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Kava is a South Pacific plant-based medicine with anxiolytic properties, but little is known about the impact kava has on gene expression or whether gene expression can serve as a marker of kava response. This study aimed to determine whether kava treatment alters the expression of genes with physiological relevance to anxiety pathophysiology and whether the baseline expression of these physiologically relevant genes modifies the efficacy of kava treatment. In this post hoc analysis, we examined the expression of 48 genes relevant to the pathophysiology of anxiety collected from a double-blind randomized controlled trial that assessed the efficacy of kava treatment in generalized anxiety disorder. Peripheral blood gene expression was measured in 71 (34 kava, 37 placebo) adults at baseline and in 40 (19 kava, 21 placebo) after 8 weeks of treatment by reverse transcription polymerase chain reaction (PCR). Results revealed that kava decreased the expression of a subunit of the GABAA -rho receptor gene (GABRR2) and catechol-O-methyltransferase (COMT), a gene related to catecholamine metabolism. Kava efficacy was not found to be modified by baseline (pretreatment) expression of relevant genes. Although these results did not withstand statistical correction for multiple comparisons and require external validation, they support the notion that kava's mechanism of action includes interaction with GABAergic and catecholaminergic systems. © 2023 John Wiley & Sons Ltd.

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.

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.

For healthcare professionals, the volume of literature available on herb-drug interactions often makes it difficult to separate experimental/potential interactions from those deemed clinically relevant. There is a need for concise and conclusive information to guide pharmacotherapy in HIV/AIDS. In this review, the bases for potential interaction of medicinal herbs with specific antiretroviral drugs are presented, and several botanicals are discussed for which clinically relevant interactions in humans are established. Such studies have provided, in most cases, sufficient ground to warrant the avoidance of concurrent administration of antiretroviral (ARVs) drugs with St John's wort (Hypericum perforatum), black pepper (Piper species) and grapefruit juice. Other botanicals that require caution in the use with antiretrovirals include African potato (Hypoxis hemerocallidea), ginkgo (Ginkgo biloba), ginseng (Panax species), garlic (Allium sativum), goldenseal (Hydrastis canadensis) and kava kava (Piper methysticum). The knowledge of clinically significant herb-drug interaction will be important in order to avoid herb-induced risk of sub-therapeutic exposure to ARVs (which can lead to viral resistance) or the precipitation of toxicity (which may lead to poor compliance and/or discontinuation of antiretroviral therapy).

This paper examines the debate about the safety of kava (Piper methysticum Forst. f, Piperaceae), a plant native to Oceania, where it has a long history of traditional use. Kava became popular as an anti-anxiety treatment in Western countries in the late 1990s, but it was subsequently banned in many places due to adverse reports of liver toxicity. This paper focuses on the responses to the bans by scientists involved in kava research, contrasting their evidential culture with that employed by clinicians and regulatory officials. Cultural constructions and social negotiations of risk are shown to be context-specific, and are shaped by professional, disciplinary, and organizational factors, among others. Though the science of hepatotoxicity is uncertain enough to allow for multiple interpretations of the same data, the biomedical/clinical narrative about kava remains dominant. This case study explores the influence of these cultural, social, and political factors on the production of scientific knowledge and the assessment of benefit/risk posed by comestibles.

