The effectiveness and safety of Kava Kava for treating anxiety symptoms: A systematic review and analysis of randomized clinical trials

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Highlights

  • Kava Kava has the ability to lower the severity of anxiety symptoms.

  • Kava Kava has better effectiveness in younger and female populations.

  • Hepatotoxicity is not a concern if taking Kava for less than 8 weeks.

  • A long-term trial would determine the safety of Kava use past 8 weeks in duration.

  • Kavalactone composition should be emphasized in future trials.

Abstract

Background

To determine if Kava Kava is an effective treatment for combating symptoms of anxiety despite warnings of hepatotoxicity from the Centers for Disease Control and Prevention (CDC).

Methods

Databases PubMed, CINAHL, and PsycINFO were utilized to obtain clinical trials on Kava Kava and its effects on anxiety. A total of 11 articles met inclusion/exclusion criteria: 2 for Kava Kava vs. another anti-anxiety medication, 2 detailing additional adverse events, and 7 for Kava Kava vs. placebo. Mantel-Haenszel fixed–effects model was used to analyze the data, with responder rates being pooled to compute weighted risk ratios.

Results

Kava Kava was shown to be more effective than placebo in 3 of the 7 trials. A final risk ratio of 1.50 (95% CI: 1.12, 2.01) from responder rates was calculated in favor of the intervention from 5 clinical trials (n = 330). Adverse events were shown to be the same as placebo (P = 0.574), and laboratory values analyzing hepatotoxicity were no different when compared to baseline except in two studies.

Conclusions

Kava Kava appears to be a short-term treatment for anxiety, but not a replacement for prolonged anti-anxiety use. Although not witnessed in this review, liver toxicity is especially possible if taken longer than 8 weeks.

Introduction

The use of complementary and alternative therapies (CAM) has been on the rise in the United States, with an increase in usage from 34% in 1990 to 62% in 2002. The National Health Interview Survey of 2007 estimated a further increase of 14.2% since 2002 [1]. The high cost of healthcare along with convenience [1,2] are cited as major reasons why individuals are turning towards CAM instead of prescription drugs to treat a variety of medical conditions, including psychological diseases. Kava Kava is one such over-the-counter CAM medication.

Kava Kava is a herb extracted from the roots of the plant Piper methysticum. Clinical trials have analyzed the effects of the drug on generalized anxiety disorder (GAD) symptoms, including excessive worrying, insomnia [3], headaches, fatigue, muscle strain, and tension [4] due to the anxiolytic and muscle relaxing properties of Kava Kava's kavalactones [2]. The active ingredients found in Kava Kava are kavain (K) and methysticin (M), with dihydrokawaiin (DHK), dihydromethysticin (DHM), yangonin, flavokawain A (FLKA), and flavokawain B (FLKB) occurring in lesser known quantities [5].

Due to Kava Kava's polarity, the utilization of an alcoholic extraction technique leads to a higher kavalactone content [5,6]. The kavalactones K, DHK, M, and DHM were noted to be 1.5 to 5 times higher in the samples extracted with 95% ethanol as compared to samples extracted with 100% water, while FLKA and FLKB were reported at levels 50 times higher in the 95% ethanol extract [5]. These higher quantities—specifically K, DHK, M, and DHM—promote a greater feeling of calmness, thus being potentially more effective in treating excess apprehension found in basic anxiety or anxiety disorders [2,7]. Unfortunately, higher portions of these kavalactones are also associated with Kava Kava induced liver failure [5]. After a series of published case reports, the Centers for Disease Control and Prevention (CDC) issued a statement cautioning against extended and heightened use of the herbal supplement [8]. Currently, there are still no specific dosage or extended user guidelines defined by the Food and Drug Administration for Kava Kava [9]. However, extracts are now made utilizing non-alcoholic extraction techniques to reduce the amount of toxic kavalactones thought to induce adverse events [5,6,10].

