WO2019040828A1

WO2019040828A1 - Kava extracts, isolated kavalactones, and uses in treating tobacco and nicotine addiction

Info

Publication number: WO2019040828A1
Application number: PCT/US2018/047879
Authority: WO
Inventors: Chengguo Xing
Original assignee: University Of Florida Research Foundation, Incorporated
Priority date: 2017-08-25
Filing date: 2018-08-24
Publication date: 2019-02-28

Abstract

The instant invention relates to kava (e.g., Piper methysticum) extract compositions, enriched active fractions, isolated active agents, and methods of use for the treatment of tobacco addiction and nicotine addiction.

Description

KAVA EXTRACTS, ISOLATED KAVALACTONES, AND USES IN TREATING TOBACCO AND NICOTINE ADDICTION CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application No.

62/550,409, filed August 25, 2017, U.S. Provisional Application No. 62/550,382, filed August 25, 2017, and U.S. Provisional Application No. 62/550,396, filed August 25, 2017, each of which is incorporated herein by reference in its entirety.

BACKGROUND

This invention relates to kava {Piper methysticum) extract compositions, enriched active fractions, isolated active agents, and methods of use for the treatment of tobacco addiction and nicotine addiction.

Approximately 220,000 people in the United States are diagnosed of lung cancer with over 155,000 associated deaths annually. In Florida, around 19,000 new lung cancer cases are expected in 2017 with nearly 12,000 deaths. Since the five-year survival of lung cancer patients has been hovering around 15% for decades without significant improvement, preventing lung cancer is an important strategy for its effective management. The primary risk factor for lung cancer is tobacco use, accounting for an estimated 80-90% occurrence. Quitting is challenging, however, and many smokers who use pharmacological and psychosocial interventions do not succeed even after multiple attempts. This demonstrates the need for better strategies to facilitate tobacco cessation as well as therapies to prevent lung carcinogenesis (a process that turns a normal cell into a cancer cell). Racial disparities also exist in lung cancer incidence and mortality [Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA: a cancer journal for clinicians. 2016;66(l):7-30; DeSantis CE, Siegel RL, Sauer AG, Miller KD, Fedewa SA, Alcaraz KI, et al. Cancer statistics for African Americans, 2016: Progress and opportunities in reducing racial disparities. CA: a cancer journal for clinicians. 2016;66(4):290-308.], at least partially due to the inequities in smoking outcomes. African American (AA) smokers, with the same cigarette consumption, are at the highest risk of developing lung cancer [Haiman CA, Stram DO, Wilkens LR, Pike MC, Kolonel LN, Henderson BE, et al. Ethnic and racial differences in the smoking-related risk of lung cancer. The New England journal of medicine. 2006;354(4):333-42.]. The results of a recent multi-ethnic study by Hecht et al. suggest that differential uptake of NNAL may account for such a disparity [Park SL, Carmella SG, Ming X, Vielguth E, Stram DO, Le Marchand L, et al. Variation in levels of the lung carcinogen NNAL and its glucuronides in the urine of cigarette smokers from five ethnic groups with differing risks for lung cancer. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2015;24(3):561-9.]. AAs are also less likely to engage in tobacco treatment and less successful at quitting, possibly because of health inequity in access and utilization of cessation treatments [Services USDoHaH. Tobacco Use Among U.S. Racial/Ethnic Minority Groups— African Americans, American Indians and Alaska Natives, Asian Americans and Pacific Islanders, and Hispanics: A Report of the Surgeon General. Atlanta: US Department of Health and Human Services, Centers for Disease Control and Prevention, Office on Smoking and Health, 1998 2015.].

Tobacco smoke contains various classes of carcinogens. 4-

(Methylnitrosamino)-l-(3-pyridyl)-l-butanone (NNK), a tobacco specific carcinogen, has potent pulmonary carcinogenicity, inducing lung adenoma and adenocarcinoma formation in multiple species [Hecht SS. Biochemistry, biology, and carcinogenicity of tobacco- specific N-nitrosamines. Chemical research in toxicology. 1998;11(6):559- 603.]. Considerable evidence suggests that NNK contributes to lung adenocarcinoma formation among U.S. smokers [Devesa SS, Shaw GL, Blot WJ. Changing patterns of lung cancer incidence by histological type. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 1991 ; l(l):29-34; Burns DM, Anderson CM, Gray N. Do changes in cigarette design influence the rise in adenocarcinoma of the lung? Cancer causes & control : CCC. 2011;22(1): 13-22; Hoffmann D, Rivenson A, Hecht SS. The biological significance of tobacco- specific N-nitrosamines: smoking and adenocarcinoma of the lung. Critical reviews in toxicology. 1996;26(2): 199-211; Thun MJ, Lopez AD, Hartge P. Smoking-related mortality in the United States. The New England journal of medicine.

2013;368(18): 1753; Hoffmann D, Rivenson A, Murphy SE, Chung FL, Amin S, Hecht SS. Cigarette smoking and adenocarcinoma of the lung: the relevance of nicotine-derived N-nitrosamines. Journal of Smoking-related disorders. 1993;4: 165- 89.]. Recent cohort studies also showed that the urinary metabolites of NNK (4- (Methylnitrosamino)-l-(3-pyridyl)-l-butanol, NNAL) were significantly associated with risk of lung cancer in humans, directly linking its exposure to lung cancer development [Yuan JM, Koh WP, Murphy SE, Fan Y, Wang R, Carmella SG, et al. Urinary levels of tobacco-specific nitrosamine metabolites in relation to lung cancer development in two prospective cohorts of cigarette smokers. Cancer research.

2009;69(7):2990-5; Yuan JM, Gao YT, Murphy SE, Carmella SG, Wang R, Zhong Y, et al. Urinary levels of cigarette smoke constituent metabolites are prospectively associated with lung cancer development in smokers. Cancer research.

2011;71(21):6749-57.]. NNK metabolism has been well characterized (FIG. 1), including a-hydroxylation, carbonyl reduction, and pyridine N-oxidation (a minor detoxification pathway). a-Hydroxylation of NNK generates two reactive species, leading to two types of DNA damages [Hecht SS. Lung carcinogenesis by tobacco smoke. International journal of cancer Journal international du cancer.

2012;131(12):2724-32; Hecht SS. Biochemistry, biology, and carcinogenicity of tobacco-specific N-nitrosamines. Chemical research in toxicology. 1998; 11(6):559- 603.]. Carbonyl reduction of NNK generates NNAL and is the major pathway in humans (no NNK can be detected in human blood or urine) [Carmella SG, Akerkar S, Hecht SS. Metabolites of the tobacco- specific nitrosamine 4-(methylnitrosamino)-l- (3-pyridyl)-l-butanone in smokers' urine. Cancer research. 1993;53(4):721-4.].

NNAL, also a potent pulmonary carcinogen [Upadhyaya P, Kenney PM, Hochalter JB, Wang M, Hecht SS. Tumorigenicity and metabolism of 4-(methylnitrosamino)-l- (3-pyridyl)-l-butanol enantiomers and metabolites in the A/J mouse. Carcinogenesis. 1999;20(8): 1577-82.], can be activated via a-hydroxylation as well to generate two reactive species, leading to DNA damage. DNA damage is a major underlying cause for NNK and NNAL carcinogenesis [Hecht SS. Biochemistry, biology, and carcinogenicity of tobacco- specific N-nitrosamines. Chemical research in toxicology. 1998; 11(6):559-603.] . Some of these DNA damage will be released in the urine, which can potentially reflect the level of such DNA damage in tissues, such as 3- methyl adenine. Besides bioactivation, NNAL can be detoxified via urinary excretion in its free form and glucuronidated form [Carmella SG, Le Ka KA, Upadhyaya P,

Hecht SS. Analysis of N- and O-glucuronides of 4-(methylnitrosamino)-l-(3-pyridyl)- 1-butanol (NNAL) in human urine. Chemical research in toxicology. 2002;15(4):545- 50.] and enhanced urinary excretion of NNAL is expected to reduce its

carcinogenesis. Kava has been served as a beverage in the South Pacific and Hawaii regions for centuries. Such a traditional consumption has been documented to help people relax, socialize and improve the quality of sleep [WHO. Kava: a review of the safety of tradtional and recreational beverage consumption. Food and Agriculture Organization of the United Nation. 2016;1: 1-35.]. The traditional form of kava is typically prepared by grinding the rhizome of kava kava {Piper methysticum Forst) plants in ambient temperature water or coconut milk. Kava can also be prepared by extracting the rhizomes with ethanol or acetone, which has been exclusively consumed outside of the South Pacific regions. A number of clinical studies suggest that kava has an anxiolytic effect and the organic extract preparation was once marketed as a prescribed drug to help manage mild to moderate anxiety [Stevinson C, Huntley A, Ernst E. A systematic review of the safety of kava extract in the treatment of anxiety. Drug Saf. 2002;25(4):251-61; Pittler MH, Ernst E. Kava extract for treating anxiety. Cochrane Database Syst Rev. 2003;1:CD003383; Geier FP, Konstantinowicz T. Kava treatment in patients with anxiety. Phytother Res. 2004;18(4):297-300.]. The organic extract form of kava has also been commercialized as a dietary supplement for decades in the US. Recent data indicate that kava consumption has been increasing outside of the South Pacific regions over the past few years, potentially with over 10 dosages consumed annually [Martin AC, Johnston E, Xing C, Hegeman AD. Measuring the Chemical and Cytotoxic Variability of Commercially Available Kava (Piper methysticum G. Forster). PLoS One. 2014;9(l l):el l l572. doi: 10.1371/journal.pone.Ol 11572. PubMed PMID: 25365244; PubMed Central PMCID: PMC4218769.].

Kava contains a set of structurally unique lactones that are dominantly if not exclusively detected in kava, named kavalactones. Six kavalactones have been reported as the major ones, including kavain, dihydrokavain (DHK), methysticin, dihydromethysticin (DHM), desmethoxyyangonin and yangonin (FIG. 2), which could account for up to 96% of the total kavalactones in certain kava preparations [Clouatre DL. Kava kava: examining new reports of toxicity. Toxicol Lett.

2004;150(l):85-96.]. These kavalactones are generally accepted as the active ingredients responsible for its relaxing effect and the total abundance of kavalactone has been used for kava dosing standardization [Lasme P, Davrieux F, Montet D, Lebot V. Quantification of kavalactones and determination of kava (Piper

methysticum) chemotypes using near-infrared reflectance spectroscopy for quality control in Vanuatu. Journal of agricultural and food chemistry. 2008;56(13):4976-81. doi: 10.1021/jf800439g. PubMed PMID: 18540613.]. However, these kavalactones may have different contributions to kava' s anxiolytic effect and other biological activities in spite of their high structural similarity [Jamieson DD, Duffield PH. The Antinociceptive Actions of Kava Components in Mice. Clin Exp Pharmacol P.

1990;17(7):495-508. doi: DOI 10.1111/j.1440-1681.1990.tb01349.x. PubMed PMID: WOS:A1990DU15100004; Baum SS, Hill R, Rommelspacher H. Effect of kava extract and individual kavapyrones on neurotransmitter levels in the nucleus accumbens of rats. Prog Neuropsychopharmacol Biol Psychiatry. 1998;22(7): 1105- 20.]. For instance, two in vivo studies suggested that DHK might be more anxiolytic than other kavalactones [Feltenstein MW, Lambdin LC, Ganzera M, Ranjith H, Dharmaratne W, Nanayakkara NP, et al. Anxiolytic properties of Piper methysticum extract samples and fractions in the chick social- separation- stress procedure.

Phytotherapy research : PTR. 2003;17(3):210-6; Smith KK, Dharmaratne HR, Feltenstein MW, Broom SL, Roach JT, Nanayakkara NP, et al. Anxiolytic effects of kava extract and kavalactones in the chick social separation- stress paradigm.

Psychopharmacology (Berl). 2001;155(l):86-90.], although kavain has been traditionally considered as the major anxiolytic ingredient [Lehmann E, Klieser E, Klimke A, Krach H, Spatz R. The efficacy of Cavain in patients suffering from anxiety. Pharmacopsychiatry. 1989;22(6):258-62.]. Similarly, DHM was shown to effectively block 4-(methylnitrosamino)-l-(3-pyridyl)-l-butanone (NNK, a tobacco specific carcinogen)-induced lung tumorigenesis in an A/J mouse model while DHK, under the same conditions, had no effect at all [NarayanapiUai SC, Balbo S, Leitzman P, Grill AE, Upadhyaya P, Shaik AA, et al. Dihydromethysticin from kava blocks tobacco carcinogen 4-(methylnitrosamino)-l-(3-pyridyl)-l-butanone-induced lung tumorigenesis and differentially reduces DNA damage in A/J mice. Carcinogenesis. 2014;35(10):2365-72. doi: 10.1093/carcin/bgul49. PubMed PMID: 25053626;

PubMed Central PMCID: PMC4178470.]. On the other hand, these kavalactones may influence the pharmacokinetics and pharmacodynamics of one another when being used in the kava matrix. For example, the bioavailability of kavalactones generally increased when being administered in the kava matrix than being administered alone [Mathews JM, Etheridge AS, Valentine JL, Black SR, Coleman DP, Patel P, et al. Pharmacokinetics and disposition of the kavalactone kawain: interaction with kava extract and kavalactones in vivo and in vitro. Drug Metab Dispos. 2005;33(10): 1555- 63; Keledjian J, Duffield PH, Jamieson DD, Lidgard RO, Duffield AM. Uptake into Mouse-Brain of 4 Compounds Present in the Psychoactive Beverage Kava. J Pharm Sci. 1988;77(12): 1003-6. doi: DOI 10.1002/jps.2600771203. PubMed PMID:

WOS:A1988R230500002.]. Kava also appeared to produce a stronger anxiolytic effect than any pure individual kavalactones at the equivalent dose [Rasmussen AK, Scheline RR, Solheim E, Hansel R. Metabolism of some kava pyrones in the rat. Xenobiotica; the fate of foreign compounds in biological systems. 1979;9(1): 1-16. Epub 1979/01/01. doi: 10.3109/00498257909034699. PubMed PMID: 760318.]. Kava products with different kavalactone profiles, therefore, could have varied

pharmacological properties and should not be considered the same even if they have the same abundance of total kavalactones. The total abundance of kavalactones should not be sufficient for kava standardization and individual kavalactones in a kava product may need to be quantified and specified.

Besides its potential benefits, reports of rare but sometimes severe hepatotoxic cases among kava users in the late 1990s have brought the public attention to its safety [Stevinson C, Huntley A, Ernst E. A systematic review of the safety of kava extract in the treatment of anxiety. Drug Saf. 2002;25(4):251-61.], which resulted in the ban of kava in Germany between 2001 - 2014 [Kuchta K, Schmidt M, Nahrstedt A. German Kava Ban Lifted by Court: The Alleged Hepatotoxicity of Kava (Piper methysticum) as a Case of Ill-Defined Herbal Drug Identity, Lacking Quality Control, and Misguided Regulatory Politics. Planta Med. 2015;81(18): 1647-53. doi: 10.1055/s- 0035-1558295. PubMed PMID: 26695707.]. The US Food and Drug Administration (FDA) has advised consumers of the hepatotoxic risk associated with the use of kava- containing dietary supplements in 2002. There has been no further actions from FDA, likely because of the lack of solid evidence of kava's hepatotoxic risk and the dispute of the cause for the observed adverse cases [Teschke R, Sarris J, Lebot V.

Contaminant hepatotoxins as culprits for kava hepatotoxicity— fact or fiction?

Phytother Res. 2013;27(3):472-4. doi: 10.1002/ptr.4729. PubMed PMID: 22585547; WHO. Assessments of the risk of hepatotoxicity with kava products. WHO Document Production Service. 2007.]. The evidence suggesting that kava induces hepatotoxicity is rather controversial and the purported incidence rate (mostly mild and reversible) is extremely low (0.3 case per one million daily doses) [Organization WH. Assessments of the risk of hepatotoxicity with kava products. WHO Document Production Service. 2007; Teschke R, Schwarzenboeck A, Hennermann KH. Kava hepatotoxicity: a clinical survey and critical analysis of 26 suspected cases. European journal of gastroenterology & hepatology. 2008;20(12): 1182-93.]. Kava has been on the US market as a dietary supplement for decades, which based on FDA's criteria is generally safe and the ban on kava in Germany was recently lifted [Kuchta K, Schmidt M, Nahrstedt A. German Kava Ban Lifted by Court: The Alleged

Hepatotoxicity of Kava (Piper methysticum) as a Case of Ill-Defined Herbal Drug Identity, Lacking Quality Control, and Misguided Regulatory Politics. Planta Med. 2015;81(18): 1647-53.]. Nevertheless, no signs of hepatotoxicity were observed when kava was evaluated alone even at elevated dosages and extended exposures [Leitzman P, NarayanapiUai SC, Balbo S, Zhou B, Upadhyaya P, Shaik AA, et al. Kava blocks 4-(methylnitrosamino)-l-(3-pyridyl)-l-butanone-induced lung tumorigenesis in association with reducing 06-methylguanine DNA adduct in A/J mice. Cancer prevention research. 2014;7(l):86-96; Triolet J, Shaik AA, Gallaher DD, O'Sullivan MG, Xing C. Reduction in colon cancer risk by consumption of kava or kava fractions in carcinogen-treated rats. Nutrition and cancer. 2012;64(6):838-46; Tang SN, Zhang J, Jiang P, Datta P, Leitzman P, O'Sullivan MG, et al. Gene expression signatures associated with suppression of TRAMP prostate carcinogenesis by a kavalactone-rich Kava fraction. Molecular carcinogenesis. 2016; NarayanapiUai SC, Balbo S, Leitzman P, Grill AE, Upadhyaya P, Shaik AA, et al. Dihydromethysticin (DHM) from kava blocks tobacco carcinogen 4-(methylnitrosamino)-l-(3-pyridyl)-l-butanone (NNK)- induced lung tumorigenesis and differentially reduces DNA damage in A/J mice. Carcinogenesis. 2014;35(10):2365-72; Johnson TE, Kassie F, O'Sullivan MG, Negia M, Hanson TE, Upadhyaya P, et al. Chemopreventive effect of kava on 4- (methylnitrosamino)-l-(3-pyridyl)-l-butanone plus benzo[a]pyrene-induced lung tumorigenesis in A/J mice. Cancer prevention research. 2008;l(6):430-8; Johnson TE, Hermanson D, Wang L, Kassie F, Upadhyaya P, O'Sullivan MG, et al. Lung tumorigenesis suppressing effects of a commercial kava extract and its selected compounds in A/J mice. The American journal of Chinese medicine. 2011;39(4):727- 42; NarayanapiUai SC, Leitzman P, O'Sullivan MG, Xing C. Flavokawains a and B in kava, not dihydromethysticin, potentiate acetaminophen-induced hepatotoxicity in C57BL/6 mice. Chemical research in toxicology. 2014;27(10): 1871-6.]. Upon revisiting the rare human hepatotoxic cases associated with kava usage, kava's hepatotoxic risk may be due to herb-drug interactions [Organization WH.

Assessments of the risk of hepatotoxicity with kava products. WHO Document Production Service. 2007; Teschke R, Schwarzenboeck A, Hennermann KH. Kava hepatotoxicity: a clinical survey and critical analysis of 26 suspected cases. European journal of gastroenterology & hepatology. 2008;20(12): 1182-93.]. This was supported by the results of a recent study, demonstrating that kava could enhance

acetaminophen-induced hepatotoxicity in vivo due to two chalcone-based chemicals, flavokavains A and B [Narayanapillai SC, Leitzman P, O'Sullivan MG, Xing C. Flavokawains a and B in kava, not dihydromethysticin, potentiate acetaminophen- induced hepatotoxicity in C57BL/6 mice. Chemical research in toxicology.

2014;27(10): 1871-6.]. In summary, kava's safety profile may be further improved if kava contains low amounts of flavokavains A and B.

As discussed above, approximately 220,000 people in the United States are diagnosed of lung cancer with over 155,000 associated deaths annually. Since the five-year survival of lung cancer patients has been hovering around 15% for decades without significant improvement, preventing lung cancer is an important strategy for its effective management. The primary risk factor for lung cancer is tobacco use, accounting for an estimated 80-90% occurrence. Quitting is challenging, however, and many smokers who use pharmacological and psychosocial interventions do not succeed even after multiple attempts. This demonstrates the need for better strategies to facilitate tobacco cessation as well as therapies to prevent lung carcinogenesis (a process that turns a normal cell into a cancer cell). These unmet needs are addressed by the present invention.

BRIEF SUMMARY OF THE INVENTION

This invention is directed towards kava extract compositions, enriched active extracts, processes for isolation, isolated active agents, and methods of treating disease, disorders and conditions in a subject, including, tobacco and nicotine addiction, by use of the extracts, enriched active extracts, compounds, and

compositions thereof.

