Kava (Piper methysticum) in the United States: the quiet rise of a substance with often subtle effects.

Background: Piper methysticum, commonly called kava, has long been consumed in beverage form in the Pacific Islands. Kava use in the US has slowly increased since the 1990s, but is not assessed in major epidemiological surveys.Objectives: To analyze social-media posts about kava from current, past, and prospective users, for motivations, patterns of co-use, and effects.Methods: Text from Reddit posts, and accompanying metadata, were collected and thematically coded by two independent raters.Results: 423 posts were collected, spanning January 2006 through December 2021. Of the 1,211 thematic codes applied, 1,098 (90. 7%) were concordant. Motivations for use bifurcated into self-treatment (for psychiatric or physical health conditions) and recreation; these were not mutually exclusive. Kava was rarely considered strongly euphoriant, but was valued as an anxiolytic. Kava was frequently used with other substances, most commonly kratom. Kava was used at lower doses for self-treatment than for other purposes (pseudo-R2 = 0.11). Undesirable effects (gastrointestinal upset, fatigue) were mentioned, though less often than benefits. Hepatotoxicity, reported elsewhere as a rare, non-dose-related risk, was disputed on the basis of its not having been experienced by those posting.Conclusion: Kava appears to be conceptualized among Reddit posters as an anxiolytic with few risks or adverse effects. As it grows in popularity, especially among people who use other drugs that are more liable to misuse or addiction, it should be assessed in probability samples (i.e. in the major national drug surveys) and clinical practice for its risks, potential benefits, and possible drug-drug interactions.

Herbal Supplements: Precautions and Safe Use.

The Food and Drug Administration (FDA) classifies herbal preparations as food supplements. New herbal supplements and products are not governed by the strict FDA drug approval process and there is no premarket approval required. The FDA prohibits manufacturers and distributors from marketing adulterated or misbranded products but does not rigorously define safe practices. Scientific evidence related to herbal supplements is limited. Herbal supplements have been associated with adverse reactions and herbal-drug interactions. Information and precautions for 20 common herbal supplements, including St. John's wort, ginseng, echinacea, and ginkgo, are reviewed. Resources for consumers and health care professionals are highlighted.

Kava as a Clinical Nutrient: Promises and Challenges.

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 drinking in traditional settings: Towards understanding effects on cognitive function.

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.

Cases of Kava Impairment in Iowa Drivers.

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.

Liver transplantation and the use of KAVA: Case report.

BACKGROUND: Self-medication and the belief that herbal products are free of health risks are common in Brazil. The kava (Piper methysticum), known for its anxiolytic action, has a widespread popular use. Hepatotoxicity of kava is reported, including cases of liver transplantation and death. The kava had its use prohibited or restricted in countries like Germany, France, among others. Toxicity may be related to overdosage; however, factors such as botanical characteristics of the plant, the harvesting, storage, and production process may be associated with the development of hepatotoxic substances, such as triggering idiosyncratic reactions. HYPOTHESIS: In this case, there is a suspicion that the toxicide is intrinsic to the drug; however, the possibility of adulterants and contaminants must be ruled out. STUDY DESIGN: This study reports the case of a patient who, after using the herbal kava for 52 days, evolved into acute liver failure and liver transplantation. METHODS: The data were collected directly with the patient and compared with their clinical records. Causality was determined through the RUCAM algorithm. In addition, a phytochemical analysis of the drug used was performed. RESULTS: According to the patient's report, there is no evidence of overdosage. Results from RUCAM algorithm infer causality between liver damage and the use of kava. The analysis chemical constituents did not find any possible contaminants and major changes in the active compounds. Seven months after transplantation, the patient is well and continues to be followed up by a medical team. CONCLUSION: Our investigation indicates that there was kava-induced hepatotoxicity at standard dosages. In Brazil, self-medication by herbal medicines is frequent and many patients and health professionals do not know the risks associated with their use. Diagnosing and notifying cases in which plants and herbal medicine induce liver damage is of paramount importance to increase the knowledge about DILI and to prevent or treat similar cases quickly.

The Pharmacology, Pharmacokinetics, Efficacy, and Adverse Events Associated With Kava.

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.

Is driving under the influence of kava associated with motor vehicle crashes? A systematic review of the epidemiological literature.

