this study. Yangonin proved to be the most potent MAO inhibitor with IC
values of 1.29 and 0.085 µM for MAO-A and MAO-B, respectively. It may be concluded that some of the central effects (e.g., anxiolytic) of kava may be mediated by MAO inhibition.
Kava is a perennial shrub native to some islands of the South Pacific and has been cultivated for centuries to prepare a psychoactive beverage from its rhizoma by means of extraction. Subsequently, ...kava extracts are commonly used as herbal anxiolytic drugs also in many other countries all over the world including European ones and the USA. Toxicological and clinical studies have shown that kava extracts are virtually devoid of toxic effects with the exception of rare hepatotoxic side effects reported in few patients. When assessed primarily by the British regulatory authority MCA but also by us, a critical analysis of the suspected cases (n = 19) in Germany reveals that only in 1 single patient a very probable causal relationship could be established between kava treatment and the development of toxic liver disease due to a positive result of an unscheduled reexposure test, whereas in another patient there might be a possible association. Out of the remaining 17 cases 12 patients were not yet assessable due to insufficient data and in 5 other cases a causal relationship was unlikely or could be excluded. The German regulatory authority might therefore well be advised to provide now additional information for those 12 patients with so far unsatisfactory data, facilitating a more appropriate assessment of causality. Nevertheless, in the meantime physicians and patients should continue to keep an eye on possible hepatotoxic side effects in the course of kava treatment, to stop the treatment alredy at first suspicion and to start with a careful diagnostic work up ruling out all other causes.
Abstract Herbal hepatotoxicity by the anxiolytic kava ( Piper methysticum Forst. f.) emerged unexpectedly and was observed in a few patients worldwide. Liver injury occurred after the use of ...traditional aqueous kava extracts in the South Pacific region and of acetonic and ethanolic extracts in Western countries in rare cases, suggesting that the solvents used play no major causative role. In this review, we discuss actual pathogenetic issues of kava hepatotoxicity with special focus on developments regarding pipermethystine, flavokavain B, and mould hepatotoxins as possible culprits. There is abundant data of in vitro cytotoxicity including apoptosis by pipermethystine and flavokavain B added to the incubation media, yet evidence is lacking of in vivo hepatotoxicity in experimental animals under conditions similar to human kava use. Furthermore, in commercial Western kava extracts, pipermethystine was not detectable and flavokavain B was present as a natural compound in amounts much too low to cause experimental liver injury. There is concern, however, that due to high temperature and humidity in the South Pacific area, kava raw material might have been contaminated by mould hepatotoxins such as aflatoxins after harvest and during storage. Whether kava hepatotoxicity may be due to aflatoxicosis or other mould hepatotoxins, requires further studies.
The association of kava product use with liver-related risks has prompted regulatory action in many countries. We studied the changes in gene expression of drug metabolizing enzymes in the livers of ...Fischer 344 male rats administered kava extract by gavage for 14 weeks. Analysis of 22,226 genes revealed that there were 14, 41, 110, 386, and 916 genes significantly changed in the 0.125, 0.25, 0.5, 1.0, and 2.0
g/kg treatment groups, respectively. There were 16 drug metabolizing genes altered in all three high-dose treatment groups, among which seven genes belong to cytochrome P450 isozymes. While gene expression of Cyp1a1, 1a2, 2c6, 3a1, and 3a3 increased; Cyp 2c23 and 2c40 decreased, all in a dose-dependent manner. Real-time PCR analyses of several genes verified these results. Our results indicate that kava extract can significantly modulate drug metabolizing enzymes, particularly the CYP isozymes, which could cause herb–drug interactions and may potentially lead to hepatotoxicity.
There was a significant increase in the incidence of retinal degeneration in F344/N rats chronically exposed to Kava kava extract (KKE) in National Toxicology Program (NTP) bioassay. A retrospective ...evaluation of these rat retinas indicated a similar spatial and morphological alteration as seen in light-induced retinal degeneration in albino rats. Therefore, it was hypothesized that KKE has a potential to exacerbate the light-induced retinal degeneration. To investigate the early mechanism of retinal degeneration, we conducted a 90-day F344/N rat KKE gavage study at doses of 0 and 1.0 g/kg (dose which induced retinal degeneration in the 2-year NTP rat KKE bioassay). The morphological evaluation indicated reduced number of phagosomes in the retinal pigment epithelium (RPE) of the superior retina. Transcriptomic alterations related to retinal epithelial homeostasis and melatoninergic signaling were observed in microarray analysis. Phagocytosis of photoreceptor outer segment by the underlying RPE is essential to maintain the homeostasis of the photoreceptor layer and is regulated by melatonin signaling. Therefore, reduced photoreceptor outer segment disc shedding and subsequent lower number of phagosomes in the RPE and alterations in the melatonin pathway may have contributed to the increased incidences of retinal degeneration observed in F344/N rats in the 2-year KKE bioassay.
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.
There is increasing evidence for the involvement of chronic inflammation and oxidative stress in the pathogenesis of Alzheimer's disease (AD). Nuclear factor erythroid 2-related factor 2 (Nrf2) is an ...anti-inflammatory transcription factor that regulates the oxidative stress defense. Our previous experiments demonstrated that kavalactones protect neuronal cells against Amyloid β (Aβ)-induced oxidative stress in vitro by Nrf2 pathway activation. Here, we tested an in vivo kavalactone treatment in a mouse model of AD.
The kavalactone methysticin was administered once a week for a period of 6 months to 6 month old transgenic APP/Psen1 mice by oral gavage. Nrf2 pathway activation was measured by methysticin treatment of ARE-luciferase mice, by qPCR of Nrf2-target genes and immunohistochemical detection of Nrf2. Aβ burden was analyzed by CongoRed staining, immunofluorescent detection and ELISA. Neuroinflammation was assessed by immunohistochemical stainings for microglia and astrocytes. Pro-inflammatory cytokines in the hippocampus was determined by Luminex multi-plex assays. The hippocampal oxidative damage was detected by oxyblot technique and immunohistochemical staining against DT3 and 4-HNE. The cognitive ability of mice was evaluated using Morris water maze.
Methysticin treatment activated the Nrf2 pathway in the hippocampus and cortex of mice. The Aβ deposition in brains of methysticin-treated APP/Psen1 mice was not altered compared to untreated mice. However, methysticin treatment significantly reduced microgliosis, astrogliosis and secretion of the pro-inflammatory cytokines TNF-α and IL-17A. In addition, the oxidative damage of hippocampi from APP/Psen1 mice was reduced by methysticin treatment. Most importantly, methysticin treatment significantly attenuated the long-term memory decline of APP/Psen1 mice.
In summary, these findings show that methysticin administration activates the Nrf2 pathway and reduces neuroinflammation, hippocampal oxidative damage and memory loss in a mouse model of AD. Therefore, kavalactones might be suitable candidates to serve as lead compounds for the development of a new class of neuroprotective drugs.
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