179. J Soc Integr Oncol. 2009 Fall;7(4):170-2. Kava (Piper methysticum). [No authors listed]

The concomitant use of herbal medicines and pharmacotherapy is wide spread. We have reviewed the literature to determine the possible interactions between seven popular herbal medicines (ginkgo, St John's wort, ginseng, garlic, echinacea, saw palmetto and kava) and conventional drugs. Literature searches were performed using MEDLINE, Cochrane Library and EMBASE and we identified 128 case reports or case series, and 80 clinical trials. Clinical trials indicate that St John's wort (Hypericum perforatum), via cytochrome P450 (CYP) and/or P-glycoprotein induction, reduces the plasma concentrations (and/or increases the clearance) of alprazolam, amitriptyline, atorvastatin, chlorzoxazone, ciclosporin, debrisoquine, digoxin, erythromycin, fexofenadine, gliclazide, imatinib, indinavir, irinotecan, ivabradine, mephenytoin, methadone, midazolam, nifedipine, omeprazole, oral contraceptives, quazepam, simvastatin, tacrolimus, talinolol, verapamil, voriconazole and warfarin. Case reports or case series suggest interactions of St John's wort with adrenergic vasopressors, anaesthetics, bupropion, buspirone, ciclosporin, eletriptan, loperamide, nefazodone, nevirapine, oral contraceptives, paroxetine, phenprocoumon, prednisone, sertraline, tacrolimus, theophylline, tibolone, tryptophan, venlafaxine and warfarin. Ginkgo (Ginkgo biloba) decreases the plasma concentrations of omeprazole, ritonavir and tolbutamide. Clinical cases indicate interactions of ginkgo with antiepileptics, aspirin (acetylsalicylic acid), diuretics, ibuprofen, risperidone, rofecoxib, trazodone and warfarin. Ginseng (Panax ginseng) may interact with phenelzine and warfarin. Kava (Piper methysticum) increases the clearance of chlorzoxazone (a CYP2E1 substrate) and may interact with alprazolam, levodopa and paroxetine. Garlic (Allium sativum) interacts with chlorpropamide, fluindione, ritonavir and warfarin; it also reduces plasma concentrations of chlorzoxazone (a CYP2E1 probe). Echinacea might affect the clearance of caffeine (a CYP1A2 probe) and midazolam (a CYP3A4 probe). No interactions have been reported for saw palmetto (Serenoa repens). Numerous interactions between herbal medicines and conventional dr

Cytochrome P450 2D6 (CYP2D6), an important CYP isoform with regard to drug-drug interactions, accounts for the metabolism of approximately 30% of all medications. To date, few studies have assessed the effects of botanical supplementation on human CYP2D6 activity in vivo. Six botanical extracts were evaluated in three separate studies (two extracts per study), each incorporating 16 healthy volunteers (eight females). Subjects were randomized to receive a standardized botanical extract for 14 days on separate occasions. A 30-day washout period was interposed between each supplementation phase. In study 1, subjects received milk thistle (Silybum marianum) and black cohosh (Cimicifuga racemosa). In study 2, kava kava (Piper methysticum) and goldenseal (Hydrastis canadensis) extracts were administered, and in study 3 subjects received St. John's wort (Hypericum perforatum) and Echinacea (Echinacea purpurea). The CYP2D6 substrate, debrisoquine (5 mg), was administered before and at the end of supplementation. Pre- and post-supplementation phenotypic trait measurements were determined for CYP2D6 using 8-h debrisoquine urinary recovery ratios (DURR). Comparisons of pre- and post-supplementation DURR revealed significant inhibition (approximately 50%) of CYP2D6 activity for goldenseal, but not for the other extracts. Accordingly, adverse herb-drug interactions may result with concomitant ingestion of goldenseal supplements and drugs that are CYP2D6 substrates. Supplementation with goldenseal (Hydrastis canadensis), but not kava kava (Piper methysticum), inhibits human CYP3A activity in vivo. Gurley BJ(1), Swain A, Hubbard MA, Hartsfield F, Thaden J, Williams DK, Gentry WB, Tong Y. Author information: (1)Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA. [email protected] The effects of goldenseal (Hydrastis canadensis) and kava kava (Piper methysticum) supplementation on human CYP3A activity were evaluated using midazolam (MDZ) as a phenotypic probe. Sixteen healthy volunteers were randomly assigned to receive either goldenseal or kava kava for 14 days. Each supplementation phase w

