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.
Background
Kava drinking is a tradition among Pacific Island people, although growing in popularity with other ethnicities. However, drinking substantial quantities of kava has raised concerns ...regarding physical manifestations of slow response and lack of precision in bodily control. These impairments can have significant consequences when after consuming large volumes of kava an individual makes a choice to drive.
Aims
The objective of this study was to measure selected cognitive functions following high traditionally consumed kava volumes (greater than 2,000 mg of kavalactones) aimed at identifying potential risks for kava drink‐drivers.
Methods
The reaction and divided attention of 20 control participants was assessed against 20 active kava‐drinking participants during and following a 6‐hr kava session in a “naturalised” setting. Assessment measures were drawn from Vienna Test System—Traffic's test battery.
Results/Outcomes
Results showed no statistical significant difference between control and active participants at any measurement point over a 6‐hr testing period regardless that the movements and speech of the active participants were observed to slow as the test session and kava consumption progressed.
Conclusion
Inconsistencies between test results and observations during testing and by road policing officers demonstrate an urgent need for more research in this field.
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.
Objectives
Phytochemical‐mediated modulation of cytochrome P450 (CYP) activity may underlie many herb‐drug interactions. Single‐time point phenotypic metabolic ratios were used to determine whether ...long‐term supplementation of goldenseal (Hydrastis canadensis), black cohosh (Cimicifuga racemosa), kava kava (Piper methysticum), or valerian (Valeriana officinalis) extracts affected CYP1A2, CYP2D6, CYP2E1, or CYP3A4/5 activity.
Methods
Twelve healthy volunteers (6 women) were randomly assigned to receive goldenseal, black cohosh, kava kava, or valerian for 28 days. For each subject, a 30‐day washout period was interposed between each supplementation phase. Probe drug cocktails of midazolam and caffeine, followed 24 hours later by chlorzoxazone and debrisoquin (INN, debrisoquine), were administered before (baseline) and at the end of supplementation. Presupplementation and postsupplementation phenotypic trait measurements were determined for CYP3A4/5, CYP1A2, CYP2E1, and CYP2D6 by use of 1‐hydroxymidazolam/midazolam serum ratios (1‐hour sample), paraxanthine/caffeine serum ratios (6‐hour sample), 6‐hydroxychlorzoxazone/chlorzoxazone serum ratios (2‐hour sample), and debrisoquin urinary recovery ratios (8‐hour collection), respectively. The content of purported “active” phytochemicals was determined for each supplement.
Results
Comparisons of presupplementation and postsupplementation phenotypic ratio means revealed significant inhibition (approximately 40%) of CYP2D6 (difference, −0.228; 95% confidence interval CI, −0.268 to −0.188) and CYP3A4/5 (difference, −1.501; 95% CI, −1.840 to −1.163) activity for goldenseal. Kava produced significant reductions (approximately 40%) in CYP2E1 only (difference, −0.192; 95% CI, −0.325 to −0.060). Black cohosh also exhibited statistically significant inhibition of CYP2D6 (difference, −0.046; 95% CI, −0.085 to −0.007), but the magnitude of the effect (approximately 7%) did not appear to be clinically relevant. No significant changes in phenotypic ratios were observed for valerian.
Conclusions
Botanical supplements containing goldenseal strongly inhibited CYP2D6 and CYP3A4/5 activity in vivo, whereas kava inhibited CYP2E1 and black cohosh weakly inhibited CYP2D6. Accordingly, serious adverse interactions may result from the concomitant ingestion of goldenseal supplements and drugs that are CYP2D6 and CYP3A4/5 substrates. Kava kava and black cohosh may interact with CYP2E1 and CYP2D6 substrates, respectively. Valerian appears to be less likely to produce CYP‐mediated herb‐drug interactions.
Clinical Pharmacology & Therapeutics (2005) 77, 415–426; doi: 10.1016/j.clpt.2005.01.009
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.
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.
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.
ClinicalTrials.gov with the identifier: NCT05081882. Registered on October 18, 2021.
This documentary film is a result of multi-sited ethnographic research between 2015-2019, which explores cultural identity, gender, music, and spirituality through contemporary and common kava ...practices. Drawing from over 17 years of participation in kava communities, this film is grounded in Tongan experiences, while also including a mobile and expanding Moana/Wansolwara/Oceanic perspective with contributions from Fijians, Sāmoans, Māori, and more. The knowledge holders in this film span across four territories, including Te Ika a Māui in Aotearoa, Utah (US) on Turtle Island, The Kingdom of Tonga, and Kamberra, Australia. They share a complex web of experiences, purpose, and tensions within the contemporary practices of common kava gatherings known in Tongan as faikava. Contemporary kava gatherings are spaces to release the pressures of modern life, nurture ancestral and social relationships, reveal truths, build community, produce and transmit knowledge, negotiate identity, heal, and foster positive well-being through comradery and openness. This film cannot cover all of the complexity of kava culture, yet attempts to be a meaningful introduction to the dynamic practices that are alive and expanding throughout the world.
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 pretreatment 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.
PDF