Another aspect of this invention is a composition comprising a kava extract herein (e.g., extract Piper methysticum). Another aspect is a composition comprising an enriched active extract from a kava extract herein. Another aspect is a composition comprising an isolated compound from a kava extract herein.

In another aspect, the invention provides a pharmaceutical composition comprising a kava extract and a pharmaceutically acceptable carrier. In another aspect, the invention provides a pharmaceutical composition comprising an enriched kava extract and a pharmaceutically acceptable carrier.

In another aspect, the invention provides a pharmaceutical composition comprising one or more kavalactones or salts thereof, and a pharmaceutically acceptable carrier.

Certain aspects of the invention comprise a composition or kava extract as described herein and a pharmaceutically acceptable carrier.

Another aspect of the invention is a composition comprising at least one compound selected from kavain, dihydrokavain, methysticin, dihydromethysticin, yangonin, desmethoxyyangonin, and salts thereof. In certain aspects, the composition comprises at least two compounds selected from kavain, dihydrokavain, methysticin, dihydromethysticin, yangonin, desmethoxyyangonin, and salts thereof. In certain aspects, the composition comprises at least three compounds selected from kavain, dihydrokavain, methysticin, dihydromethysticin, yangonin, desmethoxyyangonin, and salts thereof. In certain aspects, the composition comprises at least four compounds selected from kavain, dihydrokavain, methysticin, dihydromethysticin, yangonin, desmethoxyyangonin, and salts thereof. In certain aspects, the composition comprises at least five compounds selected from kavain, dihydrokavain, methysticin, dihydromethysticin, yangonin, desmethoxyyangonin, and salts thereof. In certain aspects, the composition comprises kavain, dihydrokavain, methysticin,

dihydromethysticin, yangonin, and desmethoxyyangonin.

Another aspect of the invention is a composition comprising at least one compound selected from kavain, dihydrokavain, methysticin, dihydromethysticin, yangonin, and desmethoxyyangonin, wherein the composition is substantially free of flavokawain A and/or flavokawain B. In certain aspects, the composition comprises at least two compounds selected from kavain, dihydrokavain, methysticin,

dihydromethysticin, yangonin, and desmethoxyyangonin, wherein the composition is substantially free of flavokawain A and/or flavokawain B. In certain aspects, the composition comprises at least three compounds selected from kavain, dihydrokavain, methysticin, dihydromethysticin, yangonin, and desmethoxyyangonin, wherein the composition is substantially free of flavokawain A and/or flavokawain B. In certain aspects, the composition comprises at least four compounds selected from kavain, dihydrokavain, methysticin, dihydromethysticin, yangonin, and desmethoxyyangonin, wherein the composition is substantially free of flavokawain A and/or flavokawain B. In certain aspects, the composition comprises at least five compounds selected from kavain, dihydrokavain, methysticin, dihydromethysticin, yangonin, and

desmethoxyyangonin, wherein the composition is substantially free of flavokawain A and/or flavokawain B. In certain aspects, the composition comprises kavain, dihydrokavain, methysticin, dihydromethysticin, yangonin, and desmethoxyyangonin, wherein the composition is substantially free of flavokawain A and/or flavokawain B.

Another aspect of the invention is a composition comprising at least one compound selected from kavain, dihydrokavain, methysticin, dihydromethysticin, and desmethoxyyangonin. In certain aspects, the composition comprises at least two compounds selected from kavain, dihydrokavain, methysticin, dihydromethysticin, and desmethoxyyangonin. In certain aspects, the composition comprises at least three compounds selected from kavain, dihydrokavain, methysticin, dihydromethysticin, and desmethoxyyangonin. In certain aspects, the composition comprises at least four compounds selected from kavain, dihydrokavain, methysticin, dihydromethysticin, and desmethoxyyangonin. In certain aspects, the composition comprises kavain, dihydrokavain, methysticin, dihydromethysticin, and desmethoxyyangonin.

Another aspect of the invention is a composition comprising at least one compound selected from kavain, dihydrokavain, methysticin, dihydromethysticin, and desmethoxyyangonin, wherein the composition is substantially free of flavokawain A and/or flavokawain B. In certain aspects, the composition comprises at least two compounds selected from kavain, dihydrokavain, methysticin, dihydromethysticin, and desmethoxyyangonin, wherein the composition is substantially free of

flavokawain A and/or flavokawain B. In certain aspects, the composition comprises at least three compounds selected from kavain, dihydrokavain, methysticin,

dihydromethysticin, and desmethoxyyangonin, wherein the composition is substantially free of flavokawain A and/or flavokawain B. In certain aspects, the composition comprises at least four compounds selected from kavain, dihydrokavain, methysticin, dihydromethysticin, and desmethoxyyangonin, wherein the composition is substantially free of flavokawain A and/or flavokawain B. In certain aspects, the composition comprises kavain, dihydrokavain, methysticin, dihydromethysticin, and desmethoxyyangonin, wherein the composition is substantially free of flavokawain A and/or flavokawain B.

Another aspect of the invention is a composition comprising kavain and at least one compound selected from dihydrokavain, methysticin, dihydromethysticin, yangonin, and desmethoxyyangonin. In certain aspects, the composition comprises kavain and at least two compounds selected from dihydrokavain, methysticin, dihydromethysticin, yangonin, and desmethoxyyangonin. In certain aspects, the composition comprises kavain and at least three compounds selected from

dihydrokavain, methysticin, dihydromethysticin, yangonin, and desmethoxyyangonin. In certain aspects, the composition comprises kavain and at least four compounds selected from dihydrokavain, methysticin, dihydromethysticin, yangonin, and desmethoxyyangonin.

Another aspect of the invention is a composition comprising kavain and at least one compound selected from dihydrokavain, methysticin, dihydromethysticin, yangonin, and desmethoxyyangonin, wherein the composition is substantially free of flavokawain A and/or flavokawain B. In certain aspects, the composition comprises kavain and at least two compounds selected from dihydrokavain, methysticin, dihydromethysticin, yangonin, and desmethoxyyangonin, wherein the composition is substantially free of flavokawain A and/or flavokawain B. In certain aspects, the composition comprises kavain and at least three compounds selected from

dihydrokavain, methysticin, dihydromethysticin, yangonin, and desmethoxyyangonin, wherein the composition is substantially free of flavokawain A and/or flavokawain B. In certain aspects, the composition comprises kavain and at least four compounds selected from dihydrokavain, methysticin, dihydromethysticin, yangonin, and desmethoxyyangonin, wherein the composition is substantially free of flavokawain A and/or flavokawain B.

Another aspect of the invention is a composition comprising kavain and at least one compound selected from dihydrokavain, methysticin, dihydromethysticin, and desmethoxyyangonin. In certain aspects, the composition comprises kavain and at least two compounds selected from dihydrokavain, methysticin, dihydromethysticin, and desmethoxyyangonin. In certain aspects, the composition comprises kavain and at least three compounds selected from dihydrokavain, methysticin, dihydromethysticin, and desmethoxyyangonin.

Another aspect of the invention is a composition comprising kavain and at least one compound selected from dihydrokavain, methysticin, dihydromethysticin, and desmethoxyyangonin, wherein the composition is substantially free of

flavokawain A and/or flavokawain B. In certain aspects, the composition comprises kavain and at least two compounds selected from dihydrokavain, methysticin, dihydromethysticin, and desmethoxyyangonin, wherein the composition is substantially free of flavokawain A and/or flavokawain B. In certain aspects, the composition comprises kavain and at least three compounds selected from

dihydrokavain, methysticin, dihydromethysticin, and desmethoxyyangonin, wherein the composition is substantially free of flavokawain A and/or flavokawain B.

Another aspect of the invention is a composition comprising dihydrokavain and at least one compound selected from kavain, methysticin, dihydromethysticin, yangonin, and desmethoxyyangonin. In certain aspects, the composition comprises dihydrokavain and at least two compounds selected from kavain, methysticin, dihydromethysticin, yangonin, and desmethoxyyangonin. In certain aspects, the composition comprises dihydrokavain and at least three compounds selected from kavain, methysticin, dihydromethysticin, yangonin, and desmethoxyyangonin. In certain aspects, the composition comprises dihydrokavain and at least four compounds selected from kavain, methysticin, dihydromethysticin, yangonin, and desmethoxyyangonin.

Another aspect of the invention is a composition comprising dihydrokavain and at least one compound selected from kavain, methysticin, dihydromethysticin, yangonin, and desmethoxyyangonin, wherein the composition is substantially free of flavokawain A and/or flavokawain B. In certain aspects, the composition comprises dihydrokavain and at least two compounds selected from kavain, methysticin, dihydromethysticin, yangonin, and desmethoxyyangonin, wherein the composition is substantially free of flavokawain A and/or flavokawain B. In certain aspects, the composition comprises dihydrokavain and at least three compounds selected from kavain, methysticin, dihydromethysticin, yangonin, and desmethoxyyangonin, wherein the composition is substantially free of flavokawain A and/or flavokawain B. In certain aspects, the composition comprises dihydrokavain and at least four compounds selected from kavain, methysticin, dihydromethysticin, yangonin, and desmethoxyyangonin, wherein the composition is substantially free of flavokawain A and/or flavokawain B.

Another aspect of the invention is a composition comprising dihydrokavain and at least one compound selected from kavain, methysticin, dihydromethysticin, and desmethoxyyangonin. In certain aspects, the composition comprises

dihydrokavain and at least two compounds selected from kavain, methysticin, dihydromethysticin, and desmethoxyyangonin. In certain aspects, the composition comprises dihydrokavain and at least three compounds selected from kavain, methysticin, dihydromethysticin, and desmethoxyyangonin.

Another aspect of the invention is a composition comprising dihydrokavain and at least one compound selected from kavain, methysticin, dihydromethysticin, and desmethoxyyangonin, wherein the composition is substantially free of

flavokawain A and/or flavokawain B. In certain aspects, the composition comprises dihydrokavain and at least two compounds selected from kavain, methysticin, dihydromethysticin, and desmethoxyyangonin, wherein the composition is substantially free of flavokawain A and/or flavokawain B. In certain aspects, the composition comprises dihydrokavain and at least three compounds selected from kavain, methysticin, dihydromethysticin, and desmethoxyyangonin, wherein the composition is substantially free of flavokawain A and/or flavokawain B.

Another aspect of the invention is a composition comprising methysticin and at least one compound selected from kavain, dihydrokavain, dihydromethysticin, yangonin, and desmethoxyyangonin. In certain aspects, the composition comprises methysticin and at least two compounds selected from kavain, dihydrokavain, dihydromethysticin, yangonin, and desmethoxyyangonin. In certain aspects, the composition comprises methysticin and at least three compounds selected from kavain, dihydrokavain, dihydromethysticin, yangonin, and desmethoxyyangonin. In certain aspects, the composition comprises methysticin and at least four compounds selected from kavain, dihydrokavain, dihydromethysticin, yangonin, and

desmethoxyyangonin.

Another aspect of the invention is a composition comprising methysticin and at least one compound selected from kavain, dihydrokavain, dihydromethysticin, yangonin, and desmethoxyyangonin, wherein the composition is substantially free of flavokawain A and/or flavokawain B. In certain aspects, the composition comprises methysticin and at least two compounds selected from kavain, dihydrokavain, dihydromethysticin, yangonin, and desmethoxyyangonin, wherein the composition is substantially free of flavokawain A and/or flavokawain B. In certain aspects, the composition comprises methysticin and at least three compounds selected from kavain, dihydrokavain, dihydromethysticin, yangonin, and desmethoxyyangonin, wherein the composition is substantially free of flavokawain A and/or flavokawain B. In certain aspects, the composition comprises methysticin and at least four compounds selected from kavain, dihydrokavain, dihydromethysticin, yangonin, and desmethoxyyangonin, wherein the composition is substantially free of flavokawain A and/or flavokawain B.

Another aspect of the invention is a composition comprising methysticin and at least one compound selected from kavain, dihydrokavain, dihydromethysticin, and desmethoxyyangonin. In certain aspects, the composition comprises methysticin and at least two compounds selected from kavain, dihydrokavain, dihydromethysticin, and desmethoxyyangonin. In certain aspects, the composition comprises methysticin and at least three compounds selected from kavain, dihydrokavain, dihydromethysticin, and desmethoxyyangonin.

Another aspect of the invention is a composition comprising methysticin and at least one compound selected from kavain, dihydrokavain, dihydromethysticin, and desmethoxyyangonin, wherein the composition is substantially free of flavokawain A and/or flavokawain B. In certain aspects, the composition comprises methysticin and at least two compounds selected from kavain, dihydrokavain, dihydromethysticin, and desmethoxyyangonin, wherein the composition is substantially free of flavokawain A and/or flavokawain B. In certain aspects, the composition comprises methysticin and at least three compounds selected from kavain, dihydrokavain, dihydromethysticin, and desmethoxyyangonin, wherein the composition is substantially free of flavokawain A and/or flavokawain B.

Another aspect of the invention is a composition comprising

dihydromethysticin and at least one compound selected from kavain, dihydrokavain, methysticin, yangonin, and desmethoxyyangonin. In certain aspects, the composition comprises dihydromethysticin and at least two compounds selected from kavain, dihydrokavain, methysticin, yangonin, and desmethoxyyangonin. In certain aspects, the composition comprises dihydromethysticin and at least three compounds selected from kavain, dihydrokavain, methysticin, yangonin, and desmethoxyyangonin. In certain aspects, the composition comprises dihydromethysticin and at least four compounds selected from kavain, dihydrokavain, methysticin, yangonin, and desmethoxyyangonin.

Another aspect of the invention is a composition comprising

dihydromethysticin and at least one compound selected from kavain, dihydrokavain, methysticin, yangonin, and desmethoxyyangonin, wherein the composition is substantially free of flavokawain A and/or flavokawain B. In certain aspects, the composition comprises dihydromethysticin and at least two compounds selected from kavain, dihydrokavain, methysticin, yangonin, and desmethoxyyangonin, wherein the composition is substantially free of flavokawain A and/or flavokawain B. In certain aspects, the composition comprises dihydromethysticin and at least three compounds selected from kavain, dihydrokavain, methysticin, yangonin, and

desmethoxyyangonin, wherein the composition is substantially free of flavokawain A and/or flavokawain B. In certain aspects, the composition comprises

dihydromethysticin and at least four compounds selected from kavain, dihydrokavain, methysticin, yangonin, and desmethoxyyangonin, wherein the composition is substantially free of flavokawain A and/or flavokawain B.

Another aspect of the invention is a composition comprising

dihydromethysticin and at least one compound selected from kavain, dihydrokavain, methysticin, and desmethoxyyangonin. In certain aspects, the composition comprises dihydromethysticin and at least two compounds selected from kavain, dihydrokavain, methysticin, and desmethoxyyangonin. In certain aspects, the composition comprises dihydromethysticin and at least three compounds selected from kavain,

dihydrokavain, methysticin, and desmethoxyyangonin.

Another aspect of the invention is a composition comprising

dihydromethysticin and at least one compound selected from kavain, dihydrokavain, methysticin, and desmethoxyyangonin, wherein the composition is substantially free of flavokawain A and/or flavokawain B. In certain aspects, the composition comprises dihydromethysticin and at least two compounds selected from kavain, dihydrokavain, methysticin, and desmethoxyyangonin, wherein the composition is substantially free of flavokawain A and/or flavokawain B. In certain aspects, the composition comprises dihydromethysticin and at least three compounds selected from kavain,

dihydrokavain, methysticin, and desmethoxyyangonin, wherein the composition is substantially free of flavokawain A and/or flavokawain B.

Another aspect of the invention is a composition comprising yangonin and at least one compound selected from kavain, dihydrokavain, methysticin,

dihydromethysticin, and desmethoxyyangonin. In certain aspects, the composition comprises yangonin and at least two compounds selected from kavain, dihydrokavain, methysticin, dihydromethysticin, and desmethoxyyangonin. In certain aspects, the composition comprises yangonin and at least three compounds selected from kavain, dihydrokavain, methysticin, dihydromethysticin, and desmethoxyyangonin. In certain aspects, the composition comprises yangonin and at least four compounds selected from kavain, dihydrokavain, methysticin, dihydromethysticin, and desmethoxyyangonin.

dihydromethysticin, and desmethoxyyangonin, wherein the composition is

substantially free of flavokawain A and/or flavokawain B. In certain aspects, the composition comprises yangonin and at least two compounds selected from kavain, dihydrokavain, methysticin, dihydromethysticin, and desmethoxyyangonin, wherein the composition is substantially free of flavokawain A and/or flavokawain B. In certain aspects, the composition comprises yangonin and at least three compounds selected from kavain, dihydrokavain, methysticin, dihydromethysticin, and

desmethoxyyangonin, wherein the composition is substantially free of flavokawain A and/or flavokawain B. In certain aspects, the composition comprises yangonin and at least four compounds selected from kavain, dihydrokavain, methysticin,

dihydromethysticin, and desmethoxyyangonin, wherein the composition is

substantially free of flavokawain A and/or flavokawain B.

Another aspect of the invention is a composition comprising

desmethoxyyangonin and at least one compound selected from kavain, dihydrokavain, methysticin, dihydromethysticin, and yangonin. In certain aspects, the composition comprises desmethoxyyangonin and at least two compounds selected from kavain, dihydrokavain, methysticin, dihydromethysticin, and yangonin. In certain aspects, the composition comprises desmethoxyyangonin and at least three compounds selected from kavain, dihydrokavain, methysticin, dihydromethysticin, and yangonin. In certain aspects, the composition comprises desmethoxyyangonin and at least four compounds selected from kavain, dihydrokavain, methysticin, dihydromethysticin, and yangonin.

Another aspect of the invention is a composition comprising

desmethoxyyangonin and at least one compound selected from kavain, dihydrokavain, methysticin, dihydromethysticin, and yangonin, wherein the composition is substantially free of flavokawain A and/or flavokawain B. In certain aspects, the composition comprises desmethoxyyangonin and at least two compounds selected from kavain, dihydrokavain, methysticin, dihydromethysticin, and yangonin, wherein the composition is substantially free of flavokawain A and/or flavokawain B. In certain aspects, the composition comprises desmethoxyyangonin and at least three compounds selected from kavain, dihydrokavain, methysticin, dihydromethysticin, and yangonin, wherein the composition is substantially free of flavokawain A and/or flavokawain B. In certain aspects, the composition comprises desmethoxyyangonin and at least four compounds selected from kavain, dihydrokavain, methysticin, dihydromethysticin, and yangonin, wherein the composition is substantially free of flavokawain A and/or flavokawain B.

Another aspect of the invention is a composition comprising

desmethoxyyangonin and at least one compound selected from kavain, dihydrokavain, methysticin, and dihydromethysticin. In certain aspects, the composition comprises desmethoxyyangonin and at least two compounds selected from kavain,

dihydrokavain, methysticin, and dihydromethysticin. In certain aspects, the composition comprises desmethoxyyangonin and at least three compounds selected from kavain, dihydrokavain, methysticin, and dihydromethysticin.

Another aspect of the invention is a composition comprising

desmethoxyyangonin and at least one compound selected from kavain, dihydrokavain, methysticin, and dihydromethysticin, wherein the composition is substantially free of flavokawain A and/or flavokawain B. In certain aspects, the composition comprises desmethoxyyangonin and at least two compounds selected from kavain,

dihydrokavain, methysticin, and dihydromethysticin, wherein the composition is substantially free of flavokawain A and/or flavokawain B. In certain aspects, the composition comprises desmethoxyyangonin and at least three compounds selected from kavain, dihydrokavain, methysticin, and dihydromethysticin, wherein the composition is substantially free of flavokawain A and/or flavokawain B.

In any of the embodiments presented herein, the amount of kavain in the composition is 5-300 mg. In any of the embodiments presented herein, the amount of kavain in the composition is 10-200 mg. In any of the embodiments presented herein, the amount of kavain in the composition is 10-150 mg. In any of the embodiments presented herein, the amount of kavain in the composition is 10-100 mg. In any of the embodiments presented herein, the amount of kavain in the composition is 10-50 mg. In any of the embodiments presented herein, the amount of kavain in the composition is 26 mg + 5 mg, 26 mg + 10 mg, 26 mg + 15 mg, 26 mg + 20 mg.

In any of the embodiments presented herein, the amount of dihydrokavain in the composition is 1-200 mg. In any of the embodiments presented herein, the amount of dihydrokavain in the composition is 5-150 mg. In any of the embodiments presented herein, the amount of dihydrokavain in the composition is 5-100 mg. In any of the embodiments presented herein, the amount of dihydrokavain in the composition is 5-50 mg. In any of the embodiments presented herein, the amount of dihydrokavain in the composition is 14 mg + 3 mg, 14 mg + 5 mg, 14 mg + 8 mg, 14 mg + 10 mg, or 14 mg + 12 mg.

