nutrients Review Kava as a Clinical Nutrient: Promises and Challenges 1, 1, 1, 1, 2 Tengfei Bian y, Pedro Corral y , Yuzhi Wang y, Jordy Botello y, Rick Kingston , Tyler Daniels 3, Ramzi G. Salloum 4 , Edward Johnston 5, Zhiguang Huo 6, Junxuan Lu 7, Andrew C. Liu 8 and Chengguo Xing 1,* 1 Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA; [email protected]fl.edu (T.B.); [email protected]fl.edu (P.C.); [email protected]fl.edu (Y.W.); [email protected] (J.B.) 2 College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA; [email protected] 3 Thorne Research Inc., Industrial Road, 620 Omni Dr, Summerville, SC 29483, USA; [email protected] 4 Department of Health Outcome & Biomedical Informatics, College of Medicine, University of Florida, Gainesville, FL 32610, USA; rsalloum@ufl.edu 5 The Association for Hawaiian Awa (kava), Pepe’ekeo, HI 96783, USA; [email protected] 6 Department of Biostatistics, College of Public Health & Health Professions, College of Medicine, University of Florida, Gainesville, FL 32610, USA; zhuo@ufl.edu 7 Department of Pharmacology, Penn State University College of Medicine, Hershey, PA 17033, USA; [email protected] 8 Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville, FL 32610, USA; andrew.liu@ufl.edu * Correspondence: [email protected]fl.edu; Tel.: +1-352-294-8511 These four authors contributed equally to this review. y Received: 29 August 2020; Accepted: 25 September 2020; Published: 5 October 2020 Abstract: 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. Keywords: kava; kavalactone; cultivars; quality control; quality assurance; stress; anxiety; cancer; hepatotoxicity; inflammation Nutrients 2020, 12, 3044; doi:10.3390/nu12103044 www.mdpi.com/journal/nutrients Nutrients 2020, 12, 3044 2 of 34 Nutrients 2020, 12, 3044 2 of 35 1.1. IntroductionIntroduction Kava,Kava, alsoalso known as kav kavaa kava, kava, ‘Awa, ‘Awa, or or ‘awa, ‘awa, is is a atype type of ofperennial perennial shrub shrub that that belongs belongs to the to thepepper pepper family family,, known known as Piperaceae as Piperaceae [1]. [Piper1]. Piper methysticum methysticum is itsis botanical its botanical name, name, which which derives derives from fromthe Latin the Latin “methysticum”. “methysticum”. In the In thelocal local language language and and culture, culture, the the word word “kava” “kava” is is used toto denotedenote somethingsomething “bitter”.“bitter”. Kava is is native native to to Oceania Oceania,, with with important important cultural cultural and and historical historical signi significance.ficance. It Ithas has been been grown grown throughout throughout the the regions regions of ofMicronesia, Micronesia, Polynesia Polynesia and and Melanesia Melanesia for forits relaxant its relaxant and andmedicinal medicinal effects eff ectsas a aspain a pain reliever, reliever, muscle muscle relaxant, relaxant, and andas a asremedy a remedy for anxiety, for anxiety, nervousness nervousness and andinsomnia. insomnia. Kava Kava has been has beendomesticated domesticated in these in theseregions regions for thousands for thousands of years of [2] years (Figure [2] (Figure 1a). Female1a). Femaleflowers flowers of kava of are kava scarce are scarce and fruit and pollination fruit pollination is not is particularly not particularly productive. productive. Kava Kava is cultivated is cultivated by bypropagation propagation from from stem stem cuttings cuttings [3] [.3 It]. has It has over over one one hundred hundred different different chemotypes chemotypes and and cultivars. cultivars. A Aset set of oflactones lactones are are abundant abundant and and present present almost almost exclusively exclusively in kava, in kava, thus named thus named kavalactones. kavalactones. These Thesekavalactones kavalactones are also are alsobelieved believed to be to beresponsible responsible for for th thee health health benefits benefits of traditionaltraditional kavakava preparationspreparations [ 4[4]]. Their. Their fingerprints fingerprints have have also also been been used used to distinguish to distinguish different different kava kava cultivars. cultivars. The sum The ofsum the of six the major six kavalactonesmajor kavalactones has been has used been to standardizeused to standardize different kavadifferent products. kava Kavaproducts. is consumed Kava is inconsumed the traditional in the formtraditional as a beverage, form as a in beverage, a more merchandized in a more merchandized form as either form an as anxiolytic either an agent anxiolytic or a dietaryagent or supplement, a dietary supplement, or more recently or more as arecently recreational as a recreational drink served drink in kava served bars. in kava bars. FigureFigure 1.1. ((aa)) TheThe wholewhole kavakava plant,plant, kavakava roots,roots, andand thethe powderpowder fromfrom kavakava roots;roots; (b(b)) traditionaltraditional preparation;preparation; and and ( c(c)) a a commercial commercial dietary dietary supplement supplement form form of of kava kava product. product. BasedBased onon exportexport datadata fromfrom thethe mainmain producingproducing regions,regions, kava’skava’s demanddemand andand exposureexposure hashas increasedincreased significantlysignificantly inin thethe pastpast fewfew yearsyears [5[5––1010]] (Figure(Figure2 ).2). Consistency Consistency andand quality,quality, however, however, remainremain important important issuesissues thatthat needneed toto bebe betterbetter controlled,controlled, becausebecause theythey areare criticalcritical toto thethe eefficacyfficacy andand safetysafety ofof kavakava products,products, asas reviewedreviewed later.later. WhereasWhereas thethe neurologicalneurological benefitsbenefits ofof properproper kavakava useuse appearappear toto bebe undeniable,undeniable, particularlyparticularly inin reducingreducing stressstress andand anxiety,anxiety, therethere isis growinggrowing evidenceevidence thatthat itsits consumptionconsumption couldcould bebe associatedassociated withwith lowlow incidence incidence of of cancer. cancer. Furthermore, Furthermore, anti-inflammatoryanti-inflammatory activitiesactivities have have beenbeen reportedreported for for kavakava andand itsits compounds,compounds, suggestingsuggesting theirtheirpotential potential forfor thethe treatmenttreatment ofof inflammatoryinflammatory diseases.diseases. TheThe mechanismsmechanisms andand responsibleresponsible ingredientsingredients forfor thesethese functionsfunctions requirerequire further exploration and validation. This review, therefore, focuses on kava’s chemical composition Nutrients 2020, 12, 3044 3 of 34 Nutrients 2020, 12, 3044 3 of 35 further exploration and validation. This review, therefore, focuses on kava’s chemical composition and anddiversity, diversity, its anti-inflammatory its anti-inflammatory potential, potential, its neurological its neurological effects, effects, its anti-cancer its anti-cancer properties, properties, and, finally, and, finallyissues, relating issues relating to its safety. to its safety. FigureFigure 2. 2. KavaKava exports exports from from the the main main exporting exporting countries countries between between 2015 and 2019. 2. Kava and Its Diversity 2. Kava and Its Diversity 2.1. Different Forms of Kava 2.1. Different Forms of Kava The consumption of traditional forms of kava has a long history, with the product considered sacredThe in consumption Pacific cultures of andtrad beingitional