OBJECTIVE: Kava is marketed as a herbal anxiolytic in several countries and is consumed recreationally in high doses in many indigenous Pacific and Australian Aboriginal communities. We reviewed the published literature examining the association (if any) between kava use and motor vehicle crashes (MVCs), MVC-related injuries or driving performance. METHODS: Search of MEDLINE, EMBASE, PsycINFO, CINAHL, Scopus, AMED, Australian Medical Index, Australian Transport Index and trials registries and injury journals up to August 2014. RESULTS: No studies quantifying the effects of kava on MVCs or related injury were located. Four experimental studies using computer-based driving simulation examined the effects of pharmacological doses of kavalactones on cognitive and visuomotor performance. While no statistically significant adverse changes attributable to kava were found, there was weak evidence of slowed reaction time. One study found the visuo-motor performance on driving simulation to be significantly impaired when kava was consumed with alcohol. CONCLUSIONS: With equivocal evidence limited to experimental studies using simulated driving settings, the contribution of kava to MVCs is unknown. IMPLICATIONS: The gap in knowledge regarding the potential risk of injuries associated with therapeutic and recreational use of kava requires priority attention.

Analgesic effect of Hypericum perforatum, Valeriana officinalis and Piper methysticum for orofacial pain

To evaluate in vivo the association of hypericum Hypericum perforatum, valerian Valeriana officinalis and kava Piper methysticum with analgesia by assessing their effects in reducing orofacial pain as well as the possible hepatic, hematologic and biochemical alterations induced by regular administration of these extracts. METHODS: Orofacial pain was induced in mice with the administration of 2.5% formalin in the upper lip. After 60 min, the animals were treated with saline, carbamazepine and hydroalcoholic plant extracts. The nociceptive intensity was determined by the timing at which the animal remained rubbing the injected area. To assess the hepatotoxic effect, mice were chronically treated for 25 days with saline, carbamazepine and hydroalcoholic extract. The animals were euthanized and the liver weighed, followed by a differential count of leukocytes and measurement of alanine transaminase and alkaline phosphatase. RESULTS: The evaluation of analgesic activity in phase 1 reduced the time of rubbing compared to the control by 86% 0.05 mL/10 g and 76% 0.10 mL/10 g. In phase 2, the extracts reduced rubbing time by 94% and 85%, respectively. In the evaluation of alkaline phosphatase, the groups treated with extracts at doses of 0.05 mL/10 g and 0.1 mL/10 g increased by 16.1% and 9.5% compared to the control group and a reduction of 8.5% and 9.1% in the evaluation of alanine transaminase respectively. It was demonstrated that in the differential counts showed an increase in eosinophils in the treated group with 0.05 mL/10 g. CONCLUSIONS: The use of hydroalcoholic extract of the associated plants reduced the orofacial formalin-induced pain with better results than carbamazepine, at both the neural conductor level of pain phase 1 and in inflammatory or later pain phase 2 without presenting hepatotoxicity. The observed eosinophilia is suggestive of a phenomenon called hormesis...

Hepatitis A outbreak associated with kava drinking.

Hepatitis A is caused by the hepatitis A virus (HAV), with transmission occurring through the faecal-oral route. In May 2013, a case of hepatitis A infection was reported to a Western Australian regional public health unit, with infection acquired in Fiji. Following this, 2 further cases were linked to the index case by kava drinking and 1 further case was a household contact of a secondary case. This outbreak highlights that the preparation of kava drink and/or the use of a common drinking vessel could be a vehicle for the transmission of HAV.

Sebotropic eruption associated with use of oral kava kava supplement.

Supplement use is prevalent, and its use is increasing among older adults. Dermatologists need to be aware of the adverse cutaneous effects that can result from herbal supplement use. A 55-year-old man presented with an eruption in a sebotropic distribution after consuming kava kava for 3 weeks, which resolved after discontinuation of the supplement. This case highlights the need for clinicians to consider kava kava in the differential of sebotropic eruptions. The biology, mechanism of action, and potential systemic and cutaneous effects of kava kava are reviewed.

Non-infectious skin disease in Indigenous Australians.

The burden of non-infectious skin disease in the Indigenous Australian population has not been previously examined. This study considers the published data on the epidemiology and clinical features of a number of non-infectious skin diseases in Indigenous Australians. It also outlines hypotheses for the possible differences in the prevalence of such diseases in this group compared with the general Australian population. There is a paucity of literature on the topic but, from the material available, Indigenous Australians appear to have a reduced prevalence of psoriasis, type 1 hypersensitivity reactions and skin cancer but increased rates of lupus erythematosus, kava dermopathy and vitamin D deficiency when compared to the non-Indigenous Australian population. This article profiles the prevalence and presentation of non-infectious skin diseases in the Indigenous Australian population to synthesise our limited knowledge and highlight deficiencies in our understanding.

Herbal hepatotoxicity: analysis of cases with initially reported positive re-exposure tests.