In any of the embodiments presented herein, the amount of methysticin in the composition is 1-200 mg. In any of the embodiments presented herein, the amount of methysticin in the composition is 1-150 mg. In any of the embodiments presented herein, the amount of methysticin in the composition is 1-100 mg. In any of the embodiments presented herein, the amount of methysticin in the composition is 1-50 mg. In any of the embodiments presented herein, the amount of methysticin in the composition is 1-25 mg. In any of the embodiments presented herein, the amount of methysticin in the composition is 8 mg + 2 mg , 8 mg + 3 mg , 8 mg + 4 mg, 8 mg + 5 mg, or 8 mg + 7 mg.

In any of the embodiments presented herein, the amount of

dihydromethysticin in the composition is 5-300 mg. In any of the embodiments presented herein, the amount of dihydromethysticin in the composition is 10-200 mg. In any of the embodiments presented herein, the amount of dihydromethysticin in the composition is 10-150 mg. In any of the embodiments presented herein, the amount of dihydromethysticin in the composition is 5-100 mg. In any of the embodiments presented herein, the amount of dihydromethysticin in the composition is 5-50 mg. In any of the embodiments presented herein, the amount of dihydromethysticin in the composition is 10-50 mg. In any of the embodiments presented herein, the amount of dihydromethysticin in the composition is 21 mg + 5 mg, 21 mg + 8 mg, 21 mg + 10 mg, 21 mg + 12 mg, or 21 mg + 15 mg.

In any of the embodiments presented herein, the amount of

desmethoxyyangonin in the composition is 1-200 mg. In any of the embodiments presented herein, the amount of desmethoxyyangonin in the composition is 1-150 mg. In any of the embodiments presented herein, the amount of desmethoxyyangonin in the composition is 1-100 mg. In any of the embodiments presented herein, the amount of desmethoxyyangonin in the composition is 1-50 mg. In any of the embodiments presented herein, the amount of desmethoxyyangonin in the composition is 1-25 mg. In any of the embodiments presented herein, the amount of desmethoxyyangonin in the composition is 8 mg + 2 mg , 8 mg + 3 mg , 8 mg + 5 mg, or 8 mg + 7 mg. Another aspect of the invention is a composition comprising at least one (e.g. , 1, 2, 3, 4, or 5) compound selected from kavain, wherein the amount of kavain in the composition is 26 mg + 10 mg; dihydrokavain, wherein the amount of dihydrokavain in the composition is 14 mg + 5 mg; methysticin, wherein the amount of methysticin in the composition is 8 mg + 5 mg; dihydromethysticin, wherein the amount of dihydromethysticin in the composition is 21 mg + 10 mg; and desmethoxyyangonin, wherein the amount of desmethoxyyangonin in the composition is 8 mg + 5 mg.

Another aspect of the invention is a composition comprising at least one (e.g. , 1, 2, 3, 4, or 5) compound selected from kavain, wherein the amount of kavain in the composition is 100 mg + 20 mg; dihydrokavain, wherein the amount of dihydrokavain in the composition is 14 mg + 5 mg; methysticin, wherein the amount of methysticin in the composition is 8 mg + 5 mg; dihydromethysticin, wherein the amount of dihydromethysticin in the composition is 21 mg + 10 mg; and desmethoxyyangonin, wherein the amount of desmethoxyyangonin in the composition is 8 mg + 5 mg.

Another aspect of the invention is a composition comprising at least one (e.g. ,

1, 2, 3, 4, or 5) compound selected from kavain, wherein the amount of kavain in the composition is 26 mg + 10 mg; dihydrokavain, wherein the amount of dihydrokavain in the composition is 50 mg + 15 mg; methysticin, wherein the amount of methysticin in the composition is 8 mg + 5 mg; dihydromethysticin, wherein the amount of dihydromethysticin in the composition is 21 mg + 10 mg; and desmethoxyyangonin, wherein the amount of desmethoxyyangonin in the composition is 8 mg + 5 mg.

Another aspect of the invention is a composition comprising at least one (e.g. , 1, 2, 3, 4, or 5) compound selected from kavain, wherein the amount of kavain in the composition is 26 mg + 10 mg; dihydrokavain, wherein the amount of dihydrokavain in the composition is 14 mg + 5 mg; methysticin, wherein the amount of methysticin in the composition is 50 mg + 20 mg; dihydromethysticin, wherein the amount of dihydromethysticin in the composition is 21 mg + 10 mg; and desmethoxyyangonin, wherein the amount of desmethoxyyangonin in the composition is 8 mg + 5 mg.

Another aspect of the invention is a composition comprising at least one (e.g. , 1, 2, 3, 4, or 5) compound selected from kavain, wherein the amount of kavain in the composition is 26 mg + 10 mg; dihydrokavain, wherein the amount of dihydrokavain in the composition is 14 mg + 5 mg; methysticin, wherein the amount of methysticin in the composition is 8 mg + 5 mg; dihydromethysticin, wherein the amount of dihydromethysticin in the composition is 100 mg + 25 mg; and desmethoxyyangonin, wherein the amount of desmethoxyyangonin in the composition is 8 mg + 5 mg.

Another aspect of the invention is a composition comprising at least one (e.g. , 1, 2, 3, 4, or 5) compound selected from kavain, wherein the amount of kavain in the composition is 26 mg + 10 mg; dihydrokavain, wherein the amount of dihydrokavain in the composition is 14 mg + 5 mg; methysticin, wherein the amount of methysticin in the composition is 8 mg + 5 mg; dihydromethysticin, wherein the amount of dihydromethysticin in the composition is 21 mg + 10 mg; and desmethoxyyangonin, wherein the amount of desmethoxyyangonin in the composition is 50 mg + 20 mg.

Another aspect of the invention is a composition comprising kavain, wherein the amount of kavain in the composition is 26 mg + 10 mg; dihydrokavain, wherein the amount of dihydrokavain in the composition is 14 mg + 5 mg; methysticin, wherein the amount of methysticin in the composition is 8 mg + 5 mg;

dihydromethysticin, wherein the amount of dihydromethysticin in the composition is 21 mg + 10 mg; and desmethoxyyangonin, wherein the amount of

desmethoxyyangonin in the composition is 8 mg + 5 mg.

Another aspect of the invention is a composition comprising kavain, wherein the amount of kavain in the composition is 100 mg + 20 mg; dihydrokavain, wherein the amount of dihydrokavain in the composition is 14 mg + 5 mg; methysticin, wherein the amount of methysticin in the composition is 8 mg + 5 mg;

desmethoxyyangonin in the composition is 8 mg + 5 mg.

Another aspect of the invention is a composition comprising kavain, wherein the amount of kavain in the composition is 26 mg + 10 mg; dihydrokavain, wherein the amount of dihydrokavain in the composition is 50 mg + 15 mg; methysticin, wherein the amount of methysticin in the composition is 8 mg + 5 mg;

desmethoxyyangonin in the composition is 8 mg + 5 mg.

Another aspect of the invention is a composition comprising kavain, wherein the amount of kavain in the composition is 26 mg + 10 mg; dihydrokavain, wherein the amount of dihydrokavain in the composition is 14 mg + 5 mg; methysticin, wherein the amount of methysticin in the composition is 50 mg + 20 mg;

dihydromethysticin, wherein the amount of dihydromethysticin in the composition is 21 mg + 10 mg; and desmethoxyyangonin, wherein the amount of desmethoxyyangonin in the composition is 8 mg + 5 mg.

dihydromethysticin, wherein the amount of dihydromethysticin in the composition is 100 mg + 25 mg; and desmethoxyyangonin, wherein the amount of

desmethoxyyangonin in the composition is 8 mg + 5 mg.

desmethoxyyangonin in the composition is 50 mg + 20 mg.

Another aspect of the invention is a composition consisting essentially of at least one (e.g. , 1, 2, 3, 4, or 5) compound selected from kavain, wherein the amount of kavain in the composition is 26 mg + 10 mg; dihydrokavain, wherein the amount of dihydrokavain in the composition is 14 mg + 5 mg; methysticin, wherein the amount of methysticin in the composition is 8 mg + 5 mg; dihydromethysticin, wherein the amount of dihydromethysticin in the composition is 21 mg + 10 mg; and

desmethoxyyangonin, wherein the amount of desmethoxyyangonin in the composition is 8 mg + 5 mg.

Another aspect of the invention is a composition consisting essentially of at least one (e.g. , 1, 2, 3, 4, or 5) compound selected from kavain, wherein the amount of kavain in the composition is 100 mg + 20 mg; dihydrokavain, wherein the amount of dihydrokavain in the composition is 14 mg + 5 mg; methysticin, wherein the amount of methysticin in the composition is 8 mg + 5 mg; dihydromethysticin, wherein the amount of dihydromethysticin in the composition is 21 mg + 10 mg; and

Another aspect of the invention is a composition consisting essentially of at least one (e.g. , 1, 2, 3, 4, or 5) compound selected from kavain, wherein the amount of kavain in the composition is 26 mg + 10 mg; dihydrokavain, wherein the amount of dihydrokavain in the composition is 50 mg + 15 mg; methysticin, wherein the amount of methysticin in the composition is 8 mg + 5 mg; dihydromethysticin, wherein the amount of dihydromethysticin in the composition is 21 mg + 10 mg; and

Another aspect of the invention is a composition consisting essentially of at least one (e.g. , 1, 2, 3, 4, or 5) compound selected from kavain, wherein the amount of kavain in the composition is 26 mg + 10 mg; dihydrokavain, wherein the amount of dihydrokavain in the composition is 14 mg + 5 mg; methysticin, wherein the amount of methysticin in the composition is 50 mg + 20 mg; dihydromethysticin, wherein the amount of dihydromethysticin in the composition is 21 mg + 10 mg; and

Another aspect of the invention is a composition consisting essentially of at least one (e.g. , 1, 2, 3, 4, or 5) compound selected from kavain, wherein the amount of kavain in the composition is 26 mg + 10 mg; dihydrokavain, wherein the amount of dihydrokavain in the composition is 14 mg + 5 mg; methysticin, wherein the amount of methysticin in the composition is 8 mg + 5 mg; dihydromethysticin, wherein the amount of dihydromethysticin in the composition is 100 mg + 25 mg; and

desmethoxyyangonin, wherein the amount of desmethoxyyangonin in the composition is 50 mg + 20 mg.

Another aspect of the invention is a composition consisting essentially of kavain, wherein the amount of kavain in the composition is 26 mg + 10 mg;

dihydrokavain, wherein the amount of dihydrokavain in the composition is 14 mg + 5 mg; methysticin, wherein the amount of methysticin in the composition is 8 mg + 5 mg; dihydromethysticin, wherein the amount of dihydromethysticin in the

composition is 21 mg + 10 mg; and desmethoxyyangonin, wherein the amount of desmethoxyyangonin in the composition is 8 mg + 5 mg.

Another aspect of the invention is a composition consisting essentially of kavain, wherein the amount of kavain in the composition is 100 mg + 20 mg;

dihydrokavain, wherein the amount of dihydrokavain in the composition is 50 mg + 15 mg; methysticin, wherein the amount of methysticin in the composition is 8 mg + 5 mg; dihydromethysticin, wherein the amount of dihydromethysticin in the

dihydrokavain, wherein the amount of dihydrokavain in the composition is 14 mg + 5 mg; methysticin, wherein the amount of methysticin in the composition is 50 mg + 20 mg; dihydromethysticin, wherein the amount of dihydromethysticin in the

composition is 100 mg + 25 mg; and desmethoxyyangonin, wherein the amount of desmethoxyyangonin in the composition is 8 mg + 5 mg.

composition is 21 mg + 10 mg; and desmethoxyyangonin, wherein the amount of desmethoxyyangonin in the composition is 50 mg + 20 mg.

1, 2, 3, 4, or 5) compound selected from kavain, wherein the amount of kavain in the composition is 26 mg + 10 mg; dihydrokavain, wherein the amount of dihydrokavain in the composition is 14 mg + 5 mg; methysticin, wherein the amount of methysticin in the composition is 8 mg + 5 mg; dihydromethysticin, wherein the amount of dihydromethysticin in the composition is 21 mg + 10 mg; and desmethoxyyangonin, wherein the amount of desmethoxyyangonin in the composition is 8 mg + 5 mg, wherein the composition is substantially free of flavokawain A and/or flavokawain B .

desmethoxyyangonin in the composition is 8 mg + 5 mg, wherein the composition is substantially free of flavokawain A and/or flavokawain B.

Another aspect of the invention is a composition comprising at least one (e.g. , 1, 2, 3, or 4) compound selected from kavain, wherein the amount of kavain in the composition is 100 mg + 20 mg; dihydrokavain, wherein the amount of dihydrokavain in the composition is 14 mg + 5 mg; methysticin, wherein the amount of methysticin in the composition is 8 mg + 5 mg; dihydromethysticin, wherein the amount of dihydromethysticin in the composition is 21 mg + 10 mg; and desmethoxyyangonin, wherein the amount of desmethoxyyangonin in the composition is 8 mg + 5 mg, wherein the composition is substantially free of flavokawain A and/or flavokawain B .

Another aspect of the invention is a composition comprising at least one (e.g. , 1, 2, 3, or 4) compound selected from kavain, wherein the amount of kavain in the composition is 26 mg + 10 mg; dihydrokavain, wherein the amount of dihydrokavain in the composition is 50 mg + 15 mg; methysticin, wherein the amount of methysticin in the composition is 8 mg + 5 mg; dihydromethysticin, wherein the amount of dihydromethysticin in the composition is 21 mg + 10 mg; and desmethoxyyangonin, wherein the amount of desmethoxyyangonin in the composition is 8 mg + 5 mg, wherein the composition is substantially free of flavokawain A and/or flavokawain B .

Another aspect of the invention is a composition comprising at least one (e.g. , 1, 2, 3, or 4) compound selected from kavain, wherein the amount of kavain in the composition is 26 mg + 10 mg; dihydrokavain, wherein the amount of dihydrokavain in the composition is 14 mg + 5 mg; methysticin, wherein the amount of methysticin in the composition is 50 mg + 20 mg; dihydromethysticin, wherein the amount of dihydromethysticin in the composition is 21 mg + 10 mg; and desmethoxyyangonin, wherein the amount of desmethoxyyangonin in the composition is 8 mg + 5 mg, wherein the composition is substantially free of flavokawain A and/or flavokawain B .

Another aspect of the invention is a composition comprising at least one (e.g. , 1, 2, 3, or 4) compound selected from kavain, wherein the amount of kavain in the composition is 26 mg + 10 mg; dihydrokavain, wherein the amount of dihydrokavain in the composition is 14 mg + 5 mg; methysticin, wherein the amount of methysticin in the composition is 8 mg + 5 mg; dihydromethysticin, wherein the amount of dihydromethysticin in the composition is 100 mg + 25 mg; and desmethoxyyangonin, wherein the amount of desmethoxyyangonin in the composition is 8 mg + 5 mg, wherein the composition is substantially free of flavokawain A and/or flavokawain B .

Another aspect of the invention is a composition comprising at least one (e.g. , 1, 2, 3, or 4) compound selected from kavain, wherein the amount of kavain in the composition is 26 mg + 10 mg; dihydrokavain, wherein the amount of dihydrokavain in the composition is 14 mg + 5 mg; methysticin, wherein the amount of methysticin in the composition is 8 mg + 5 mg; dihydromethysticin, wherein the amount of dihydromethysticin in the composition is 21 mg + 10 mg; and desmethoxyyangonin, wherein the amount of desmethoxyyangonin in the composition is 50 mg + 20 mg, wherein the composition is substantially free of flavokawain A and/or flavokawain B .

desmethoxyyangonin in the composition is 8 mg + 5 mg, wherein the composition is substantially free of flavokawain A and/or flavokawain B. Another aspect of the invention is a composition comprising kavain, wherein the amount of kavain in the composition is 100 mg + 20 mg; dihydrokavain, wherein the amount of dihydrokavain in the composition is 14 mg + 5 mg; methysticin, wherein the amount of methysticin in the composition is 8 mg + 5 mg;

desmethoxyyangonin in the composition is 50 mg + 20 mg, wherein the composition is substantially free of flavokawain A and/or flavokawain B .

Another aspect of the invention is a composition comprising at least one (e.g. , 1, 2, 3, or 4) of kavain, dihydrokavain, methysticin, dihydromethysticin, and desmethoxyyangonin. In other aspects, kavain comprises 10- 100% of the total kavalactone content in the composition (e.g. , 10-90%, 20-90%, 30-90%, 40-90%, 50- 90%, 60-90%, 70-90%, and the like). In other aspects, dihydrokavain comprises 10- 100% of the total kavalactone content in the composition (e.g. , 10-90%, 20-90%, 30- 90%, 40-90%, 50-90%, 60-90%, 70-90%, and the like). In other aspects, methysticin comprises 10- 100% of the total kavalactone content in the composition (e.g. , 10-90%, 20-90%, 30-90%, 40-90%, 50-90%, 60-90%, 70-90%, and the like). In other aspects, dihydromethysticin comprises 10- 100% of the total kavalactone content in the composition (e.g. , 10-90%, 20-90%, 30-90%, 40-90%, 50-90%, 60-90%, 70-90%, and the like). In other aspects, desmethoxyyangonin comprises 10- 100% of the total kavalactone content in the composition (e.g. , 10-90%, 20-90%, 30-90%, 40-90%, 50- 90%, 60-90%, 70-90%, and the like).

Another aspect of the invention is a composition comprising: 1) at least one (e.g. , 1, 2, 3, 4, or 5) compound selected from kavain, dihydrokavain, methysticin, dihydromethysticin, and desmethoxyyangonin; and 2) nicotine. In another aspect, this composition is one wherein the composition is substantially free of flavokawain A and/or flavokawain B.

Another aspect of the invention is a composition comprising: 1) at least one (e.g. , 1, 2, 3, 4, or 5) compound selected from kavain, wherein the amount of kavain in the composition is 26 mg + 10 mg; dihydrokavain, wherein the amount of dihydrokavain in the composition is 14 mg + 5 mg; methysticin, wherein the amount of methysticin in the composition is 8 mg + 5 mg; dihydromethysticin, wherein the amount of dihydromethysticin in the composition is 21 mg + 10 mg; and

desmethoxyyangonin, wherein the amount of desmethoxyyangonin in the composition is 8 mg + 5 mg; and 2) nicotine, wherein the amount of nicotine in the composition is 1-25 mg (e.g. , 1-20 mg, 1- 15 mg, 1-10 mg, 1-5 mg, and the like). In another aspect, this composition is one wherein the composition is substantially free of flavokawain A and/or flavokawain B.

Another aspect of the invention is a composition comprising: 1) at least one (e.g., 1, 2, 3, 4, or 5) compound selected from kavain, wherein the amount of kavain in the composition is 26 mg ± 10 mg; dihydrokavain, wherein the amount of dihydrokavain in the composition is 14 mg ± 5 mg; methysticin, wherein the amount of methysticin in the composition is 8 mg ± 5 mg; dihydromethysticin, wherein the amount of dihydromethysticin in the composition is 21 mg ± 10 mg; and

desmethoxyyangonin, wherein the amount of desmethoxyyangonin in the composition is 8 mg ± 5 mg; and 2) nicotine, wherein the amount of nicotine in the composition is 1-15 mg (e.g., 1-10 mg; 1-9 mg, 1-8 mg; 1-7 mg; 1-6 mg; 1-5 mg; 1-4 mg, and the like). In another aspect, this composition is one wherein the composition is substantially free of flavokawain A and/or flavokawain B.

In other aspects, the invention provides a method of treating a disease, disorder, or symptom thereof in a subject, comprising administering to the subject any compound, composition, or kava extract herein. In another aspect, the compound, composition, or kava extract is administered in an amount and under conditions sufficient to ameliorate the disease, disorder, or symptom thereof in a subject. In another aspect, the disease, disorder, or symptom includes nicotine or tobacco addiction.

In other aspects, the invention provides a method of treating a disease, disorder, or symptom thereof in a subject, comprising administering to the subject any compound, composition, or kava extract herein. In another aspect, the compound, composition, or kava extract is administered in an amount and under conditions sufficient to ameliorate the disease, disorder, or symptom thereof in a subject. In another aspect, the disease, disorder, or symptom includes nicotine or tobacco addiction. In another aspect, the disease, disorder, or symptom includes nicotine and tobacco addiction. In another aspect, the subject is African American.

In other aspects, the invention provides a method of aiding a subject in the cessation of tobacco use, the method comprising the administration of any compound, composition, or kava extract herein to the subject.

In other aspects, the invention provides a method of aiding a subject in the cessation of tobacco use, the method comprising the administration to the subject any compound, composition, or kava extract herein. In another aspect, the subject is non- Caucasian. In another aspect, the subject is African American.