The introduction of aqueous and non-polar extraction methods has been shown to decrease the concentration of toxic kavalactones in commercial Kava Kava products. Both M and FLKB are found in lesser quantities in the lipid/aqueous extract as compared to the polar solvent [5]. Methysticin is harmful in that it decreases the viability of human lymphoblastoid cells by 40%, while flavokawain B can induce apoptosis through the use of reactive oxygen species (ROS) as well as causing the rash-like symptoms often associated with Kava Kava [11]. In addition, both FLKA and FLKB in higher quantities were found to decrease cell viability [5,11]. More recent research has also shown genetic variability's role in Kava Kava induced hepatotoxicity. In the South Pacific, where Kava Kava is traditionally used, the side effect of liver damage is usually absent [6]. South Pacific islanders are thought to have a genetic advantage that allows them to periodically consume Kava Kava [12,13]. Seventy-nine percent of those from Caucasian descent are estimated to be deficient in CYP2D6, an important enzyme necessary for drug metabolism and prevention of drug-drug interactions [13]. Despite Kava Kava-induced hepatitis being considered a rare event [14], this enzyme is thought to be responsible for the hepatotoxicity in non-South Pacific Islanders because of improper breakdown and clearance of kavalactone metabolites [6]. Toxicity may also arise from using the aerial part of the plant, which contains toxic alkaloids [13].

Other than being classified as an anti-anxiety agent, Kava Kava has also been used to treat insomnia, major depressive disorder (MDD), and other comorbid disorders [2]. Decreased cognitive function (declined visual attention accuracy) and awareness are frequent side effects of benzodiazepines, which are commonly used to treat clinical anxiety [11]. Kava Kava has been shown to have similar negative effects in higher doses, but also has been shown to increase visual processing and working memory [13]. Previous trials have also shown Kava has an absence of severe side effects if the dose remains under 400 mg of kavalactones per day [14], and it has increased effectiveness when taken by females and/or younger adults [15]. Given the increased use of Kava Kava as an alternative therapy for anxiety, this systematic review and meta-analysis will analyze the general effectiveness of Kava Kava as well as address its potential to inflict liver damage in both the short and long-term from more recent studies. Previous reviews have summarized the findings of studies performed prior to the year 2000. The primary goal of this review and meta-analysis is to supplement current findings, make comparisons to previous meta analyses [7,15], and effectively construct recommendations for any further studies conducted to study Kava Kava and its capability in treating anxiety symptoms.

Section snippets

Methods

A systematic review and meta-analysis were conducted to evaluate randomized clinical trial research on Kava Kava's effectiveness in treating anxiety among adults 18 years of age and older. Databases PubMed, CINAHL, and PsycInfo were utilized, with the search strategy last repeated on January 23, 2018. Key terms were defined based on pre-existing dictionary items from each database.

Inclusion criteria included: English language, published between January 1, 2000, and December 31, 2017,

Results

The 11 articles meeting inclusion/exclusion criteria included 9 studies that were randomized, double-blinded studies with at least two parallel groups [[16], [17], [18], [19], [20], [21], [22], [23],26] and 2 that detailed more information on adverse events [24,25].

Discussion

Results point to Kava Kava as an all-around treatment for anxiety relief. Individual studies confirm Kava Kava decreases anxiety symptomatology with the absence of liver failure. Previous reviews of articles published prior to the year 2000 have found similar results confirming Kava Kava's clinical effectiveness. Pittler and Ernst (2003) and Witte et al. (2005) also concluded Kava Kava may be more clinically effective in patients who are younger and/or female [7,15]. Individual RCT conclusions

Conclusions

Kava Kava appears to alleviate anxiety symptoms as previously described in Pittler and Ernst (2003) and Witte et al. (2005) with no additional AEs as compared to placebo [7,15]. Study samples in this analysis provided a wide range of demographics to examine. Trends previously mentioned in other reviews were noted to be present in this analysis. The research team found Kava Kava to increase anxiety relief in both younger and female samples. There is also some concern over long term Kava Kava use

Conflicts of Interest

This review did not receive any grant funding from agencies in the public, commercial, or not-for-profit sectors. The authors do not have any conflicts of interest to disclose.

Authorship

All authors participated in the preparation, reading and approval of the final manuscript.

References (31)

  • From the Centers for Disease Control and Prevention

    Hepatic toxicity possibly associated with kava-containing products--United States, Germany, and Switzerland, 1999-2002

    J. Am. Med. Assoc.

    (2003)
  • U.S. Food and Drug Administration. Safety alerts for human medical products: kava (piper methysticum). Silver Spring,...
  • R. Teschke et al.

    Kava, the anxiolytic herb: back to basics to prevent liver injury?

    Br. J. Clin. Pharmacol.

    (2011)
  • L.R. Olsen et al.

    Constituents in kava extracts potentially involved in hepatotoxicity: a review

    Chem. Res. Toxicol.

    (2011)
  • B.J. Gurley et al.

    Clinical assessment of CYP2D6city: a Review. nt liver injury?

    Br. J. Clin. Pharmacol.

    (2011)
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