9. Clin Pharmacol Ther. 2008 Jan;83(1):61-9. doi: 10.1038/sj.clpt.6100222. Epub 2007 May 9. Supplementation with goldenseal (Hydrastis canadensis), but not kava kava (Piper methysticum), inhibits human CYP3A activity in vivo. Gurley BJ(1), Swain A, Hubbard MA, Hartsfield F, Thaden J, Williams DK

Phytochemical-mediated modulation of P-glycoprotein (P-gp) and other drug transporters may give rise to many herb-drug interactions. Serial plasma concentration-time profiles of the P-gp substrate, digoxin, were used to determine whether supplementation with goldenseal or kava kava modified P-gp activity in vivo. Twenty healthy volunteers were randomly assigned to receive a standardized goldenseal (3210 mg daily) or kava kava (1227 mg daily) supplement for 14 days, followed by a 30-day washout period. Subjects were also randomized to receive rifampin (600 mg daily, 7 days) and clarithromycin (1000 mg daily, 7 days) as positive controls for P-gp induction and inhibition, respectively. Digoxin (Lanoxin, 0.5 mg) was administered p.o. before and at the end of each supplementation and control period. Serial digoxin plasma concentrations were obtained over 24 h and analyzed by chemiluminescent immunoassay. Comparisons of area under the curve (AUC)((0-3)), AUC((0-24)), C(max,) CL/F, and elimination half-life were used to assess the effects of goldenseal, kava kava, rifampin, and clarithromycin on digoxin pharmacokinetics. Rifampin produced significant reductions (p < 0.01) in AUC((0-3)), AUC((0-24)), CL/F, t(1/2), and C(max), whereas clarithromycin increased these parameters significantly (p < 0.01). With the exception of goldenseal's effect on C(max) (14% increase), no statistically significant effects on digoxin pharmacokinetics were observed following supplementation with either goldenseal or kava kava. When compared with rifampin and clarithromycin, supplementation with these specific formulations of goldenseal or kava kava did not appear to affect digoxin pharmacokinetics, suggesting that these supplements are not potent modulators of P-gp in vivo.

In recent years, Kava kava (Piper methysticum, Forst. f., Piperaceae), a folkloric beverage and popular herbal remedy, has been implicated in a number of liver failure cases. Many hypotheses as to the mechanism of its hepatotoxicity, for example interactions with other co-ingested medication, have been postulated. This present study investigated whether pharmacokinetic interactions between kava constituents and alcohol via alcohol dehydrogenase (ADH) inhibition by individual kavalactones might explain its claimed hepatotoxic effects. Four kavalactones, (+/-)-kavain, methysticin, yangonin and desmethoxyyangonin, fail to inhibit ADH in vitro at 1, 10 or 100 microM concentrations.

BACKGROUND: Kava is a beverage made from the ground roots of the plant Piper Methysticum and has long-held a significant place within Pacific island communities. Active compounds were extracted from kava, and secondary metabolites include kavalactones, chalcones, cinnamic acid derivatives and flavanones. It is thought that components of kava may exert an antiproliferative effect through cell cycle arrest and promotion of apoptosis. METHODS: We conducted a systematic review to summarize available evidence of the anticancer effects of kava components and investigate their potential use for oral squamous cell carcinoma (OSCC) treatment. Eligible studies were identified through a comprehensive search of OVID EMBASE, OVID MEDLINE and Web of Science, as at April 2018. RESULTS: Of 39 papers that met the inclusion criteria, 32 included in vitro models and 13 included animal studies. A total of 26 different cancers were assessed with 32 studies solely assessing epithelial cancers, 6 mesenchymal cancers and 1 study including both. There was only one report assessing an OSCC cell line. Antiproliferative properties were demonstrated in 32 out of 39 papers. The most researched constituent of kava was flavokavain B followed by flavokavain A. Both were associated with increased expression of pro-apoptotic proteins and decreased expression of anti-apoptotic proteins. Further, they were associated with a dose-dependent reduction of angiogenesis. CONCLUSION: There was heterogeneity of study models and methods of investigation across the studies identified. Components of kava appear to present an area of interest with chemotherapeutic potential in cancer prevention and treatment, particularly for epithelial neoplasms. To date, there is a paucity of literature of the utility of kava components in the prevention and treatment of oral squamous cell carcinoma. © 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

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.