In other aspects, the invention provides a method of aiding a subject in the cessation of tobacco use, the method comprising the administration to the subject of a composition comprising at least one (e.g. , 1, 2, 3, 4, or 5) compound selected from kavain, wherein the amount of kavain in the composition is 26 mg + 10 mg;

dihydrokavain, wherein the amount of dihydrokavain in the composition is 14 mg + 5 mg; methysticin, wherein the amount of methysticin in the composition is 8 mg + 5 mg; dihydromethysticin, wherein the amount of dihydromethysticin in the composition is 21 mg + 10 mg; and desmethoxyyangonin, wherein the amount of desmethoxyyangonin in the composition is 8 mg + 5 mg.

dihydrokavain, wherein the amount of dihydrokavain in the composition is 14 mg + 5 mg; methysticin, wherein the amount of methysticin in the composition is 8 mg + 5 mg; dihydromethysticin, wherein the amount of dihydromethysticin in the composition is 21 mg + 10 mg; and desmethoxyyangonin, wherein the amount of desmethoxyyangonin in the composition is 8 mg + 5 mg. In another aspect, the subject is non-Caucasian. In another aspect, the subject is African American.

In other aspects, the invention provides a method of aiding a subject in the cessation of tobacco use, the method comprising the administration of a composition comprising at least one (e.g., 1, 2, 3, 4, or 5) compound selected from kavain, wherein the amount of kavain in the composition is 26 mg ± 10 mg; dihydrokavain, wherein the amount of dihydrokavain in the composition is 14 mg ± 5 mg; methysticin, wherein the amount of methysticin in the composition is 8 mg ± 5 mg;

dihydromethysticin, wherein the amount of dihydromethysticin in the composition is 21 mg ± 10 mg; and desmethoxyyangonin, wherein the amount of

desmethoxyyangonin in the composition is 8 mg + 5 mg.

In other aspects, the invention provides a method of aiding a subject in the cessation of tobacco use, the method comprising the administration to the subject any compound, composition, or kava extract herein, wherein said subject is administered one (e.g. , 1, 2, 3, 4, or 5) or more of the group consisting of 75 mg + 25 mg of kavain per day, 40 mg + 20 mg of dihydrokavain per day, 25 mg + 15 mg of methysticin per day, 60 mg + 30 mg of dihydromethysticin per day, and 25 mg + 15 mg of desmethoxyyangonin per day.

In other aspects, the invention provides a method of aiding a subject in the cessation of tobacco use, the method comprising the administration to the subject any compound, composition, or kava extract herein, wherein said subject is administered one (e.g. , 1, 2, 3, 4, or 5) or more of the group consisting of 75 mg + 25 mg of kavain per day, 40 mg + 20 mg of dihydrokavain per day, 25 mg + 15 mg of methysticin per day, 60 mg + 30 mg of dihydromethysticin per day, and 25 mg + 15 mg of desmethoxyyangonin per day. In another aspect, the subject is non-Caucasian. In another aspect, the subject is African American.

In other aspects, the invention provides a method of treating tobacco addiction in a subject, the method comprising the administration of any compound,

composition, or kava extract herein to the subject.

composition, or kava extract herein to the subject. In another aspect, the subject is non-Caucasian. In another aspect, the subject is African American.

In other aspects, the invention provides a method of treating tobacco addiction in a subject, the method comprising the administration to the subject a composition comprising at least one (e.g. , 1, 2, 3, 4, or 5) compound selected from kavain, wherein the amount of kavain in the composition is 26 mg + 10 mg; dihydrokavain, wherein the amount of dihydrokavain in the composition is 14 mg + 5 mg; methysticin, wherein the amount of methysticin in the composition is 8 mg + 5 mg;

desmethoxyyangonin in the composition is 8 mg + 5 mg.

dihydromethysticin, wherein the amount of dihydromethysticin in the composition is 21 mg + 10 mg; and desmethoxyyangonin, wherein the amount of desmethoxyyangonin in the composition is 8 mg + 5 mg. In another aspect, the subject is non-Caucasian. In another aspect, the subject is African American.

In other aspects, the invention provides a method of treating tobacco addiction in a subject, wherein the subject is identified as in need thereof, the method comprising the administration of any compound, composition, or kava extract herein to the subject.

In other aspects, the invention provides a method of treating tobacco addiction in a subject, wherein the subject is identified as in need thereof, the method comprising the administration of any compound, composition, or kava extract herein to the subject. In another aspect, the subject is non-Caucasian. In another aspect, the subject is African American.

In other aspects, the invention provides a method of treating tobacco addiction in a subject, the method comprising the administration to the subject any compound, composition, or kava extract herein, wherein said subject is administered one (e.g. , 1, 2, 3, 4, or 5) or more of the group consisting of 75 mg + 25 mg of kavain per day, 40 mg + 20 mg of dihydrokavain per day, 25 mg + 15 mg of methysticin per day, 60 mg + 30 mg of dihydromethysticin per day, and 25 mg + 15 mg of desmethoxyyangonin per day.

composition, or kava extract herein to the subject, wherein said subject is

administered one (e.g. , 1, 2, 3, 4, or 5) or more of the group consisting of 75 mg + 25 mg of kavain per day, 40 mg + 20 mg of dihydrokavain per day, 25 mg + 15 mg of methysticin per day, 60 mg + 30 mg of dihydromethysticin per day, and 25 mg + 15 mg of desmethoxyyangonin per day. In another aspect, the subject is non-Caucasian. In another aspect, the subject is African American.

In other aspects, the invention provides a method of treating tobacco addiction in a subject, the method comprising the administration to the subject any compound, composition, or kava extract herein to the subject, wherein said subject is

administered one (e.g. , 1, 2, 3, 4, or 5) or more of the group consisting of 75 mg + 25 mg of kavain per day, 40 mg + 20 mg of dihydrokavain per day, 25 mg + 15 mg of methysticin per day, 60 mg + 30 mg of dihydromethysticin per day, and 25 mg + 15 mg of desmethoxyyangonin per day. In another aspect, the subject is non-Caucasian. In another aspect, the subject is African American. In other aspects, the invention provides a method of treating nicotine addiction in a subject, the method comprising the administration of any compound,

composition, or kava extract herein to the subject.

In other aspects, the invention provides a method of treating nicotine addiction in a subject, the method comprising the administration of any compound,

In other aspects, the invention provides a method of treating nicotine addiction in a subject, the method comprising the administration to the subject a composition comprising at least one (e.g. , 1, 2, 3, 4, or 5) compound selected from kavain, wherein the amount of kavain in the composition is 26 mg + 10 mg; dihydrokavain, wherein the amount of dihydrokavain in the composition is 14 mg + 5 mg; methysticin, wherein the amount of methysticin in the composition is 8 mg + 5 mg;

desmethoxyyangonin in the composition is 8 mg + 5 mg.

desmethoxyyangonin in the composition is 8 mg + 5 mg. In another aspect, the subject is non-Caucasian. In another aspect, the subject is African American.

In other aspects, the invention provides a method of treating nicotine addiction in a subject, wherein the subject is identified as in need thereof, the method comprising the administration of any compound, composition, or kava extract herein to the subject.

In other aspects, the invention provides a method of treating nicotine addiction in a subject, wherein the subject is identified as in need thereof, the method comprising the administration of any compound, composition, or kava extract herein to the subject. In another aspect, the subject is non-Caucasian. In another aspect, the subject is African American.

In other aspects, the invention provides a method of treating nicotine addiction in a subject, the method comprising the administration to the subject any compound, composition, or kava extract herein, wherein said subject is administered one (e.g. , 1, 2, 3, 4, or 5) or more of the group consisting of 75 mg + 25 mg of kavain per day, 40 mg + 20 mg of dihydrokavain per day, 25 mg + 15 mg of methysticin per day, 60 mg + 30 mg of dihydromethysticin per day, and 25 mg + 15 mg of desmethoxyyangonin per day.

composition, or kava extract herein to the subject, wherein said subject is

In other aspects, the invention provides a method of treating nicotine addiction in a subject, the method comprising the administration to the subject any compound, composition, or kava extract herein to the subject, wherein said subject is

In other aspects, the invention provides a method of inhibiting the metabolism of nicotine in a subject, the method comprising the administration to the subject any compound, composition, or kava extract herein. In aspects the "inhibiting" is relative to metabolism of nicotine in the subject in the absence of administration of a kavalactone compound, kavalactone composition, or kava extract described herein.

In other aspects, the invention provides a method of inhibiting the metabolism of nicotine in a subject, the method comprising the administration of any compound, composition, or kava extract herein to the subject. In aspects the "inhibiting" is relative to metabolism of nicotine in the subject in the absence of administration of a kavalactone compound, kavalactone composition, or kava extract described herein. In another aspect, the subject is non-Caucasian. In another aspect, the subject is African American.

In other aspects, the invention provides a method of inhibiting the metabolism of nicotine in a subject, the method comprising the administration to the subject any compound, composition, or kava extract herein to the subject. In aspects the

"inhibiting" is relative to metabolism of nicotine in the subject in the absence of administration of a kavalactone compound, kavalactone composition, or kava extract described herein. In another aspect, the subject is non-Caucasian. In another aspect, the subject is African American.

In other aspects, the invention provides a method of inhibiting the metabolism of nicotine in a subject, the method comprising the administration to the subject a composition comprising at least one (e.g. , 1, 2, 3, 4, or 5) compound selected from kavain, wherein the amount of kavain in the composition is 26 mg + 10 mg;

In other aspects, the invention provides a method of inhibiting the metabolism of nicotine in a subject, the method comprising the administration to the subject any compound, composition, or kava extract herein, wherein said subject is administered one (e.g. , 1, 2, 3, 4, or 5) or more of the group consisting of 75 mg + 25 mg of kavain per day, 40 mg + 20 mg of dihydrokavain per day, 25 mg + 15 mg of methysticin per day, 60 mg + 30 mg of dihydromethysticin per day, and 25 mg + 15 mg of desmethoxyyangonin per day.

In other aspects, the invention provides a method of inhibiting the metabolism of nicotine in a subject, the method comprising the administration to the subject any compound, composition, or kava extract herein, wherein said subject is administered one (e.g. , 1, 2, 3, 4, or 5) or more of the group consisting of 75 mg + 25 mg of kavain per day, 40 mg + 20 mg of dihydrokavain per day, 25 mg + 15 mg of methysticin per day, 60 mg + 30 mg of dihydromethysticin per day, and 25 mg + 15 mg of desmethoxyyangonin per day. In another aspect, the subject is non-Caucasian. In another aspect, the subject is African American.

In other aspects, the invention provides a treatment regimen for smoking cessation in a subject, the regimen comprising the administration of any compound, composition, or kava extract herein to the subject.

In other aspects, the invention provides a treatment regimen for smoking cessation in a subject, the regimen comprising the administration of any compound, composition, or kava extract herein to the subject. In another aspect, the subject is non-Caucasian. In another aspect, the subject is African American.

In other aspects, the invention provides a treatment regimen for smoking cessation in a subject, wherein the subject is identified as in need thereof, the regimen comprising the administration of any compound, composition, or kava extract herein to the subject.

In other aspects, the invention provides a treatment regimen for smoking cessation in a subject, wherein the subject is identified as in need thereof, the regimen comprising the administration of any compound, composition, or kava extract herein to the subject. In another aspect, the subject is non-Caucasian. In another aspect, the subject is African American.

In other aspects, the invention provides a treatment regimen for smoking cessation in a subject, the regimen comprising the administration to the subject a composition comprising at least one (e.g. , 1, 2, 3, 4, or 5) compound selected from kavain, wherein the amount of kavain in the composition is 26 mg + 10 mg;

dihydrokavain, wherein the amount of dihydrokavain in the composition is 14 mg + 5 mg; methysticin, wherein the amount of methysticin in the composition is 8 mg + 5 mg; dihydromethysticin, wherein the amount of dihydromethysticin in the composition is 21 mg + 10 mg; and desmethoxyyangonin, wherein the amount of desmethoxyyangonin in the composition is 8 mg + 5 mg. In other aspects, the invention provides a treatment regimen for smoking cessation in a subject, the regimen comprising the administration to the subject a composition comprising at least one (e.g. , 1, 2, 3, 4, or 5) compound selected from kavain, wherein the amount of kavain in the composition is 26 mg + 10 mg;

In other aspects, the invention provides a treatment regimen for smoking cessation in a subject, the regimen comprising the administration to the subject any compound, composition, or kava extract herein, wherein said subject is administered one (e.g. , 1, 2, 3, 4, or 5) or more of the group consisting of 75 mg + 25 mg of kavain per day, 40 mg + 20 mg of dihydrokavain per day, 25 mg + 15 mg of methysticin per day, 60 mg + 30 mg of dihydromethysticin per day, and 25 mg + 15 mg of desmethoxyyangonin per day.

In other aspects, the invention provides a treatment regimen for smoking cessation in a subject, the regimen comprising the administration to the subject any compound, composition, or kava extract herein, wherein said subject is administered one (e.g. , 1, 2, 3, 4, or 5) or more of the group consisting of 75 mg + 25 mg of kavain per day, 40 mg + 20 mg of dihydrokavain per day, 25 mg + 15 mg of methysticin per day, 60 mg + 30 mg of dihydromethysticin per day, and 25 mg + 15 mg of desmethoxyyangonin per day. In another aspect, the subject is non-Caucasian. In another aspect, the subject is African American.

In other aspects, the invention provides a treatment regimen for smoking cessation and inhibiting nicotine metabolism in a subject, the regimen comprising the administration of any compound, composition, or kava extract herein to the subject.

In other aspects, the invention provides a treatment regimen for smoking cessation and inhibiting nicotine metabolism in a subject, the regimen comprising the administration to the subject any compound, composition, or kava extract herein. In another aspect, the subject is non-Caucasian. In another aspect, the subject is African American. In other aspects, the invention provides a treatment regimen for smoking cessation and inhibiting nicotine metabolism in a subject, the regimen comprising the administration of any compound, composition, or kava extract herein. In another aspect, the subject is non-Caucasian. In another aspect, the subject is African

American.

In other aspects, the invention provides a treatment regimen for smoking cessation and inhibiting nicotine metabolism in a subject, the regimen comprising the administration to the subject a composition comprising at least one (e.g. , 1, 2, 3, 4, or 5) compound selected from kavain, wherein the amount of kavain in the composition is 26 mg + 10 mg; dihydrokavain, wherein the amount of dihydrokavain in the composition is 14 mg + 5 mg; methysticin, wherein the amount of methysticin in the composition is 8 mg + 5 mg; dihydromethysticin, wherein the amount of

dihydromethysticin in the composition is 21 mg + 10 mg; and desmethoxyyangonin, wherein the amount of desmethoxyyangonin in the composition is 8 mg + 5 mg.

dihydromethysticin in the composition is 21 mg + 10 mg; and desmethoxyyangonin, wherein the amount of desmethoxyyangonin in the composition is 8 mg + 5 mg. In another aspect, the subject is non-Caucasian. In another aspect, the subject is African American.

In other aspects, the invention provides a treatment regimen for smoking cessation and inhibiting nicotine metabolism in a subject, wherein the subject is identified as in need thereof, the regimen comprising the administration of any compound, composition, or kava extract herein to the subject.

In other aspects, the invention provides a treatment regimen for smoking cessation and inhibiting nicotine metabolism in a subject, wherein the subject is identified as in need thereof, the regimen comprising the administration to the subject any compound, composition, or kava extract herein. In another aspect, the subject is non-Caucasian. In another aspect, the subject is African American. In other aspects, the invention provides a treatment regimen for smoking cessation and inhibiting nicotine metabolism in a subject, wherein the subject is identified as in need thereof, the regimen comprising the administration of any compound, composition, or kava extract herein. In another aspect, the subject is non- Caucasian. In another aspect, the subject is African American.

In other aspects, the invention provides a treatment regimen for smoking cessation and inhibiting nicotine metabolism in a subject, wherein the subject is identified as in need thereof, the regimen comprising the administration to the subject any compound, composition, or kava extract herein, wherein said subject is administered one (e.g. , 1, 2, 3, 4, or 5) or more of the group consisting of 75 mg + 25 mg of kavain per day, 40 mg + 20 mg of dihydrokavain per day, 25 mg + 15 mg of methysticin per day, 60 mg + 30 mg of dihydromethysticin per day, and 25 mg + 15 mg of desmethoxyyangonin per day.

In other aspects, the invention provides a treatment regimen for smoking cessation and inhibiting nicotine metabolism in a subject, wherein the subject is identified as in need thereof, the regimen comprising the administration to the subject any compound, composition, or kava extract herein, wherein said subject is administered one (e.g. , 1, 2, 3, 4, or 5) or more of the group consisting of 75 mg + 25 mg of kavain per day, 40 mg + 20 mg of dihydrokavain per day, 25 mg + 15 mg of methysticin per day, 60 mg + 30 mg of dihydromethysticin per day, and 25 mg + 15 mg of desmethoxyyangonin per day. In another aspect, the subject is non-Caucasian. In another aspect, the subject is African American.

In other aspects, the invention provides a method of aiding a subject in the cessation of tobacco use, the method comprising the administration to the subject any compound, composition, or kava extract herein; and nicotine. In other aspects, the amount of nicotine administered is 1-25 mg per dose or 1-50 mg per day.

In other aspects, the invention provides a method of aiding a subject in the cessation of tobacco use, the method comprising the administration to the subject any compound, composition, or kava extract herein; and nicotine. In other aspects, the amount of nicotine administered is 1-25 mg per dose or 1-50 mg per day. In another aspect, the subject is non-Caucasian. In another aspect, the subject is African

American.

In other aspects, the invention provides a method of aiding a subject in the cessation of tobacco use, the method comprising the administration of any compound, composition, or kava extract herein; and nicotine to the subject. In other aspects, the amount of nicotine administered is 1- 15 mg per dose (e.g., 1-10 mg; 1-9 mg, 1-8 mg; 1-7 mg; 1-6 mg; 1-5 mg; 1-4 mg, and the like) or 1-50 mg per day (e.g., 1-40 mg; 1- 30 mg, 1-20 mg; 1- 15 mg; 1-10 mg; 1-5 mg, and the like).

In other aspects, the invention provides a method of aiding a subject in the cessation of tobacco use, the method comprising the administration to the subject any compound, composition, or kava extract herein; and nicotine to the subject. In other aspects, the amount of nicotine administered is 1- 15 mg per dose (e.g., 1- 10 mg; 1-9 mg, 1-8 mg; 1-7 mg; 1-6 mg; 1-5 mg; 1-4 mg, and the like) or 1-50 mg per day (e.g., 1-40 mg; 1-30 mg, 1-20 mg; 1- 15 mg; 1-10 mg; 1-5 mg, and the like).

In other aspects, the invention provides a method of aiding a subject in the cessation of tobacco use, the method comprising the administration to the subject a composition comprising: 1) at least one (e.g. , 1, 2, 3, 4, or 5) compound selected from kavain, wherein the amount of kavain in the composition is 26 mg + 10 mg;

dihydrokavain, wherein the amount of dihydrokavain in the composition is 14 mg + 5 mg; methysticin, wherein the amount of methysticin in the composition is 8 mg + 5 mg; dihydromethysticin, wherein the amount of dihydromethysticin in the composition is 21 mg + 10 mg; and desmethoxyyangonin, wherein the amount of desmethoxyyangonin in the composition is 8 mg + 5 mg; and 2) nicotine, wherein the amount of nicotine in the composition is 1-25 mg (e.g. , 1-20 mg, 1- 15 mg, 1-10 mg, 1-5 mg, and the like).

dihydrokavain, wherein the amount of dihydrokavain in the composition is 14 mg + 5 mg; methysticin, wherein the amount of methysticin in the composition is 8 mg + 5 mg; dihydromethysticin, wherein the amount of dihydromethysticin in the composition is 21 mg + 10 mg; and desmethoxyyangonin, wherein the amount of desmethoxyyangonin in the composition is 8 mg + 5 mg; and 2) nicotine, wherein the amount of nicotine in the composition is 1-25 mg (e.g. , 1-20 mg, 1- 15 mg, 1-10 mg, 1-5 mg, and the like). In another aspect, the subject is non-Caucasian. In another aspect, the subject is African American. In other aspects, the invention provides a method of aiding a subject in the cessation of tobacco use, the method comprising the administration to the subject a composition comprising: 1) at least one (e.g., 1, 2, 3, 4, or 5) compound selected from kavain, wherein the amount of kavain in the composition is 26 mg + 10 mg;

composition is 21 mg + 10 mg; and desmethoxyyangonin, wherein the amount of desmethoxyyangonin in the composition is 8 mg + 5 mg; and 2) nicotine, wherein the amount of nicotine in the composition is 1-15 mg (e.g., 1-10 mg; 1-9 mg, 1-8 mg; 1-7 mg; 1-6 mg; 1-5 mg; 1-4 mg, and the like).