BACKGROUND: Positive re-exposure tests are diagnostic hallmarks for hepatotoxicity. OBJECTIVE: To test validity of positive re-exposures in herb induced liver injury. METHODS: We searched Medline database for cases of herb induced liver injury with positive re-exposures and analysed 34 cases for positive re-exposure test criteria of baseline alanine aminotransferase< 5N before re-exposure, and re-exposure alanine aminotransferase ≥ 2× baseline alanine aminotransferase. Re-exposure test was negative, if baseline alanine aminotransferase< 5N combined with re-exposure alanine aminotransferase< 2× baseline alanine aminotransferase, or if baseline alanine aminotransferase≥ 5N regardless of the re-exposure alanine aminotransferase including no available re-exposure alanine aminotransferase result. RESULTS: In 21/34 cases (61.8%), criteria for a positive re-exposure were fulfilled, with negative tests in 6/34 cases (17.6%) or uninterpretable ones in 7/34 cases (20.6%). Confirmed positive re-exposure tests established potential of herb induced liver injury for Aloe, Chaparral, Chinese herbal mixtures, Chinese Jin Bu Huan, Chinese Syo Saiko To, Germander, Greater Celandine, Green tea, Kava, Mistletoe, Polygonum multiflorum, and Senna, with up to 4 case reports per herb. CONCLUSIONS: Among 34 cases of herb-induced liver injury with initially reported positive re-exposure tests, 61.8% of the cases actually fulfilled established test criteria and provided firm diagnoses of herb induced liver injury by various herbs.

Herbal hepatotoxicity and WHO global introspection method.

Herbal hepatotoxicity is a rare but highly disputed disease because numerous confounding variables may complicate accurate causality assessment. Case evaluation is even more difficult when the WHO global introspection method (WHO method) is applied as diagnostic algorithm. This method lacks liver specificity, hepatotoxicity validation, and quantitative items, basic qualifications required for a sound evaluation of hepatotoxicity cases. Consequently, there are no data available for reliability, sensitivity, specificity, positive and negative predictive value. Its scope is also limited by the fact that it cannot discriminate between a positive and a negative causality attribution, thereby stimulating case overdiagnosing and overreporting. The WHO method ignores uncertainties regarding daily dose, temporal association, start, duration, and end of herbal use, time to onset of the adverse reaction, and course of liver values after herb discontinuation. Insufficiently considered or ignored are comedications, preexisting liver diseases, alternative explanations upon clinical assessment, and exclusion of infections by hepatitis A-C, cytomegalovirus (CMV), Epstein-Barr virus (EBV), herpes simplex virus (HSV), and varicella zoster virus (VZV). We clearly prefer as alternative the scale of CIOMS (Council for International Organizations of Medical Sciences) which is structured, quantitative, liver specific, and validated for hepatotoxicity. In conclusion, causality of herbal hepatotoxicity is best assessed by the liver specific CIOMS scale validated for hepatotoxicity rather than the obsolete WHO method that is liver unspecific and not validated for hepatotoxicity. CIOMS based assessments will ensure the correct diagnosis and exclude alternative diagnosis that may require other specific therapies.

Does a medicinal dose of kava impair driving? A randomized, placebo-controlled, double-blind study.

OVERVIEW: Increasing concerns over the potentially impairing effects of prescriptive sedative drugs such as benzodiazepines on driving have been raised. However, other alternatives such as natural medicines may also carry similar risks with respect to driving safety. Kava (Piper methysticum) is a psychotropic plant commonly used both recreationally and medicinally in the United States, Australia, and the South Pacific to elicit a physically tranquilizing effect. To date no controlled study has tested a medicinal dose of kava versus placebo and a standard sedative drug on driving ability and driving safety. OBJECTIVE: Due to the need to establish the safety of kava in operating a motor vehicle, we compared the acute effects of the plant extract versus the benzodiazepine oxazepam and placebo using a driving simulator. METHODS: A driving simulator (AusEd) was used by 22 adults aged between 18 and 65 years after being randomly administered an acute medicinal dose of kava (180 mg of kavalactones), oxazepam (30 mg), or placebo one week apart in a crossover design trial. RESULTS: No impairing effects on driving outcomes were found after kava administration compared to placebo. Results on specific driving outcome domains revealed that the oxazepam condition had significantly slower braking reaction time compared to the placebo condition (p =.002) and the kava condition (p =.003). The kava condition had significantly fewer lapses of concentration compared to the oxazepam condition (p =.033). No significant differences were found between conditions for steering deviation, speed deviation, and number of crashes. Results were not modified by driving experience. On the Bond-Lader visual analogue sub-scale of alertness, a significant Treatment × Time interaction (p =.032) was found, with a significant reduction over time for oxazepam decreasing alertness (p <.001), whereas no significant reduction was found in the kava or placebo conditions. CONCLUSION: The results indicate that a medicinal dose of kava containing 180 mg of kavalactones does not impair driving ability, whereas 30 mg of oxazepam shows some impairment. Research assessing larger recreational doses of kava on driving ability should now be conducted.