INTRODUCTION: The objective was to evaluate efficacy/safety of complementary and alternative medicine (CAM) methods for generalized anxiety disorder (GAD) based on randomized controlled trials in adults. METHODS: Data sources. Six electronic databases ("generalized anxiety (disorder)" and "randomized trial") and reference lists of identified publications were searched to March 2017. STUDY SELECTION: Eligibility: full-text publications (English, German language); CAM versus conventional treatment, placebo/sham or no treatment; GAD diagnosed according to standard criteria; and a validated scale for disease severity. Of the 6693 screened records, 32 were included (18 on biologically-based therapies, exclusively herbal preparations; eight on manipulative and body-based therapies; and three on alternative medical systems and three on mind-body therapies). DATA EXTRACTION: Cochrane Collaboration methodology was used for quality assessment and data extraction. RESULTS: Direct comparisons of Kava Kava (Piper methysticum) extracts to placebo (4 quality trials, n = 233) were highly heterogeneous. Network meta-regression reduced heterogeneity and suggested a modest Kava effect [end-of-treatment Hamilton Anxiety scale score difference adjusted for baseline scores and trial duration: - 3.24 (95% CI - 6.65, 0.17; P = 0.059), Kava Kava 4 arms, n = 139; placebo 5 arms, n = 359]. Lavender (Lavandula angustifolia) extract (1 quality trial, 10 weeks, n = 523) and a combination of extracts of C. oxycantha, E. californica and magnesium (1 quality trial, 12 weeks, n = 264) were superior to placebo and balneotherapy was superior to paroxetine (1 quality trial, 8 weeks, n = 237) indicating efficacy. All other trials were small and/or of modest/low quality and/or lacked assay sensitivity. Safety reporting was poor. CONCLUSION: Evidence about efficacy/safety of most CAM methods in GAD is limited. Apparent efficacy of certain herbal preparations and body-based therapies requires further confirmation.

RATIONALE: Kava (Piper methysticum) elicits dose-dependent psychotropic effects and thus may potentially deleteriously affect cognitive performance. Clinical trials have assessed the effects of kava on cognition, however, to our knowledge no systematic review has been conducted in this area. OBJECTIVE: To systematically review the effects of kava on cognition, providing an analysis of the individual study's methodological quality, results and effect sizes. METHODS: A systematic review was conducted of publications up to June 15th 2010, using the electronic databases MEDLINE, PsychINFO, CINAHL, Web of Science and The Cochrane Library. The search criteria involved kava and cognition related terms, e.g. memory and attention. RESULTS: Ten human clinical trials met inclusion criteria (acute n = 7, chronic n = 3). One acute study found that kava significantly improved visual attention and working memory processes while another found that kava increased body sway. One chronic study found that kava significantly impaired visual attention during high-cognitive demand. Potential enhanced cognition may be attributed to the ability of kava to inhibit re-uptake of noradrenaline in the pre-frontal cortex, while increased body sway may be due to GABA pathway modulation. CONCLUSIONS: The majority of evidence suggests that kava has no replicated significant negative effects on cognition.