In other aspects, the invention provides a method of aiding a subject in the cessation of tobacco use, the method comprising the administration to the subjectany compound, composition, or kava extract herein, wherein said subject is administered one (e.g., 1, 2, 3, 4, or 5) or more of the group consisting of 75 mg + 25 mg of kavain per day, 40 mg + 20 mg of dihydrokavain per day, 25 mg + 15 mg of methysticin per day, 60 mg + 30 mg of dihydromethysticin per day, and 25 mg + 15 mg of desmethoxyyangonin per day; and 1-50 mg of nicotine per day (e.g., 1-40 mg, 1-30 mg, 1-25 mg, 1-20 mg, 1-15 mg, 1-10 mg, 1-5 mg, and the like).

In other aspects, the invention provides a method of aiding a subject in the cessation of tobacco use, the method comprising the administration to the subject any compound, composition, or kava extract herein, wherein said subject is administered one (e.g., 1, 2, 3, 4, or 5) or more of the group consisting of 75 mg + 25 mg of kavain per day, 40 mg + 20 mg of dihydrokavain per day, 25 mg + 15 mg of methysticin per day, 60 mg + 30 mg of dihydromethysticin per day, and 25 mg + 15 mg of desmethoxyyangonin per day; and 1-50 mg of nicotine per day (e.g., 1-40 mg, 1-30 mg, 1-25 mg, 1-20 mg, 1-15 mg, 1-10 mg, 1-5 mg, and the like). In another aspect, the subject is non-Caucasian. In another aspect, the subject is African American.

In other aspects, the invention provides a method of aiding a subject in the cessation of tobacco use, the method comprising the administration of any compound, composition, or kava extract herein, wherein said subject is administered one (e.g., 1, 2, 3, 4, or 5) or more of the group consisting of 75 mg + 25 mg of kavain per day, 40 mg + 20 mg of dihydrokavain per day, 25 mg + 15 mg of methysticin per day, 60 mg + 30 mg of dihydromethysticin per day, and 25 mg + 15 mg of desmethoxyyangonin per day; and 1-25 mg of nicotine per day (e.g., 1-20 mg, 1- 15 mg, 1- 10 mg, 1-5 mg, and the like).

In other aspects, the invention provides a method of aiding a subject in the cessation of tobacco use, the method comprising the administration to the subject any compound, composition, or kava extract herein, wherein said subject is administered one (e.g., 1, 2, 3, 4, or 5) or more of the group consisting of 75 mg + 25 mg of kavain per day, 40 mg + 20 mg of dihydrokavain per day, 25 mg + 15 mg of methysticin per day, 60 mg + 30 mg of dihydromethysticin per day, and 25 mg + 15 mg of desmethoxyyangonin per day; and 1-25 mg of nicotine per day (e.g., 1-20 mg, 1- 15 mg, 1- 10 mg, 1-5 mg, and the like).

In other aspects, the invention provides a method of treating tobacco addiction in a subject, the method comprising the administration to the subject any compound, composition, or kava extract herein; and nicotine. In other aspects, the amount of nicotine administered is 1-25 mg per dose or 1-50 mg per day.

In other aspects, the invention provides a method of treating tobacco addiction in a subject, the method comprising the administration to the subject any compound, composition, or kava extract herein; and nicotine. In other aspects, the amount of nicotine administered is 1-25 mg per dose or 1-50 mg per day. In another aspect, the subject is non-Caucasian. In another aspect, the subject is African American.

In other aspects, the invention provides a method of treating tobacco addiction in a subject, the method comprising the administration to the subject a composition comprising: 1) at least one (e.g. , 1, 2, 3, 4, or 5) compound selected from kavain, wherein the amount of kavain in the composition is 26 mg + 10 mg; dihydrokavain, wherein the amount of dihydrokavain in the composition is 14 mg + 5 mg;

methysticin, wherein the amount of methysticin in the composition is 8 mg + 5 mg; dihydromethysticin, wherein the amount of dihydromethysticin in the composition is 21 mg + 10 mg; and desmethoxyyangonin, wherein the amount of

desmethoxyyangonin in the composition is 8 mg + 5 mg; and 2) nicotine, wherein the amount of nicotine in the composition is 1-50 mg of nicotine per day (e.g. , 1-40 mg, 1-30 mg, 1-25 mg, 1-20 mg, 1-15 mg, 1-10 mg, 1-5 mg, and the like).

desmethoxyyangonin in the composition is 8 mg + 5 mg; and 2) nicotine, wherein the amount of nicotine in the composition is 1-50 mg of nicotine per day (e.g. , 1-40 mg, 1-30 mg, 1-25 mg, 1-20 mg, 1-15 mg, 1-10 mg, 1-5 mg, and the like). In another aspect, the subject is non-Caucasian. In another aspect, the subject is African

American.

In other aspects, the invention provides a method of treating tobacco addiction in a subject, the method comprising the administration to the subject any compound, composition, or kava extract herein, wherein said subject is administered one (e.g. , 1, 2, 3, 4, or 5) or more of the group consisting of 75 mg + 25 mg of kavain per day, 40 mg + 20 mg of dihydrokavain per day, 25 mg + 15 mg of methysticin per day, 60 mg + 30 mg of dihydromethysticin per day, and 25 mg + 15 mg of desmethoxyyangonin per day; and 1-50 mg of nicotine per day (e.g. , 1-40 mg, 1-30 mg, 1-25 mg, 1-20 mg, 1-15 mg, 1- 10 mg, 1-5 mg, and the like).

In other aspects, the invention provides a method of treating tobacco addiction in a subject, the method comprising the administration to the subject any compound, composition, or kava extract herein, wherein said subject is administered one (e.g. , 1, 2, 3, 4, or 5) or more of the group consisting of 75 mg + 25 mg of kavain per day, 40 mg + 20 mg of dihydrokavain per day, 25 mg + 15 mg of methysticin per day, 60 mg + 30 mg of dihydromethysticin per day, and 25 mg + 15 mg of desmethoxyyangonin per day; and 1-50 mg of nicotine per day (e.g. , 1-40 mg, 1-30 mg, 1-25 mg, 1-20 mg, 1-15 mg, 1- 10 mg, 1-5 mg, and the like). In another aspect, the subject is non- Caucasian. In another aspect, the subject is African American.

In other aspects, the invention provides a treatment regimen for smoking cessation in a subject, the regimen comprising the administration to the subject any compound, composition, or kava extract herein; and nicotine. In other aspects, the amount of nicotine administered is 1-25 mg per dose or 1-50 mg per day. In another aspect, the subject is non-Caucasian. In another aspect, the subject is African

American.

In other aspects, the invention provides a treatment regimen for smoking cessation in a subject, the regimen comprising the administration to the subject any compound, composition, or kava extract herein; and nicotine. In other aspects, the amount of nicotine administered is 1-25 mg per dose or 1-50 mg per day. In another aspect, the subject is non-Caucasian. In another aspect, the subject is African American.

In other aspects, the invention provides a treatment regimen for smoking cessation in a subject, the regimen comprising the administration to the subject a composition comprising: 1) at least one (e.g. , 1, 2, 3, 4, or 5) compound selected from kavain, wherein the amount of kavain in the composition is 26 mg + 10 mg;

dihydrokavain, wherein the amount of dihydrokavain in the composition is 14 mg + 5 mg; methysticin, wherein the amount of methysticin in the composition is 8 mg + 5 mg; dihydromethysticin, wherein the amount of dihydromethysticin in the composition is 21 mg + 10 mg; and desmethoxyyangonin, wherein the amount of desmethoxyyangonin in the composition is 8 mg + 5 mg; and 2) nicotine, wherein the amount of nicotine in the composition is 1-25 mg (e.g. , 1-20 mg, 1- 15 mg, 1-10 mg, 1-5 mg, and the like). In another aspect, the subject is non-Caucasian. In another aspect, the subject is African American.

In other aspects, the invention provides a treatment regimen for smoking cessation in a subject, the regimen comprising the administration to the subject any compound, composition, or kava extract herein, wherein said subject is administered one (e.g. , 1, 2, 3, 4, or 5) or more of the group consisting of 75 mg + 25 mg of kavain per day, 40 mg + 20 mg of dihydrokavain per day, 25 mg + 15 mg of methysticin per day, 60 mg + 30 mg of dihydromethysticin per day, and 25 mg + 15 mg of desmethoxyyangonin per day; and 1-50 mg of nicotine per day (e.g. , 1-40, 1-30, 1-25 mg, 1-20 mg, 1- 15 mg, 1-10 mg, 1-5 mg, and the like).

In other aspects, the invention provides a treatment regimen for smoking cessation in a subject, the regimen comprising the administration to the subject any compound, composition, or kava extract herein, wherein said subject is administered one (e.g. , 1, 2, 3, 4, or 5) or more of the group consisting of 75 mg + 25 mg of kavain per day, 40 mg + 20 mg of dihydrokavain per day, 25 mg + 15 mg of methysticin per day, 60 mg + 30 mg of dihydromethysticin per day, and 25 mg + 15 mg of

desmethoxyyangonin per day; and 1-50 mg of nicotine per day (e.g. , 1-40, 1-30, 1-25 mg, 1-20 mg, 1- 15 mg, 1-10 mg, 1-5 mg, and the like). In another aspect, the subject is non-Caucasian. In another aspect, the subject is African American.

In other aspects, the invention provides a method of aiding a subject in the cessation of tobacco use, the method comprising:

a. obtaining a urine sample from the subject;

b. analyzing the urine sample to determine the total nicotine equivalent (TNE);

c. if the TNE is > 30,000 mg/mg creatinine, then administer to the subject a composition comprising kavalactone (e.g. , 26 mg + 10 mg of kavain; 14 mg + 5 mg of dihydrokavain; 8 mg + 5 mg of methysticin; 21 mg + 10 mg of dihydromethysticin; 8 mg + 5 mg of desmethoxyyangonin) and a low dose of nicotine (e.g. , 1-15 mg, 1- 10 mg; 1-9 mg, 1-8 mg; 1- 7 mg; 1-6 mg; 1-5 mg; 1-4 mg, and the like);

d. if the TNE is < 30,000 mg/mg creatinine, then then administer to the subject a composition comprising kavalactone (e.g. , 26 mg + 10 mg of kavain; 14 mg + 5 mg of dihydrokavain; 8 mg + 5 mg of methysticin; 21 mg + 10 mg of dihydromethysticin; 8 mg + 5 mg of desmethoxyyangonin) and a high dose of nicotine (e.g. , 1-25 mg, 1-20 mg, 1- 15 mg, 1- 10 mg, 1-5 mg, and the like).

In other aspects, the invention provides a method of treating tobacco addiction in a subject, the method comprising:

a. obtaining a urine sample from the subject;

b. analyzing the urine sample to determine the total nicotine equivalent (TNE); c. if the TNE is > 30,000 mg/mg creatinine, then administer to the subject a composition comprising kavalactone (e.g. , 26 mg + 10 mg of kavain; 14 mg + 5 mg of dihydrokavain; 8 mg + 5 mg of methysticin; 21 mg + 10 mg of dihydromethysticin; 8 mg + 5 mg of desmethoxyyangonin) and a low dose of nicotine (e.g. , 1-15 mg, 1- 10 mg; 1-9 mg, 1-8 mg; 1- 7 mg; 1-6 mg; 1-5 mg; 1-4 mg, and the like);

In other aspects, the invention provides a method of treating nicotine addiction in a subject, the method comprising:

a. obtaining a urine sample from the subject;

b. analyzing the urine sample to determine the total nicotine equivalent (TNE);

In other aspects, the invention provides a treatment regimen for smoking cessation in a subject, the regimen comprising:

a. obtaining a urine sample from the subject;

In other aspects, the invention provides a treatment regimen for smoking cessation and inhibiting nicotine metabolism in a subject, the regimen comprising:

a. obtaining a urine sample from the subject;

b. analyzing the urine sample to determine the total nicotine equivalent (TNE);

In other aspects, the invention provides a method of treating a patient at high risk of failing smoking cessation therapy, the method comprising:

a. identifying the high risk patient (e.g. , a patient having a total nicotine equivalent (TNE) of > 30,000 mg/mg creatinine); and b. administering to the patient a composition comprising kavalactone (e.g. , 26 mg + 10 mg of kavain; 14 mg + 5 mg of dihydrokavain; 8 mg + 5 mg of methysticin; 21 mg + 10 mg of dihydromethysticin; 8 mg + 5 mg of desmethoxyyangonin) and a low dose of nicotine (e.g. , 1- 15 mg, 1- 10 mg; 1-9 mg, 1-8 mg; 1-7 mg; 1-6 mg; 1-5 mg; 1-4 mg, and the like).

In other aspects, the invention provides a kit for aiding a subject with a total nicotine equivalent (TNE) of > 30,000 mg/mg creatinine in the cessation of tobacco use, comprising: 1) a composition comprising kavalactone (e.g. , 26 mg + 10 mg of kavain; 14 mg + 5 mg of dihydrokavain; 8 mg + 5 mg of methysticin; 21 mg + 10 mg of dihydromethysticin; 8 mg + 5 mg of desmethoxyyangonin) and a low dose of nicotine (e.g. , 1-15 mg, 1- 10 mg; 1-9 mg, 1-8 mg; 1-7 mg; 1-6 mg; 1-5 mg; 1-4 mg, and the like); and 2) instructions for use.

In other aspects, the invention provides a kit for aiding a subject with a total nicotine equivalent (TNE) of > 30,000 mg/mg creatinine in the cessation of tobacco use, comprising: 1) a composition comprising kavalactone (e.g. , 26 mg + 10 mg of kavain; 14 mg + 5 mg of dihydrokavain; 8 mg + 5 mg of methysticin; 21 mg + 10 mg of dihydromethysticin; 8 mg + 5 mg of desmethoxyyangonin): 2) a low dose of nicotine (e.g. , 1-15 mg, 1- 10 mg; 1-9 mg, 1-8 mg; 1-7 mg; 1-6 mg; 1-5 mg; 1-4 mg, and the like); and 3) instructions for use.

In other aspects, the invention provides a kit for treating tobacco addiction in a subject with a total nicotine equivalent (TNE) of > 30,000 mg/mg creatinine in the cessation of tobacco use, comprising: 1) a composition comprising kavalactone (e.g. , 26 mg + 10 mg of kavain; 14 mg + 5 mg of dihydrokavain; 8 mg + 5 mg of methysticin; 21 mg + 10 mg of dihydromethysticin; 8 mg + 5 mg of

desmethoxyyangonin) and a low dose of nicotine (e.g. , 1-15 mg, 1-10 mg; 1-9 mg, 1- 8 mg; 1-7 mg; 1-6 mg; 1-5 mg; 1-4 mg, and the like); and 2) instructions for use.

desmethoxyyangonin): 2) a low dose of nicotine (e.g. , 1-15 mg, 1-10 mg; 1-9 mg, 1-8 mg; 1-7 mg; 1-6 mg; 1-5 mg; 1-4 mg, and the like); and 3) instructions for use. In other aspects, the invention provides a kit for treating nicotine addiction in a subject with a total nicotine equivalent (TNE) of > 30,000 mg/mg creatinine in the cessation of tobacco use, comprising: 1) a composition comprising kavalactone (e.g. , 26 mg + 10 mg of kavain; 14 mg + 5 mg of dihydrokavain; 8 mg + 5 mg of methysticin; 21 mg + 10 mg of dihydromethysticin; 8 mg + 5 mg of

In other aspects, the invention provides a kit for treating nicotine addiction in a subject with a total nicotine equivalent (TNE) of > 30,000 mg/mg creatinine in the cessation of tobacco use, comprising: 1) a composition comprising kavalactone (e.g. , 26 mg + 10 mg of kavain; 14 mg + 5 mg of dihydrokavain; 8 mg + 5 mg of methysticin; 21 mg + 10 mg of dihydromethysticin; 8 mg + 5 mg of

desmethoxyyangonin): 2) a low dose of nicotine (e.g. , 1-15 mg, 1-10 mg; 1-9 mg, 1-8 mg; 1-7 mg; 1-6 mg; 1-5 mg; 1-4 mg, and the like); and 3) instructions for use.

In other aspects, the invention provides a method for aiding a subject with a total nicotine equivalent (TNE) of > 30,000 mg/mg creatinine in the cessation of tobacco use, the method comprising administering to the subject a composition comprising kavalactone (e.g. , 26 mg + 10 mg of kavain; 14 mg + 5 mg of

dihydrokavain; 8 mg + 5 mg of methysticin; 21 mg + 10 mg of dihydromethysticin; 8 mg + 5 mg of desmethoxyyangonin) and a low dose of nicotine (e.g. , 1- 15 mg, 1- 10 mg; 1-9 mg, 1-8 mg; 1-7 mg; 1-6 mg; 1-5 mg; 1-4 mg, and the like).

In other aspects, the invention provides a method for aiding a subject with a total nicotine equivalent (TNE) of > 30,000 mg/mg creatinine in the cessation of tobacco use, the method comprising administering to the subject: 1) a composition comprising kavalactone (e.g. , 26 mg + 10 mg of kavain; 14 mg + 5 mg of

dihydrokavain; 8 mg + 5 mg of methysticin; 21 mg + 10 mg of dihydromethysticin; 8 mg + 5 mg of desmethoxyyangonin); and 2) a low dose of nicotine (e.g. , 1- 15 mg, 1- 10 mg; 1-9 mg, 1-8 mg; 1-7 mg; 1-6 mg; 1-5 mg; 1-4 mg, and the like).

In other aspects, the invention provides a method for treating tobacco addiction in a subject with a total nicotine equivalent (TNE) of > 30,000 mg/mg creatinine in the cessation of tobacco use, the method comprising administering to the subject a composition comprising kavalactone (e.g. , 26 mg + 10 mg of kavain; 14 mg + 5 mg of dihydrokavain; 8 mg + 5 mg of methysticin; 21 mg + 10 mg of

dihydromethysticin; 8 mg + 5 mg of desmethoxyyangonin) and a low dose of nicotine (e.g. , 1- 15 mg, 1- 10 mg; 1-9 mg, 1-8 mg; 1-7 mg; 1-6 mg; 1-5 mg; 1-4 mg, and the like).

In other aspects, the invention provides a method for treating tobacco addiction in a subject with a total nicotine equivalent (TNE) of > 30,000 mg/mg creatinine in the cessation of tobacco use, the method comprising administering to the subject: 1) a composition comprising kavalactone (e.g. , 26 mg + 10 mg of kavain; 14 mg + 5 mg of dihydrokavain; 8 mg + 5 mg of methysticin; 21 mg + 10 mg of dihydromethysticin; 8 mg + 5 mg of desmethoxyyangonin); and 2) a low dose of nicotine (e.g. , 1-15 mg, 1- 10 mg; 1-9 mg, 1-8 mg; 1-7 mg; 1-6 mg; 1-5 mg; 1-4 mg, and the like).

In other aspects, the invention provides a method for treating nicotine addiction in a subject with a total nicotine equivalent (TNE) of > 30,000 mg/mg creatinine in the cessation of tobacco use, the method comprising administering to the subject a composition comprising kavalactone (e.g. , 26 mg + 10 mg of kavain; 14 mg + 5 mg of dihydrokavain; 8 mg + 5 mg of methysticin; 21 mg + 10 mg of

In other aspects, the invention provides a method for treating nicotine addiction in a subject with a total nicotine equivalent (TNE) of > 30,000 mg/mg creatinine in the cessation of tobacco use, the method comprising administering to the subject: 1) a composition comprising kavalactone (e.g. , 26 mg + 10 mg of kavain; 14 mg + 5 mg of dihydrokavain; 8 mg + 5 mg of methysticin; 21 mg + 10 mg of dihydromethysticin; 8 mg + 5 mg of desmethoxyyangonin); and 2) a low dose of nicotine (e.g. , 1-15 mg, 1- 10 mg; 1-9 mg, 1-8 mg; 1-7 mg; 1-6 mg; 1-5 mg; 1-4 mg, and the like).

In other aspects, the invention provides a method for aiding tobacco cessation in a subject at high risk of lung cancer comprising administering to the subject with a total nicotine equivalent (TNE) of > 30,000 mg/mg creatinine a composition comprising kavalactone (e.g. , 26 mg + 10 mg of kavain; 14 mg + 5 mg of

dihydrokavain; 8 mg + 5 mg of methysticin; 21 mg + 10 mg of dihydromethysticin; 8 mg + 5 mg of desmethoxyyangonin) and a low dose of nicotine (e.g. , 1- 15 mg, 1- 10 mg; 1-9 mg, 1-8 mg; 1-7 mg; 1-6 mg; 1-5 mg; 1-4 mg, and the like). In other aspects, the invention provides a method for aiding tobacco cessation in a subject at high risk of lung cancer comprising administering to the subject with a total nicotine equivalent (TNE) of > 30,000 mg/mg creatinine: 1) a composition comprising kavalactone (e.g. , 26 mg + 10 mg of kavain; 14 mg + 5 mg of

In other aspects, the invention provides a method for aiding tobacco cessation in a subject with a total nicotine equivalent (TNE) of > 30,000 mg/mg comprising administering to the subject a composition comprising kavalactone (e.g. , 26 mg + 10 mg of kavain; 14 mg + 5 mg of dihydrokavain; 8 mg + 5 mg of methysticin; 21 mg + 10 mg of dihydromethysticin; 8 mg + 5 mg of desmethoxyyangonin) and a low dose of nicotine (e.g. , 1-15 mg, 1- 10 mg; 1-9 mg, 1-8 mg; 1-7 mg; 1-6 mg; 1-5 mg; 1-4 mg, and the like).