Avaliação da mutagenicidade de Piper methysticum L. f. no sistema methG1 em Aspergillus nidulans / Mutagenic evaluation of Piper methysticum L. f. in Aspergillus nidulans methG1 system

O extrato seco da raiz de Piper methysticum L. f. Forster (PIPERACEAE), a kava-kava, é usado no tratamento de diversos problemas envolvendo ansiedade como um dos sintomas. Por não causar dependência, sedação e ter ação ansiolítica, muitas pessoas têm recorrido a kava-kava para auxiliá-las no emagrecimento. Isto pode levar ao consumo indiscriminado da planta e acarretar riscos, pois todo medicamento fitoterápico deve respeitar limites de doses. Um risco na utilização de plantas medicinais é a toxicidade e, dentro deste, a mutagenicidade. Como a mutagenicidade está relacionada com a carcinogenicidade torna-se importante testar este potencial na kava-kava. Assim, o objetivo deste trabalho foi avaliar o potencial mutagênico do extrato seco da raiz de P. methysticum no sistema methG1 em Aspergillus nidulans. A linhagem utilizada foi a biA1methG1, auxotrófica para biotina e metionina. Conídios dormentes de colônias crescidas por cinco dias foram tratados com soluções da kava-kava nas concentrações de 0,35 mg mL-1 e 3,5 mg mL-1, e depois de 24h, semeados em meio seletivo contendo metionina, para análise dos sobreviventes, e sem metionina, para a análise dos mutantes. Os números de sobreviventes e mutantes dos tratamentos foram comparados aos do controle. Os resultados indicaram que o extrato da raiz da kava-kava é mutagênica, pois a freqüência de mutação dos tratamentos foi maior que da mutação espontânea, porém não ocorrendo diferença significativa entre as doses.

The dry root extract of Piper methysticum L. f. Forster (Piperaceae), kava-kava, is used as to treat several health problems involving anxiety symptoms. As it causes no addiction, it can be applied as a sedative and anxiolytic. Many people have been relying on kava-kava as an auxiliary treatment. This can lead to an indiscriminate plant consumption and lead to risks, because all phytotherapic medications must observe dosage limits. One risk in the folk medicinal plant use is toxicity, and within it, mutagenicity. As mutagenicity is closely related to carcinogenicity, it is important to test the kava-kava mutagenicity potential. Thus, the purpose of this work was to test the mutagenicity of the dry root extract of P. methysticum in the methG1 system of Aspergillus nidulans. The bia1methG1 lineage, which is auxotrophic for biotine and methione, was used. Conidia from five-day-old colonies were collected and treated with kava-kava solutions at 0.35 mg mL-1 and 3.5 mg mL-1 concentrations and, after 24h, they were planted in selective growth medium with and without methione, in order to analyze the survivors and mutants, respectively. The number of survivors and mutants analyzed under effect of the treatments was compared with the control. The results indicated that the kava-kava dry root extract is mutagenic, since the mutation frequency of the treatments was higher than spontaneous mutation, however, there were no differences between the doses tested.

[Drug-induced liver injury]. / Il danno epatico da farmaci.

Drug-induced liver injury represents the principal cause of acute liver failure and orthotopic liver transplantation in western country. A very large number of different drugs and medicinal herbs has been associated with liver injury but just for few of them we know the process that causes liver disease. All the people which ingest a large number of drugs present a risk of developing liver injury. Diagnosis is very difficult because a specific biomarker of damage is absent and the clinical picture is common to other liver diseases. A therapeutic approach is efficacy only in few cases. When a drug-induced liver injury is suspected, cessation of the drug is the first step in their management.

Kava drinking associated with suicidal behaviour among young Kanaks using kava in New Caledonia.

OBJECTIVE: To examine associations between recreational use of kava and indicators of suicidal behaviour among youth in New Caledonia. METHODS: This cross-sectional community-based survey was administered to 1,400 young people aged 16-25 years. A multivariate analysis tested for associations between lifetime kava use and lifetime suicidal ideation and attempts. Because ethnicity affected the correlation between kava use and suicidal behaviour, data were analysed separately for Kanak youth and youth of other ethnic communities. RESULTS: Overall, 42% of respondents reported any lifetime kava use, 34% reported past suicidal ideation and 12% any suicide attempts. Among Kanak youth, kava use increased the likelihood of reporting both suicidal ideation (aOR = 2.40, 95% CI: 1.58-3.66) and suicide attempts (aOR = 1.98, 95% CI: 1.11-3.52). No such association was found in the non-Kanak group. CONCLUSIONS: The discrepancy between the effects of kava drinking on suicidal behaviour between Kanak youth and youth of other ethnic groups may be related to differences in patterns and quantity of kava use. In view of the paucity of data on the effects of kava on mental health in young people, further investigation is required. IMPLICATIONS: The results call for an increased awareness of the potential adverse health effects of kava consumption in New Caledonia where it has spread in recent times and among communities where previously it was never used.