BACKGROUND: Mood and anxiety disorders pose significant health burdens on the community. Kava and St. John's wort (SJW) are the most commonly used herbal medicines in the treatment of anxiety and depressive disorders, respectively. OBJECTIVES: The objective of this study was to conduct a comprehensive review of kava and SJW, to review any evidence of efficacy, mode of action, pharmacokinetics, safety and use in major depressive disorder, bipolar disorder, seasonal affective disorder (SAD), generalized anxiety disorder, social phobia (SP), panic disorder (PD), obsessive-compulsive disorder (OCD), and post-traumatic stress disorder (PTSD). METHODS: A systematic review was conducted using the electronic databases MEDLINE, CINAHL, and The Cochrane Library during late 2008. The search criteria involved mood and anxiety disorder search terms in combination with kava, Piper methysticum, kavalactones, St. John's wort, Hypericum perforatum, hypericin, and hyperforin. Additional search criteria for safety, pharmacodynamics, and pharmacokinetics were employed. A subsequent forward search was conducted of the papers using Web of Science cited reference search. RESULTS: Current evidence supports the use of SJW in treating mild-moderate depression, and for kava in treatment of generalized anxiety. In respect to the other disorders, only weak preliminary evidence exists for use of SJW in SAD. Currently there is no published human trial on use of kava in affective disorders, or in OCD, PTSD, PD, or SP. These disorders constitute potential applications that warrant exploration. CONCLUSIONS: Current evidence for herbal medicines in the treatment of depression and anxiety only supports the use of Hypericum perforatum for depression, and Piper methysticum for generalized anxiety.

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

This paper systematically reviews the clinical evidence relating to the safety of extracts of the herbal anxiolytic kava (Piper methysticum). Literature searches were conducted in four electronic databases and the reference lists of all papers located were checked for further relevant publications. Information was also sought from the spontaneous reporting schemes of the WHO and national drug safety bodies and ten manufacturers of kava preparations were contacted. Data from short-term post-marketing surveillance studies and clinical trials suggest that adverse events are, in general, rare, mild and reversible. However, published case reports indicate that serious adverse events are possible including dermatological reactions, neurological complications and, of greatest concern, liver damage. Spontaneous reporting schemes also suggest that the most common adverse events are mild, but that serious ones occur. Controlled trials suggest that kava extracts do not impair cognitive performance and vigilance or potentiate the effects of central nervous system depressants. However, a possible interaction with benzodiazepines has been reported. It is concluded that when taken as a short-term monotherapy at recommended doses, kava extracts appear to be well tolerated by most users. Serious adverse events have been reported and further research is required to determine the nature and frequency of such events.

Despite the widespread use of herbal medicines, documented herb-drug interactions are sparse. We have reviewed the literature to determine the possible interactions between the seven top-selling herbal medicines (ginkgo, St John's wort, ginseng, garlic, echinacea, saw palmetto and kava) and prescribed drugs. Literature searches were performed using the following databases: Medline (via Pubmed), Cochrane Library, Embase and phytobase (all from their inception to July 2000). All data relating to herb-drug interactions were included regardless of whether they were based on case reports, case series, clinical trials or other types of investigation in humans. In vitro experiments were excluded. Data were extracted by the first author and validated by the second author. 41 case reports or case series and 17 clinical trials were identified. The results indicate that St John's wort (Hypericum perforatum) lowers blood concentrations of cyclosporin, amitriptyline, digoxin, indinavir, warfarin, phenprocoumon and theophylline; furthermore it causes intermenstrual bleeding, delirium or mild serotonin syndrome, respectively, when used concomitantly with oral contraceptives (ethinylestradiol/desogestrel), loperamide or selective serotonin-reuptake inhibitors (sertaline, paroxetine, nefazodone). Ginkgo (Ginkgo biloba) interactions include bleeding when combined with warfarin, raised blood pressure when combined with a thiazide diuretic and coma when combined with trazodone. Ginseng (Panax ginseng) lowers blood concentrations of alcohol and warfarin, and induces mania if used concomitantly with phenelzine. Garlic (Allium sativum) changes pharmacokinetic variables of paracetamol, decreases blood concentrations of warfarin and produces hypoglycaemia when taken with chlorpropamide. Kava (Piper methysticum) increases 'off' periods in Parkinson patients taking levodopa and can cause a semicomatose state when given concomitantly with alprazolam. No interactions were found for echinacea (Echinacea angustifolia, E. purpurea, E. pallida) and saw palmetto (Serenoa repens). In conclusion, interactions between herbal medicines and synthetic drugs exist and can have serious clinical conseque