In other aspects, the invention provides a method for aiding tobacco cessation in a subject with a total nicotine equivalent (TNE) of > 30,000 mg/mg comprising administering to the subject a composition comprising: 1) a composition comprising kavalactone (e.g. , 26 mg + 10 mg of kavain; 14 mg + 5 mg of dihydrokavain; 8 mg + 5 mg of methysticin; 21 mg + 10 mg of dihydromethysticin; 8 mg + 5 mg of desmethoxyyangonin); and 2) a low dose of nicotine (e.g. , 1-15 mg, 1- 10 mg; 1-9 mg, 1-8 mg; 1-7 mg; 1-6 mg; 1-5 mg; 1-4 mg, and the like).

In other aspects, the invention provides a method for decreasing nicotine metabolites in a subject at high risk of lung cancer while undergoing nicotine replacement therapy comprising administering to a subject having TNE of > 30,000 mg/ mg creatine a composition comprising kavalactone (e.g. , 26 mg + 10 mg of kavain; 14 mg + 5 mg of dihydrokavain; 8 mg + 5 mg of methysticin; 21 mg + 10 mg of dihydromethysticin; 8 mg + 5 mg of desmethoxyyangonin) and a low dose of nicotine (e.g. , 1-15 mg, 1- 10 mg; 1-9 mg, 1-8 mg; 1-7 mg; 1-6 mg; 1-5 mg; 1-4 mg, and the like).

In other aspects, the invention provides a method for decreasing nicotine metabolites in a subject at high risk of lung cancer while undergoing nicotine replacement therapy comprising administering to a subject having TNE of > 30,000 mg/ mg creatine a composition comprising: 1) a composition comprising kavalactone (e.g. , 26 mg + 10 mg of kavain; 14 mg + 5 mg of dihydrokavain; 8 mg + 5 mg of methysticin; 21 mg + 10 mg of dihydromethysticin; 8 mg + 5 mg of desmethoxyyangonin); and 2) a low dose of nicotine (e.g. , 1-15 mg, 1- 10 mg; 1-9 mg, 1-8 mg; 1-7 mg; 1-6 mg; 1-5 mg; 1-4 mg, and the like).

In other aspects, the invention provides a method for decreasing nicotine metabolites in a subject identified as having TNE of > 30,000 mg/ mg creatine while undergoing nicotine replacement therapy comprising administering to the subject a composition comprising kavalactone (e.g. , 26 mg + 10 mg of kavain; 14 mg + 5 mg of dihydrokavain; 8 mg + 5 mg of methysticin; 21 mg + 10 mg of dihydromethysticin; 8 mg + 5 mg of desmethoxyyangonin) and a low dose of nicotine (e.g. , 1- 15 mg, 1- 10 mg; 1-9 mg, 1-8 mg; 1-7 mg; 1-6 mg; 1-5 mg; 1-4 mg, and the like).

In other aspects, the invention provides a method for decreasing nicotine metabolites in a subject identified as having TNE of > 30,000 mg/ mg creatine while undergoing nicotine replacement therapy comprising administering to the subject a composition comprising: 1) a composition comprising kavalactone (e.g. , 26 mg + 10 mg of kavain; 14 mg + 5 mg of dihydrokavain; 8 mg + 5 mg of methysticin; 21 mg + 10 mg of dihydromethysticin; 8 mg + 5 mg of desmethoxyyangonin); and 2) a low dose of nicotine (e.g. , 1- 15 mg, 1- 10 mg; 1-9 mg, 1-8 mg; 1-7 mg; 1-6 mg; 1-5 mg; 1-

4 mg, and the like).

In other aspects, the invention provides a method for aiding tobacco cessation in a subject particularly suitable for such treatment comprising administering to a subject having TNE of > 30,000 mg/ mg creatine a composition comprising kavalactone (e.g. , 26 mg + 10 mg of kavain; 14 mg + 5 mg of dihydrokavain; 8 mg +

5 mg of methysticin; 21 mg + 10 mg of dihydromethysticin; 8 mg + 5 mg of desmethoxyyangonin) and a low dose of nicotine (e.g. , 1-15 mg, 1-10 mg; 1-9 mg, 1- 8 mg; 1-7 mg; 1-6 mg; 1-5 mg; 1-4 mg, and the like).

In other aspects, the invention provides a method for aiding tobacco cessation in a subject particularly suitable for such treatment comprising administering to a subject having TNE of > 30,000 mg/ mg creatine a composition comprising: 1) a composition comprising kavalactone (e.g. , 26 mg + 10 mg of kavain; 14 mg + 5 mg of dihydrokavain; 8 mg + 5 mg of methysticin; 21 mg + 10 mg of dihydromethysticin; 8 mg + 5 mg of desmethoxyyangonin); and 2) a low dose of nicotine (e.g. , 1- 15 mg, 1- 10 mg; 1-9 mg, 1-8 mg; 1-7 mg; 1-6 mg; 1-5 mg; 1-4 mg, and the like).

In other aspects, the invention provides a method for decreasing nicotine metabolites in a subject particularly suitable for such treatment while undergoing nicotine replacement therapy comprising administering to a subject having TNE of > 30,000 mg/ mg creatine a composition comprising kavalactone (e.g. , 26 mg + 10 mg of kavain; 14 mg + 5 mg of dihydrokavain; 8 mg + 5 mg of methysticin; 21 mg + 10 mg of dihydromethysticin; 8 mg + 5 mg of desmethoxyyangonin) and a low dose of nicotine (e.g. , 1-15 mg, 1- 10 mg; 1-9 mg, 1-8 mg; 1-7 mg; 1-6 mg; 1-5 mg; 1-4 mg, and the like).

In other aspects, the invention provides a method for decreasing nicotine metabolites in a subject particularly suitable for such treatment while undergoing nicotine replacement therapy comprising administering to a subject having TNE of > 30,000 mg/ mg creatine a composition comprising: 1) a composition comprising kavalactone (e.g. , 26 mg + 10 mg of kavain; 14 mg + 5 mg of dihydrokavain; 8 mg + 5 mg of methysticin; 21 mg + 10 mg of dihydromethysticin; 8 mg + 5 mg of desmethoxyyangonin); and 2) a low dose of nicotine (e.g. , 1-15 mg, 1- 10 mg; 1-9 mg, 1-8 mg; 1-7 mg; 1-6 mg; 1-5 mg; 1-4 mg, and the like).

BRIEF DESCRIPTION OF THE DRAWINGS

The present invention is further described below with reference to the following non-limiting examples and with reference to the following figures, in which:

FIG. 1. depicts NNK and NNAL metabolism and carcinogenesis.

FIG. 2. depicts the structures of six major kavalactones in kava.

FIG. 3. depicts reconstructed ion chromatograms of kavain, DHK,

methysticin, DHM, and desmethoxyyangonin and their corresponding mass spectra. Equal amounts of subject standards (15 pg) were injected for UPLC-MS analysis.

FIG. 4. depicts UPLC-MS analysis of the composition of kava extract that was used for the mouse study and commercial kava capsule that was used for the human trial. [ ¾]-DHM was spiked as an internal standard. (Mean + SD, n=3). The value in parentheses is the ratio of the mean value of the amount of subject kavalactone to the total kavalactones.

FIG. 5. depicts the calibration curve of DHM for two commercial forms of kava. FIG. 6. depicts the calibration curve of DHM for the animal study.

FIG. 7. depicts within-day and between-day estimates of DHK, kavain, methysticin and desmethoxyyangonin (pg/mg tissue) from mouse liver tissues of negative control group (mice were not administered with kava) spiked with the specific kavalactone at a level of 50 pg/mg tissue, a, Within-day and between-day estimates were conducted with 3 independent measurements on three diDerent days, b, Values in parentheses represent accuracy of the method.

FIGs. 8A-8D. depicts pharmacokinetics and biodistribution of five

kavalactones in the mouse liver (FIG. 8A), lung (FIG. 8B), brain (FIG. 8C), and serum (FIG. 8D). [ H₂]-DHM was used as the internal standard for the quantification. Liver, lung, brain and serum samples were collected 0.5, 1.5, 4, 8, and 24 hours after gavage kava treatment. Mice with no kava treatment were used as the negative control. -, no kava treatment; +, kava treatment. ND, below the LOD. Data represents mean + standard deviation of 3 mice per treatment group. FIGs. 9A-9E. depicts the relative abundance of kavain (FIG. 9A), DHK (FIG.

9B), methysticin (FIG. 9C), DHM (FIG. 9D) and desmethoxyyangonin (FIG. 9E) in the serum, tissues and urine of mice at different time points after kava administration. [ H₂]-DHM was spiked as an internal standard for the quantification. Serum, liver, lung, and brain tissues were collected 0.5, 1.5, 4, 8, and 24 hours after kava administration.

FIGs. 10A-10D. depicts targeted UPLC-MS² analysis of DHM in mouse liver tissues. Reconstructed ion chromatograms of DHM in liver tissues from mice with no kava (FIG. 10A), 1.5 hours (FIG. 10B) and 24 hours (FIG. IOC) after kava administration. (FIG. 10D) Mass spectra of DHM and [²H₂]-DHM. [²H₂]-DHM was used as the internal standard. DHM, [M+H]⁺, m/z 277.1 > 131.0490, 135.0438, 161.0593; [²H₂]-DHM, [M+H]⁺, m/z 279.1 > 131.0490, 137.0564, 163.0719. The mass extraction window was of + 5 ppm.

FIG. 11. depicts the relative abundance of kavain, DHK, methysticin, DHM and desmethoxyyangonin in the kava capsule, urine and plasma. FIG. 12. depicts the calibration curve of DHM the human trial study using the product ions at m/z 131.0490, m/z 137.0564 and m/z 163.0719 at the MS2 scan stage with 5 ppm mass tolerance. FIGs. 13A-13D. depicts pharmacokinetic parameters of Kavain (FIG. 13A), DHK (FIG. 13B), Methysticin (FIG. 13C), and DHM (FIG. 13D).

FIG. 14. depicts reconstructed ion chromatograms at MS 2 scan stage of [ 2 H₂]- DHM, kavain, DHK, methysticin, DHM, and demethoxyyangonin isolated from a control urine, and the urine samples collected from a subject pre- and post-kava.

[ H₂]-DHM was used as the internal standard. The mass extraction window was of + 5 ppm.

FIG. 15. depicts levels of kavain, DHK, methysticin, DHM and

desmethoxyyangonin in the urine and plasma samples of two subjects pre- and post- kava administration.

FIG. 16. depicts the impact of dietary kava on smoking behavior.

FIGs. 17A-17C. depicts the impact of dietary kava on total nicotine exposure (TNE) in all subjects (FIG. 17A), AAs (FIG. 17B) and CAs (FIG. 17C) respectively via paired two-tailed t-test. FIGs. 18A-18C. depicts the impact of dietary kava on NNAL urinary excretion in all subjects (FIG. 18A), AAs (FIG. 18B) and CAs (FIG. 18C) respectively with paired two-tailed t-test analyses.

FIGs. 19A-19C. depicts the impact of dietary kava on 3 -methyl adenine in all subjects (FIG. 19A), AAs (FIG. 19B) and CAs (FIG. 19C) respectively with paired two-tailed t-test analyses.

FIGs. 20A-20C. depicts the impact of dietary kava on NNAL urinary excretion in all subjects (FIG. 20A), subjects with high CYP2A6 activity (FIG. 20B) and subjects with low CYP2A6 activity (FIG. 20C) respectively with paired two- tailed t-test analyses

FIG. 21. depicts the impact of dietary kava on free nicotine and nicotine metabolites.

DETAILED DESCRIPTION

Definitions

In order that the invention may be more readily understood, certain terms are first defined here for convenience. As used herein, the term "treating" a disorder encompasses preventing, ameliorating, mitigating and/or managing the disorder and/or conditions that may cause the disorder. The terms "treating" and "treatment" refer to a method of alleviating or abating a disease and/or its attendant symptoms. In accordance with the present invention "treating" includes preventing, blocking, inhibiting, attenuating, protecting against, modulating, reversing the effects of and reducing the occurrence of e.g., the harmful effects of a disorder.

As used herein, "inhibiting" encompasses preventing, reducing and halting progression.

As used herein, "activating" encompasses permitting, increasing and enhancing progression.

As used herein, "enriched" encompasses greater or increased amounts of a material or desired or active compound or agent relative to its natural or other reference state. In one aspect the "enriched" kava extract is enriched in one or more kavalactones selected from kavain, dihydrokavain, methysticin, dihydomethysticin, desmethoxyyangonin, yangonin, and their respective salts.

As used herein, as "extract" is a preparation of constituents of a material (e.g., kava), including for example, solvent extracts, concentrated forms of said

constituents, concentrated solvent extracts, isolated chemical compounds or mixtures thereof.

The term "modulate" refers to increases or decreases in the activity of a cell in response to exposure to a compound of the invention.

The terms "isolated," "purified," or "biologically pure" refer to material that is substantially or essentially free from components that normally accompany it as found in its native state. Purity and homogeneity are typically determined using analytical chemistry techniques such as polyacrylamide gel electrophoresis or high performance liquid chromatography. Particularly, in embodiments the compound is at least 85% pure, more preferably at least 90% pure, more preferably at least 95% pure, and most preferably at least 99% pure.

The terms "polypeptide," "peptide" and "protein" are used interchangeably herein to refer to a polymer of amino acid residues. The terms apply to amino acid polymers in which one or more amino acid residue is an artificial chemical mimetic of a corresponding naturally occurring amino acid, as well as to naturally occurring amino acid polymers and non-naturally occurring amino acid polymer. A "peptide" is a sequence of at least two amino acids. Peptides can consist of short as well as long amino acid sequences, including proteins.

The term "amino acid" refers to naturally occurring and synthetic amino acids, as well as amino acid analogs and amino acid mimetics that function in a manner similar to the naturally occurring amino acids. Naturally occurring amino acids are those encoded by the genetic code, as well as those amino acids that are later modified, e.g., hydroxyproline, γ-carboxyglutamate, and O-phosphoserine. Amino acid analogs refers to compounds that have the same basic chemical structure as a naturally occurring amino acid, i.e., an a carbon that is bound to a hydrogen, a carboxyl group, an amino group, and an R group, e.g., homoserine, norleucine, methionine sulfoxide, methionine methyl sulfonium. Such analogs have modified R groups (e.g., norleucine) or modified peptide backbones, but retain the same basic chemical structure as a naturally occurring amino acid. Amino acid mimetics refers to chemical compounds that have a structure that is different from the general chemical structure of an amino acid, but that functions in a manner similar to a naturally occurring amino acid.

The term "protein" refers to series of amino acid residues connected one to the other by peptide bonds between the alpha-amino and carboxy groups of adjacent residues.

Amino acids may be referred to herein by either their commonly known three letter symbols or by the one-letter symbols recommended by the IUPAC-IUB

Biochemical Nomenclature Commission.

As to amino acid sequences, one of skill will recognize that subject substitutions, deletions or additions to a peptide, polypeptide, or protein sequence which alters, adds or deletes a single amino acid or a small percentage of amino acids in the encoded sequence is a "conservatively modified variant" where the alteration results in the substitution of an amino acid with a chemically similar amino acid.

Conservative substitution tables providing functionally similar amino acids are well known in the art.

Macromolecular structures such as polypeptide structures can be described in terms of various levels of organization. For a general discussion of this organization, see, e.g., Alberts et al., Molecular Biology of the Cell (3rd ed., 1994) and Cantor and Schimmel, Biophysical Chemistry Part I. The Conformation of Biological Macromolecules (1980). "Primary structure" refers to the amino acid sequence of a particular peptide. "Secondary structure" refers to locally ordered, three dimensional structures within a polypeptide. These structures are commonly known as domains. Domains are portions of a polypeptide that form a compact unit of the polypeptide and are typically 50 to 350 amino acids long. Typical domains are made up of sections of lesser organization such as stretches of β-sheet and oc-helices. "Tertiary structure" refers to the complete three dimensional structure of a polypeptide monomer. "Quaternary structure" refers to the three dimensional structure formed by the noncovalent association of independent tertiary units. Anisotropic terms are also known as energy terms.

The term "administration" or "administering" includes routes of introducing the compound(s) to a subject to perform their intended function. Examples of routes of administration which can be used include injection (subcutaneous, intravenous, parenterally, intraperitoneally, intrathecal), topical, oral, inhalation, rectal and transdermal.

The term "effective amount" includes an amount effective, at dosages and for periods of time necessary, to achieve the desired result. An effective amount of compound may vary according to factors such as the disease state, age, and weight of the subject, and the ability of the compound to elicit a desired response in the subject. Dosage regimens may be adjusted to provide the optimum therapeutic response. An effective amount is also one in which any toxic or detrimental effects (e.g., side effects) of the elastase inhibitor compound are outweighed by the therapeutically beneficial effects.

The phrases "systemic administration," "administered systemically",

"peripheral administration" and "administered peripherally" as used herein mean the administration of a compound(s), drug or other material, such that it enters the patient's system and, thus, is subject to metabolism and other like processes.

The term "therapeutically effective amount" refers to that amount of the compound being administered sufficient to prevent development of or alleviate to some extent one or more of the symptoms of the condition or disorder being treated.

A therapeutically effective amount of compound (i.e. , an effective dosage) may range from about 0.005 g/kg to about 1000 mg/kg, preferably about 0.1 mg/kg to about 1000 mg/kg, more preferably about 10 mg/kg to about 500 mg/kg of body weight. In other embodiments, the therapeutically effective amount may range from about 0.10 nM to about 500μΜ. The skilled artisan will appreciate that certain factors may influence the dosage required to effectively treat a subject, including but not limited to the severity of the disease or disorder, previous treatments, the general health and/or age of the subject, and other diseases present. Moreover, treatment of a subject with a therapeutically effective amount of a compound can include a single treatment or, preferably, can include a series of treatments. It will also be appreciated that the effective dosage of a compound used for treatment may increase or decrease over the course of a particular treatment.

The term "total kavalactone content" refers to the total amount of kavain, dihydrokavain, methysticin, dihydomethysticin, desmethoxyyangonin, and salts thereof, present in an extract or composition.

Reference to "kavalactones" herein includes salts thereof, including kavain, dihydrokavain, methysticin, dihydomethysticin, desmethoxyyangonin, yangonin, and their respective salts. Reference to each of kavain, dihydrokavain, methysticin, dihydomethysticin, desmethoxyyangonin, and yangonin includes their respective salts.

The term "high CYP2A6 activity" refers to a total nicotine equivalent (TNE) of > 30,000 mg/mg creatinine.

The term "low CYP2A6 activity" refers to a total nicotine equivalent (TNE) of

< 30,000 mg/mg creatinine.

The term "chiral" refers to molecules which have the property of non- superimposability of the mirror image partner, while the term "achiral" refers to molecules which are superimposable on their mirror image partner.

The term "diastereomers" refers to stereoisomers with two or more centers of dissymmetry and whose molecules are not mirror images of one another.

The term "enantiomers" refers to two stereoisomers of a compound which are non-superimposable mirror images of one another. An equimolar mixture of two enantiomers is called a "racemic mixture" or a "racemate."

The term "isomers" or "stereoisomers" refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space. The term "prodrug" includes compounds with moieties which can be metabolized in vivo. Generally, the prodrugs are metabolized in vivo by esterases or by other mechanisms to active drugs. Examples of prodrugs and their uses are well known in the art (See, e.g., Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66: 1-19). The prodrugs can be prepared in situ during the final isolation and purification of the compounds, or by separately reacting the purified compound in its free acid form or hydroxyl with a suitable esterifying agent. Hydroxyl groups can be converted into esters via treatment with a carboxylic acid. Examples of prodrug moieties include substituted and unsubstituted, branch or unbranched lower alkyl ester moieties, (e.g., propionoic acid esters), lower alkenyl esters, di-lower alkyl-amino lower-alkyl esters (e.g., dimethylaminoethyl ester), acylamino lower alkyl esters (e.g., acetyloxymethyl ester), acyloxy lower alkyl esters (e.g., pivaloyloxymethyl ester), aryl esters (phenyl ester), aryl-lower alkyl esters (e.g., benzyl ester), substituted (e.g., with methyl, halo, or methoxy substituents) aryl and aryl-lower alkyl esters, amides, lower-alkyl amides, di-lower alkyl amides, and hydroxy amides. Preferred prodrug moieties are propionoic acid esters and acyl esters. Prodrugs which are converted to active forms through other mechanisms in vivo are also included. In aspects, the compounds of the invention are prodrugs of any of the formulae herein.

The term "subject" refers to animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like. In certain embodiments, the subject is a human.

Furthermore the compounds of the invention include olefins having either geometry: "Z" refers to what is referred to as a "cis" (same side) conformation whereas "E" refers to what is referred to as a "trans" (opposite side) conformation. With respect to the nomenclature of a chiral center, the terms "d" and "1"

configuration are as defined by the IUPAC Recommendations. As to the use of the terms, diastereomer, racemate, epimer and enantiomer, these will be used in their normal context to describe the stereochemistry of preparations.

As used herein, the term "alkyl" refers to a straight-chained or branched hydrocarbon group containing 1 to 12 carbon atoms. The term "lower alkyl" refers to a C1-C6 alkyl chain. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, tert-butyl, and n-pentyl. Alkyl groups may be optionally substituted with one or more substituents. The term "alkenyl" refers to an unsaturated hydrocarbon chain that may be a straight chain or branched chain, containing 2 to 12 carbon atoms and at least one carbon-carbon double bond. Alkenyl groups may be optionally substituted with one or more substituents.

The term "alkynyl" refers to an unsaturated hydrocarbon chain that may be a straight chain or branched chain, containing the 2 to 12 carbon atoms and at least one carbon-carbon triple bond. Alkynyl groups may be optionally substituted with one or more substituents.

The sp or sp carbons of an alkenyl group and an alkynyl group, respectively, may optionally be the point of attachment of the alkenyl or alkynyl groups.

The term "alkoxy" refers to an -O-alkyl radical.

As used herein, the term "halogen", "hal" or "halo" means -F, -CI, -Br or -I. The term "cycloalkyl" refers to a hydrocarbon 3-8 membered monocyclic or 7-14 membered bicyclic ring system having at least one saturated ring or having at least one non-aromatic ring, wherein the non-aromatic ring may have some degree of unsaturation. Cycloalkyl groups may be optionally substituted with one or more substituents. In one embodiment, 0, 1, 2, 3, or 4 atoms of each ring of a cycloalkyl group may be substituted by a substituent. Representative examples of cycloalkyl group include cyclopropyl, cyclopentyl, cyclohexyl, cyclobutyl, cycloheptyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, and the like.

The term "aryl" refers to a hydrocarbon monocyclic, bicyclic or tricyclic aromatic ring system. Aryl groups may be optionally substituted with one or more substituents. In one embodiment, 0, 1, 2, 3, 4, 5 or 6 atoms of each ring of an aryl group may be substituted by a substituent. Examples of aryl groups include phenyl, naphthyl, anthracenyl, fluorenyl, indenyl, azulenyl, and the like.

The term "heteroaryl" refers to an aromatic 5-8 membered monocyclic, 8- 12 membered bicyclic, or 11-14 membered tricyclic ring system having 1-4 ring heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, and the remainder ring atoms being carbon (with appropriate hydrogen atoms unless otherwise indicated). Heteroaryl groups may be optionally substituted with one or more substituents. In one embodiment, 0, 1, 2, 3, or 4 atoms of each ring of a heteroaryl group may be substituted by a substituent. Examples of heteroaryl groups include pyridyl, furanyl, thienyl, pyrrolyl, oxazolyl, oxadiazolyl, imidazolyl thiazolyl, isoxazolyl, quinolinyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, isoquinolinyl, indazolyl, and the like.

The term "heterocycloalkyl" refers to a nonaromatic 3-8 membered

monocyclic, 7-12 membered bicyclic, or 10-14 membered tricyclic ring system comprising 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, S, B, P or Si, wherein the nonaromatic ring system is completely saturated. Heterocycloalkyl groups may be optionally substituted with one or more substituents. In one embodiment, 0, 1, 2, 3, or 4 atoms of each ring of a heterocycloalkyl group may be substituted by a substituent. Representative heterocycloalkyl groups include piperidinyl, piperazinyl,

tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,3-dioxolane, tetrahydrofuranyl, tetrahydrothienyl, thiirenyl, and the like.

The term "alkylamino" refers to an amino substituent which is further substituted with one or two alkyl groups. The term "aminoalkyl" refers to an alkyl substituent which is further substituted with one or more amino groups. The term "hydroxyalkyl" or "hydroxylalkyl" refers to an alkyl substituent which is further substituted with one or more hydroxyl groups. The alkyl or aryl portion of alkylamino, aminoalkyl, mercaptoalkyl, hydroxyalkyl, mercaptoalkoxy, sulfonylalkyl, sulfonylaryl, alkylcarbonyl, and alkylcarbonylalkyl may be optionally substituted with one or more substituents.

Acids and bases useful in the methods herein are known in the art. Acid catalysts are any acidic chemical, which can be inorganic (e.g., hydrochloric, sulfuric, nitric acids, aluminum trichloride) or organic (e.g., camphorsulfonic acid, p- toluenesulfonic acid, acetic acid, ytterbium triflate) in nature. Acids are useful in either catalytic or stoichiometric amounts to facilitate chemical reactions. Bases are any basic chemical, which can be inorganic (e.g., sodium bicarbonate, potassium hydroxide) or organic (e.g., triethylamine, pyridine) in nature. Bases are useful in either catalytic or stoichiometric amounts to facilitate chemical reactions.

Alkylating agents are any reagent that is capable of effecting the alkylation of the functional group at issue (e.g., oxygen atom of an alcohol, nitrogen atom of an amino group). Alkylating agents are known in the art, including in the references cited herein, and include alkyl halides (e.g., methyl iodide, benzyl bromide or chloride), alkyl sulfates (e.g., methyl sulfate), or other alkyl group-leaving group combinations known in the art. Leaving groups are any stable species that can detach from a molecule during a reaction (e.g., elimination reaction, substitution reaction) and are known in the art, including in the references cited herein, and include halides (e.g., I-, C1-, Br-, F-), hydroxy, alkoxy (e.g., -OMe, -O-t-Bu), acyloxy anions (e.g., - OAc, -OC(0)CF₃), sulfonates (e.g., mesyl, tosyl), acetamides (e.g., -NHC(O)Me), carbamates (e.g., N(Me)C(0)Ot-Bu), phosphonates (e.g., -OP(0)(OEt)₂), water or alcohols (protic conditions), and the like.

In certain embodiments, substituents on any group (such as, for example, alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl,

heterocycloalkyl) can be at any atom of that group, wherein any group that can be substituted (such as, for example, alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, heterocycloalkyl) can be optionally substituted with one or more substituents (which may be the same or different), each replacing a hydrogen atom. Examples of suitable substituents include, but are not limited to alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halogen, haloalkyl, cyano, nitro, alkoxy, aryloxy, hydroxyl, hydroxylalkyl, oxo (i.e., carbonyl), carboxyl, formyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl,

alkylcarbonyloxy, aryloxycarbonyl, heteroaryloxy, heteroaryloxycarbonyl, thio, mercapto, mercaptoalkyl, arylsulfonyl, amino, aminoalkyl, dialkylamino,

alkylcarbonylamino, alkylaminocarbonyl, alkoxycarbonylamino, alkylamino, arylamino, diarylamino, alkylcarbonyl, or arylamino-substituted aryl; arylalkylamino, aralkylaminocarbonyl, amido, alkylaminosulfonyl, arylaminosulfonyl,

dialkylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, imino, carbamido, carbamyl, thioureido, thiocyanato, sulfoamido, sulfonylalkyl, sulfonylaryl, or mercaptoalkoxy.

Compounds of the Invention

Compounds of the invention can be made by means known in the art of organic synthesis. Methods for optimizing reaction conditions, if necessary minimizing competing by-products, are known in the art. Reaction optimization and scale-up may advantageously utilize high-speed parallel synthesis equipment and computer-controlled microreactors (e.g. Design And Optimization in Organic Synthesis, 2^nd Edition, Carlson R, Ed, 2005; Elsevier Science Ltd.; Jahnisch, K et al, Angew. Chem. Int. Ed. Engl. 2004 43: 406; and references therein). Additional reaction schemes and protocols may be determined by the skilled artesian by use of commercially available structure-searchable database software, for instance,

SciFinder® (CAS division of the American Chemical Society) and CrossFire Beilstein® (Elsevier MDL), or by appropriate keyword searching using an internet search engine such as Google® or keyword databases such as the US Patent and Trademark Office text database.

The compounds herein may also contain linkages (e.g., carbon-carbon bonds) wherein bond rotation is restricted about that particular linkage, e.g. restriction resulting from the presence of a ring or double bond. Accordingly, all cis/trans and E/Z isomers are expressly included in the present invention. The compounds herein may also be represented in multiple tautomeric forms, in such instances, the invention expressly includes all tautomeric forms of the compounds described herein, even though only a single tautomeric form may be represented. All such isomeric forms of such compounds herein are expressly included in the present invention. All crystal forms and polymorphs of the compounds described herein are expressly included in the present invention. Also embodied are extracts and fractions comprising compounds of the invention. The term isomers is intended to include

diastereoisomers, enantiomers, regioisomers, structural isomers, rotational isomers, tautomers, and the like. For compounds which contain one or more stereogenic centers, e.g., chiral compounds, the methods of the invention may be carried out with an enantiomerically enriched compound, a racemate, or a mixture of diastereomers.

The present invention also contemplates solvates (e.g., hydrates) of a compound of herein, compositions thereof, and their use in the treatment of reactive oxygen species (ROS)-mediated diseases and diseases alleviated or prevented through the activation of the Nrf2-ARE (antioxidant response element) pathway. As used herein, "solvate" refers to the physical association of a compound of the invention with one or more solvent or water molecules, whether organic or inorganic. In certain instances, the solvate is capable of isolation, for example, when one or more solvate molecules are incorporated in the crystal lattice of the crystalline solid.

Preferred enantiomerically enriched compounds have an enantiomeric excess of 50% or more, more preferably the compound has an enantiomeric excess of 60%, 70%, 80%, 90%, 95%, 98%, or 99% or more. In preferred embodiments, only one enantiomer or diastereomer of a chiral compound of the invention is administered to cells or a subject. Methods of Treatment

In other aspects of the methods herein, the "subject" or "individual" includes a human having a total nicotine equivalent (TNE) of > 30,000 mg/mg creatinine, a total nicotine equivalent (TNE) of < 30,000 mg/mg creatinine, and the like.

In other aspects of the methods herein, a "high risk" subject or individual includes a human having a total nicotine equivalent (TNE) of > 30,000 mg/mg creatinine. In other aspects, this subject or individual is "suitable for low dose nicotine replacement therapy."

In other aspects, the invention provides a method of treating a disease, disorder, or symptom thereof in a subject, comprising administering to the subject any compound, composition, or kava extract herein. In another aspect, the compound, composition, or kava extract is administered in an amount and under conditions sufficient to ameliorate the disease, disorder, or symptom thereof in a subject. In another aspect, the disease, disorder, or symptom includes nicotine and tobacco addiction.

In other aspects, the invention provides a method of treating a disease, disorder, or symptom thereof in a subject, comprising administering to the subject any compound, composition, or kava extract herein. In another aspect, the compound, composition, or kava extract is administered in an amount and under conditions sufficient to ameliorate the disease, disorder, or symptom thereof in a subject. In another aspect, the disease, disorder, or symptom includes nicotine and tobacco addiction. In another aspect, the subject is African American.

In other aspects, the invention provides a method of aiding a subject in the cessation of tobacco use, the method comprising the administration of any compound, composition, or kava extract herein.

In other aspects, the invention provides a method of aiding a subject in the cessation of tobacco use, the method comprising the administration of any compound, composition, or kava extract herein. In another aspect, the subject is non-Caucasian. In another aspect, the subject is African American.

In other aspects, the invention provides a method of aiding a subject in the cessation of tobacco use, the method comprising the administration of a composition comprising at least one (e.g. , 1, 2, 3, 4, or 5) compound selected from kavain, wherein the amount of kavain in the composition is 26 mg + 10 mg; dihydrokavain, wherein the amount of dihydrokavain in the composition is 14 mg + 5 mg; methysticin, wherein the amount of methysticin in the composition is 8 mg + 5 mg;

desmethoxyyangonin in the composition is 8 mg + 5 mg.

In other aspects, the invention provides a method of aiding a subject in the cessation of tobacco use, the method comprising the administration to the subject a composition comprising at least one (e.g. , 1, 2, 3, 4, or 5) compound selected from kavain, wherein the amount of kavain in the composition is 26 mg + 10 mg;

composition is 21 mg + 10 mg; and desmethoxyyangonin, wherein the amount of desmethoxyyangonin in the composition is 8 mg + 5 mg. In another aspect, the subject is non-Caucasian. In another aspect, the subject is African American.

In other aspects, the invention provides a method of aiding a subject in the cessation of tobacco use, the method comprising the administration of any compound, composition, or kava extract herein, wherein said subject is administered one (e.g. , 1, 2, 3, 4, or 5) or more of the group consisting of 75 mg + 25 mg of kavain per day, 40 mg + 20 mg of dihydrokavain per day, 25 mg + 15 mg of methysticin per day, 60 mg + 30 mg of dihydromethysticin per day, and 25 mg + 15 mg of desmethoxyyangonin per day.

In other aspects, the invention provides a method of aiding a subject in the cessation of tobacco use, the method comprising the administration to the subject any compound, composition, or kava extract herein, wherein said subject is administered one (e.g. , 1, 2, 3, 4, or 5) or more of the group consisting of 75 mg + 25 mg of kavain per day, 40 mg + 20 mg of dihydrokavain per day, 25 mg + 15 mg of methysticin per day, 60 mg + 30 mg of dihydromethysticin per day, and 25 mg + 15 mg of

desmethoxyyangonin per day. In another aspect, the subject is non-Caucasian. In another aspect, the subject is African American.

In other aspects, the invention provides a method of aiding a subject in the cessation of tobacco use, the method comprising the administration of any compound, composition, or kava extract herein, wherein said subject is administered one (e.g. , 1, 2, 3, 4, or 5) or more of the group consisting of 75 mg + 25 mg of kavain per day, 40 mg + 20 mg of dihydrokavain per day, 25 mg + 15 mg of methysticin per day, 60 mg + 30 mg of dihydromethysticin per day, and 25 mg + 15 mg of desmethoxyyangonin per day. In another aspect, the subject is non-Caucasian. In another aspect, the subject is African American.

composition, or kava extract herein.

composition, or kava extract herein. In another aspect, the subject is non-Caucasian. In another aspect, the subject is African American.

In other aspects, the invention provides a method of treating tobacco addiction in a subject, the method comprising the administration of a composition comprising at least one (e.g. , 1, 2, 3, 4, or 5) compound selected from kavain, wherein the amount of kavain in the composition is 26 mg + 10 mg; dihydrokavain, wherein the amount of dihydrokavain in the composition is 14 mg + 5 mg; methysticin, wherein the amount of methysticin in the composition is 8 mg + 5 mg; dihydromethysticin, wherein the amount of dihydromethysticin in the composition is 21 mg + 10 mg; and

desmethoxyyangonin, wherein the amount of desmethoxyyangonin in the composition is 8 mg + 5 mg. In another aspect, the subject is non-Caucasian. In another aspect, the subject is African American.

In other aspects, the invention provides a method of treating tobacco addiction in a subject, wherein the subject is identified as in need thereof, the method comprising the administration of any compound, composition, or kava extract herein.

In other aspects, the invention provides a method of treating tobacco addiction in a subject, wherein the subject is identified as in need thereof, the method comprising the administration of any compound, composition, or kava extract herein. In another aspect, the subject is non-Caucasian. In another aspect, the subject is African American.

composition, or kava extract herein, wherein said subject is administered one (e.g. , 1, 2, 3, 4, or 5) or more of the group consisting of 75 mg + 25 mg of kavain per day, 40 mg + 20 mg of dihydrokavain per day, 25 mg + 15 mg of methysticin per day, 60 mg + 30 mg of dihydromethysticin per day, and 25 mg + 15 mg of desmethoxyyangonin per day.

composition, or kava extract herein to the subject, wherein said subject is

composition, or kava extract herein, wherein said subject is administered one (e.g. , 1, 2, 3, 4, or 5) or more of the group consisting of 75 mg + 25 mg of kavain per day, 40 mg + 20 mg of dihydrokavain per day, 25 mg + 15 mg of methysticin per day, 60 mg + 30 mg of dihydromethysticin per day, and 25 mg + 15 mg of desmethoxyyangonin per day. In another aspect, the subject is non-Caucasian. In another aspect, the subject is African American.

composition, or kava extract herein.

In other aspects, the invention provides a method of treating nicotine addiction in a subject, the method comprising the administration of any compound, composition, or kava extract herein. In another aspect, the subject is non-Caucasian. In another aspect, the subject is African American.

In other aspects, the invention provides a method of treating nicotine addiction in a subject, the method comprising the administration of a composition comprising at least one (e.g. , 1, 2, 3, 4, or 5) compound selected from kavain, wherein the amount of kavain in the composition is 26 mg + 10 mg; dihydrokavain, wherein the amount of dihydrokavain in the composition is 14 mg + 5 mg; methysticin, wherein the amount of methysticin in the composition is 8 mg + 5 mg; dihydromethysticin, wherein the amount of dihydromethysticin in the composition is 21 mg + 10 mg; and

In other aspects, the invention provides a method of treating nicotine addiction in a subject, wherein the subject is identified as in need thereof, the method comprising the administration of any compound, composition, or kava extract herein. In other aspects, the invention provides a method of treating nicotine addiction in a subject, wherein the subject is identified as in need thereof, the method comprising the administration of any compound, composition, or kava extract herein to the subject. In another aspect, the subject is non-Caucasian. In another aspect, the subject is African American.

In other aspects, the invention provides a method of treating nicotine addiction in a subject, wherein the subject is identified as in need thereof, the method comprising the administration of any compound, composition, or kava extract herein. In another aspect, the subject is non-Caucasian. In another aspect, the subject is African American.

In other aspects, the invention provides a method of treating nicotine addiction in a subject, the method comprising the administration to the subject any compound, composition, or kava extract herein, wherein said subject is administered one (e.g., 1, 2, 3, 4, or 5) or more of the group consisting of 75 mg + 25 mg of kavain per day, 40 mg + 20 mg of dihydrokavain per day, 25 mg + 15 mg of methysticin per day, 60 mg + 30 mg of dihydromethysticin per day, and 25 mg + 15 mg of desmethoxyyangonin per day.

composition, or kava extract herein to the subject, wherein said subject is

In other aspects, the invention provides a method of treating nicotine addiction in a subject, the method comprising the administration of any compound, composition, or kava extract herein, wherein said subject is administered one (e.g. , 1, 2, 3, 4, or 5) or more of the group consisting of 75 mg + 25 mg of kavain per day, 40 mg + 20 mg of dihydrokavain per day, 25 mg + 15 mg of methysticin per day, 60 mg + 30 mg of dihydromethysticin per day, and 25 mg + 15 mg of desmethoxyyangonin per day. In another aspect, the subject is non-Caucasian. In another aspect, the subject is African American.

In other aspects, the invention provides a method of inhibiting the metabolism of nicotine in a subject, the method comprising the administration of any compound, composition, or kava extract herein.

In other aspects, the invention provides a method of inhibiting the metabolism of nicotine in a subject, the method comprising the administration of any compound, composition, or kava extract herein. In aspects the "inhibiting" is relative to metabolism of nicotine in the subject in the absence of administration of a

kavalactone compound, kavalactone composition, or kava extract described herein. In another aspect, the subject is non-Caucasian. In another aspect, the subject is African American.

In other aspects, the invention provides a method of inhibiting the metabolism of nicotine in a subject, the method comprising the administration of a composition comprising at least one (e.g. , 1, 2, 3, 4, or 5) compound selected from kavain, wherein the amount of kavain in the composition is 26 mg + 10 mg; dihydrokavain, wherein the amount of dihydrokavain in the composition is 14 mg + 5 mg; methysticin, wherein the amount of methysticin in the composition is 8 mg + 5 mg; dihydromethysticin, wherein the amount of dihydromethysticin in the composition is 21 mg + 10 mg; and desmethoxyyangonin, wherein the amount of

desmethoxyyangonin in the composition is 8 mg + 5 mg.

In other aspects, the invention provides a method of inhibiting the metabolism of nicotine in a subject, the method comprising the administration of a composition comprising at least one (e.g. , 1, 2, 3, 4, or 5) compound selected from kavain, wherein the amount of kavain in the composition is 26 mg + 10 mg; dihydrokavain, wherein the amount of dihydrokavain in the composition is 14 mg + 5 mg; methysticin, wherein the amount of methysticin in the composition is 8 mg + 5 mg;

In other aspects, the invention provides a method of inhibiting the metabolism of nicotine in a subject, the method comprising the administration of any compound, composition, or kava extract herein, wherein said subject is administered one (e.g. , 1, 2, 3, 4, or 5) or more of the group consisting of 75 mg + 25 mg of kavain per day, 40 mg + 20 mg of dihydrokavain per day, 25 mg + 15 mg of methysticin per day, 60 mg + 30 mg of dihydromethysticin per day, and 25 mg + 15 mg of desmethoxyyangonin per day.

In other aspects, the invention provides a method of inhibiting the metabolism of nicotine in a subject, the method comprising the administration of any compound, composition, or kava extract herein, wherein said subject is administered one (e.g. , 1,

2, 3, 4, or 5) or more of the group consisting of 75 mg + 25 mg of kavain per day, 40 mg + 20 mg of dihydrokavain per day, 25 mg + 15 mg of methysticin per day, 60 mg + 30 mg of dihydromethysticin per day, and 25 mg + 15 mg of desmethoxyyangonin per day. In another aspect, the subject is non-Caucasian. In another aspect, the subject is African American.

In other aspects, the invention provides a treatment regimen for smoking cessation, the regimen comprising the administration of any compound, composition, or kava extract herein.

In other aspects, the invention provides a treatment regimen for smoking cessation, wherein the subject is identified as in need thereof, the regimen comprising the administration of any compound, composition, or kava extract herein.

In other aspects, the invention provides a treatment regimen for smoking cessation in a subject, wherein the subject is identified as in need thereof, the regimen comprising the administration of any compound, composition, or kava extract herein.

In another aspect, the subject is non-Caucasian. In another aspect, the subject is

African American.

In other aspects, the invention provides a treatment regimen for smoking cessation, the regimen comprising the administration of a composition comprising at least one (e.g. , 1, 2, 3, 4, or 5) compound selected from kavain, wherein the amount of kavain in the composition is 26 mg + 10 mg; dihydrokavain, wherein the amount of dihydrokavain in the composition is 14 mg + 5 mg; methysticin, wherein the amount of methysticin in the composition is 8 mg + 5 mg; dihydromethysticin, wherein the amount of dihydromethysticin in the composition is 21 mg + 10 mg; and

In other aspects, the invention provides a treatment regimen for smoking cessation in a subject, the regimen comprising the administration of a composition comprising at least one (e.g. , 1, 2, 3, 4, or 5) compound selected from kavain, wherein the amount of kavain in the composition is 26 mg + 10 mg; dihydrokavain, wherein the amount of dihydrokavain in the composition is 14 mg + 5 mg; methysticin, wherein the amount of methysticin in the composition is 8 mg + 5 mg;

In other aspects, the invention provides a treatment regimen for smoking cessation, the regimen comprising the administration of any compound, composition, or kava extract herein, wherein said subject is administered one (e.g. , 1, 2, 3, 4, or 5) or more of the group consisting of 75 mg + 25 mg of kavain per day, 40 mg + 20 mg of dihydrokavain per day, 25 mg + 15 mg of methysticin per day, 60 mg + 30 mg of dihydromethysticin per day, and 25 mg + 15 mg of desmethoxyyangonin per day. In other aspects, the invention provides a treatment regimen for smoking cessation in a subject, the regimen comprising the administration to the subject any compound, composition, or kava extract herein, wherein said subject is administered one (e.g. , 1, 2, 3, 4, or 5) or more of the group consisting of 75 mg + 25 mg of kavain per day, 40 mg + 20 mg of dihydrokavain per day, 25 mg + 15 mg of methysticin per day, 60 mg + 30 mg of dihydromethysticin per day, and 25 mg + 15 mg of desmethoxyyangonin per day. In another aspect, the subject is non-Caucasian. In another aspect, the subject is African American.

In other aspects, the invention provides a treatment regimen for smoking cessation, the regimen comprising the administration of any compound, composition, or kava extract herein, wherein said subject is administered one (e.g. , 1, 2, 3, 4, or 5) or more of the group consisting of 75 mg + 25 mg of kavain per day, 40 mg + 20 mg of dihydrokavain per day, 25 mg + 15 mg of methysticin per day, 60 mg + 30 mg of dihydromethysticin per day, and 25 mg + 15 mg of desmethoxyyangonin per day. In another aspect, the subject is non-Caucasian. In another aspect, the subject is African American.

In other aspects, the invention provides a treatment regimen for smoking cessation and inhibiting nicotine metabolism, the regimen comprising the

administration of any compound, composition, or kava extract herein.

In other aspects, the invention provides a treatment regimen for smoking cessation and inhibiting nicotine metabolism in a subject, the regimen comprising the administration of any compound, composition, or kava extract herein to the subject. In other aspects, the invention provides a treatment regimen for smoking cessation and inhibiting nicotine metabolism in a subject, the regimen comprising the administration to the subject any compound, composition, or kava extract herein. In another aspect, the subject is non-Caucasian. In another aspect, the subject is African American.

In other aspects, the invention provides a treatment regimen for smoking cessation and inhibiting nicotine metabolism in a subject, the regimen comprising the administration of any compound, composition, or kava extract herein to the subject. In other aspects, the invention provides a treatment regimen for smoking cessation and inhibiting nicotine metabolism, the regimen comprising the of any compound, composition, or kava extract herein. In another aspect, the subject is non-Caucasian. In another aspect, the subject is African American. In other aspects, the invention provides a treatment regimen for smoking cessation and inhibiting nicotine metabolism, the regimen comprising the

administration of a composition comprising at least one (e.g. , 1, 2, 3, 4, or 5) compound selected from kavain, wherein the amount of kavain in the composition is 26 mg + 10 mg; dihydrokavain, wherein the amount of dihydrokavain in the composition is 14 mg + 5 mg; methysticin, wherein the amount of methysticin in the composition is 8 mg + 5 mg; dihydromethysticin, wherein the amount of

In other aspects, the invention provides a treatment regimen for smoking cessation and inhibiting nicotine metabolism in a subject, the regimen comprising the administration of a composition comprising at least one (e.g. , 1, 2, 3, 4, or 5) compound selected from kavain, wherein the amount of kavain in the composition is 26 mg + 10 mg; dihydrokavain, wherein the amount of dihydrokavain in the composition is 14 mg + 5 mg; methysticin, wherein the amount of methysticin in the composition is 8 mg + 5 mg; dihydromethysticin, wherein the amount of

In other aspects, the invention provides a treatment regimen for smoking cessation and inhibiting nicotine metabolism, wherein the subject is identified as in need thereof, the regimen comprising the administration of any compound, composition, or kava extract herein.

In other aspects, the invention provides a treatment regimen for smoking cessation and inhibiting nicotine metabolism in a subject, wherein the subject is identified as in need thereof, the regimen comprising the administration to the subject any compound, composition, or kava extract herein. In another aspect, the subject is non-Caucasian. In another aspect, the subject is African American.

In other aspects, the invention provides a treatment regimen for smoking cessation and inhibiting nicotine metabolism in a subject, wherein the subject is identified as in need thereof, the regimen comprising the administration of any compound, composition, or kava extract herein. In another aspect, the subject is non- Caucasian. In another aspect, the subject is African American.

In other aspects, the invention provides a treatment regimen for smoking cessation and inhibiting nicotine metabolism, wherein the subject is identified as in need thereof, the regimen comprising the administration of any compound, composition, or kava extract herein, wherein said subject is administered one (e.g. , 1, 2, 3, 4, or 5) or more of the group consisting of 75 mg + 25 mg of kavain per day, 40 mg + 20 mg of dihydrokavain per day, 25 mg + 15 mg of methysticin per day, 60 mg + 30 mg of dihydromethysticin per day, and 25 mg + 15 mg of desmethoxyyangonin per day.

In other aspects, the invention provides a treatment regimen for smoking cessation and inhibiting nicotine metabolism in a subject, wherein the subject is identified as in need thereof, the regimen comprising the administration to the subject any compound, composition, or kava extract herein, wherein said subject is administered one (e.g. , 1, 2, 3, 4, or 5) or more of the group consisting of 75 mg + 25 mg of kavain per day, 40 mg + 20 mg of dihydrokavain per day, 25 mg + 15 mg of methysticin per day, 60 mg + 30 mg of dihydromethysticin per day, and 25 mg + 15 mg of desmethoxyyangonin per day. In another aspect, the subject is non-Caucasian. In another aspect, the subject is African American. In other aspects, the invention provides a treatment regimen for smoking cessation and inhibiting nicotine metabolism in a subject, wherein the subject is identified as in need thereof, the regimen comprising the administration of any compound, composition, or kava extract herein, wherein said subject is administered one (e.g. , 1, 2, 3, 4, or 5) or more of the group consisting of 75 mg + 25 mg of kavain per day, 40 mg + 20 mg of dihydrokavain per day, 25 mg + 15 mg of methysticin per day, 60 mg + 30 mg of dihydromethysticin per day, and 25 mg + 15 mg of desmethoxyyangonin per day. In another aspect, the subject is non-Caucasian. In another aspect, the subject is African American.

In other aspects, the invention provides a method of aiding a subject in the cessation of tobacco use, the method comprising the administration of any compound, composition, or kava extract herein; and nicotine. In other aspects, the amount of nicotine administered is 1-25 mg per dose or 1-50 mg per day.

American.

In other aspects, the invention provides a method of aiding a subject in the cessation of tobacco use, the method comprising the administration of any compound, composition, or kava extract herein; and nicotine. In other aspects, the amount of nicotine administered is 1-25 mg per dose or 1-50 mg per day. In another aspect, the subject is non-Caucasian. In another aspect, the subject is African American.

In other aspects, the invention provides a method of aiding a subject in the cessation of tobacco use, the method comprising the administration of a composition comprising: 1) at least one (e.g. , 1, 2, 3, 4, or 5) compound selected from kavain, wherein the amount of kavain in the composition is 26 mg + 10 mg; dihydrokavain, wherein the amount of dihydrokavain in the composition is 14 mg + 5 mg;

desmethoxyyangonin in the composition is 8 mg + 5 mg; and 2) nicotine, wherein the amount of nicotine in the composition is 1-25 mg (e.g. , 1-20 mg, 1- 15 mg, 1-10 mg, 1-5 mg, and the like).

composition is 21 mg + 10 mg; and desmethoxyyangonin, wherein the amount of desmethoxyyangonin in the composition is 8 mg + 5 mg; and 2) nicotine, wherein the amount of nicotine in the composition is 1-25 mg (e.g. , 1-20 mg, 1- 15 mg, 1-10 mg, 1-5 mg, and the like). In another aspect, the subject is non-Caucasian. In another aspect, the subject is African American.

desmethoxyyangonin in the composition is 8 mg + 5 mg; and 2) nicotine, wherein the amount of nicotine in the composition is 1-25 mg (e.g. , 1-20 mg, 1- 15 mg, 1-10 mg, 1-5 mg, and the like). In another aspect, the subject is non-Caucasian. In another aspect, the subject is African American.

In other aspects, the invention provides a method of aiding a subject in the cessation of tobacco use, the method comprising the administration of any compound, composition, or kava extract herein, wherein said subject is administered one (e.g., 1, 2, 3, 4, or 5) or more of the group consisting of 75 mg + 25 mg of kavain per day, 40 mg + 20 mg of dihydrokavain per day, 25 mg + 15 mg of methysticin per day, 60 mg + 30 mg of dihydromethysticin per day, and 25 mg + 15 mg of desmethoxyyangonin per day; and 1-50 mg of nicotine per day (e.g., 1-40 mg, 1-30 mg, 1-25 mg, 1-20 mg, 1-15 mg, 1- 10 mg, 1-5 mg, and the like). In other aspects, the invention provides a method of aiding a subject in the cessation of tobacco use, the method comprising the administration to the subject of any compound, composition, or kava extract herein, wherein said subject is administered one (e.g., 1, 2, 3, 4, or 5) or more of the group consisting of 75 mg + 25 mg of kavain per day, 40 mg + 20 mg of dihydrokavain per day, 25 mg + 15 mg of methysticin per day, 60 mg + 30 mg of dihydromethysticin per day, and 25 mg + 15 mg of desmethoxyyangonin per day; and 1-50 mg of nicotine per day (e.g., 1-40 mg, 1-30 mg, 1-25 mg, 1-20 mg, 1-15 mg, 1-10 mg, 1-5 mg, and the like). In another aspect, the subject is non-Caucasian. In another aspect, the subject is African

American.

In other aspects, the invention provides a method of aiding a subject in the cessation of tobacco use, the method comprising the administration of of any compound, composition, or kava extract herein, wherein said subject is administered one (e.g., 1, 2, 3, 4, or 5) or more of the group consisting of 75 mg + 25 mg of kavain per day, 40 mg + 20 mg of dihydrokavain per day, 25 mg + 15 mg of methysticin per day, 60 mg + 30 mg of dihydromethysticin per day, and 25 mg + 15 mg of desmethoxyyangonin per day; and 1-50 mg of nicotine per day (e.g., 1-40 mg, 1-30 mg, 1-25 mg, 1-20 mg, 1-15 mg, 1-10 mg, 1-5 mg, and the like). In another aspect, the subject is non-Caucasian. In another aspect, the subject is African American.

composition, or kava extract herein; and nicotine. In other aspects, the amount of nicotine administered is 1-25 mg per dose or 1-50 mg per day.

composition, or kava extract herein; and nicotine. In other aspects, the amount of nicotine administered is 1-25 mg per dose or 1-50 mg per day. In another aspect, the subject is non-Caucasian. In another aspect, the subject is African American. In other aspects, the invention provides a method of treating tobacco addiction in a subject, the method comprising the administration of a composition comprising: 1) at least one (e.g. , 1, 2, 3, 4, or 5) compound selected from kavain, wherein the amount of kavain in the composition is 26 mg + 10 mg; dihydrokavain, wherein the amount of dihydrokavain in the composition is 14 mg + 5 mg; methysticin, wherein the amount of methysticin in the composition is 8 mg + 5 mg; dihydromethysticin, wherein the amount of dihydromethysticin in the composition is 21 mg + 10 mg; and desmethoxyyangonin, wherein the amount of desmethoxyyangonin in the composition is 8 mg + 5 mg; and 2) nicotine, wherein the amount of nicotine in the composition is 1-50 mg of nicotine per day (e.g. , 1-40 mg, 1-30 mg, 1-25 mg, 1-20 mg, 1-15 mg, 1- 10 mg, 1-5 mg, and the like).

American.

In other aspects, the invention provides a method of treating tobacco addiction in a subject, the method comprising the administration of a composition comprising: 1) at least one (e.g. , 1, 2, 3, 4, or 5) compound selected from kavain, wherein the amount of kavain in the composition is 26 mg + 10 mg; dihydrokavain, wherein the amount of dihydrokavain in the composition is 14 mg + 5 mg;

American.

composition, or kava extract herein, wherein said subject is administered one (e.g. , 1, 2, 3, 4, or 5) or more of the group consisting of 75 mg + 25 mg of kavain per day, 40 mg + 20 mg of dihydrokavain per day, 25 mg + 15 mg of methysticin per day, 60 mg + 30 mg of dihydromethysticin per day, and 25 mg + 15 mg of desmethoxyyangonin per day; and 1-50 mg of nicotine per day (e.g. , 1-40 mg, 1-30 mg, 1-25 mg, 1-20 mg, 1-15 mg, 1- 10 mg, 1-5 mg, and the like).

composition, or kava extract herein, wherein said subject is administered one (e.g. , 1, 2, 3, 4, or 5) or more of the group consisting of 75 mg + 25 mg of kavain per day, 40 mg + 20 mg of dihydrokavain per day, 25 mg + 15 mg of methysticin per day, 60 mg + 30 mg of dihydromethysticin per day, and 25 mg + 15 mg of desmethoxyyangonin per day; and 1-50 mg of nicotine per day (e.g. , 1-40 mg, 1-30 mg, 1-25 mg, 1-20 mg, 1-15 mg, 1- 10 mg, 1-5 mg, and the like). In another aspect, the subject is non- Caucasian. In another aspect, the subject is African American.

In other aspects, the invention provides a treatment regimen for smoking cessation in a subject, the regimen comprising the administration of any compound, composition, or kava extract herein; and nicotine. In other aspects, the amount of nicotine administered is 1-25 mg per dose or 1-50 mg per day. In other aspects, the invention provides a treatment regimen for smoking cessation in a subject, the regimen comprising the administration to the subject any compound, composition, or kava extract herein; and nicotine. In other aspects, the amount of nicotine administered is 1-25 mg per dose or 1-50 mg per day. In other aspects, the invention provides a treatment regimen for smoking cessation in a subject, the regimen comprising the administration to the subject any compound, composition, or kava extract herein; and nicotine. In other aspects, the amount of nicotine administered is 1-25 mg per dose or 1-50 mg per day. In another aspect, the subject is non-Caucasian. In another aspect, the subject is African American.

composition is 21 mg + 10 mg; and desmethoxyyangonin, wherein the amount of desmethoxyyangonin in the composition is 8 mg + 5 mg; and 2) nicotine, wherein the amount of nicotine in the composition is 1- 15 mg (e.g. , 1- 10 mg; 1-9 mg, 1-8 mg; 1-7 mg; 1-6 mg; 1-5 mg; 1-4 mg, and the like).

In other aspects, the invention provides a method of aiding a subject in the cessation of tobacco use, the method comprising the administration of any compound, composition, or kava extract herein, wherein said subject is administered one (e.g. , 1, 2, 3, 4, or 5) or more of the group consisting of 75 mg + 25 mg of kavain per day, 40 mg + 20 mg of dihydrokavain per day, 25 mg + 15 mg of methysticin per day, 60 mg + 30 mg of dihydromethysticin per day, and 25 mg + 15 mg of desmethoxyyangonin per day; and 1-25 mg of nicotine per day (e.g. , 1-20 mg, 1- 15 mg, 1- 10 mg, 1-5 mg, and the like). In other aspects, the invention provides a treatment regimen for smoking cessation in a subject, the regimen comprising the administration to the subject any compound, composition, or kava extract herein; and nicotine. In other aspects, the amount of nicotine administered is 1-25 mg per dose or 1-50 mg per day.

In other aspects, the invention provides a treatment regimen for smoking cessation in a subject, the regimen comprising the administration of a composition comprising: 1) at least one (e.g. , 1, 2, 3, 4, or 5) compound selected from kavain, wherein the amount of kavain in the composition is 26 mg + 10 mg; dihydrokavain, wherein the amount of dihydrokavain in the composition is 14 mg + 5 mg;

methysticin, wherein the amount of methysticin in the composition is 8 mg + 5 mg; dihydromethysticin, wherein the amount of dihydromethysticin in the composition is 21 mg + 10 mg; and desmethoxyyangonin, wherein the amount of desmethoxyyangonin in the composition is 8 mg + 5 mg; and 2) nicotine, wherein the amount of nicotine in the composition is 1-25 mg (e.g. , 1-20 mg, 1- 15 mg, 1-10 mg, 1-5 mg, and the like). In another aspect, the subject is non-Caucasian. In another aspect, the subject is African American.

In other aspects, the invention provides a treatment regimen for smoking cessation in a subject, the regimen comprising the administration of any compound, composition, or kava extract herein, wherein said subject is administered one (e.g. , 1, 2, 3, 4, or 5) or more of the group consisting of 75 mg + 25 mg of kavain per day, 40 mg + 20 mg of dihydrokavain per day, 25 mg + 15 mg of methysticin per day, 60 mg + 30 mg of dihydromethysticin per day, and 25 mg + 15 mg of desmethoxyyangonin per day; and 1-50 mg of nicotine per day (e.g. , 1-40 mg, 1-30 mg, 1-25 mg, 1-20 mg, 1-15 mg, 1- 10 mg, 1-5 mg, and the like).

desmethoxyyangonin per day; and 1-50 mg of nicotine per day (e.g. , 1-40, l-30mg, 1- 25 mg, 1-20 mg, 1-15 mg, 1-10 mg, 1-5 mg, and the like). In another aspect, the subject is non-Caucasian. In another aspect, the subject is African American.

a. obtaining a urine sample from the subject;

b. analyzing the urine sample to determine the total nicotine equivalent (TNE);

c. if the TNE is > 30,000 mg/mg creatinine, then administer to the subject a composition comprising kavalactone (e.g. , 26 mg + 10 mg of kavain; 14 mg + 5 mg of dihydrokavain; 8 mg + 5 mg of methysticin; 21 mg +

10 mg of dihydromethysticin; 8 mg + 5 mg of desmethoxyyangonin) and a low dose of nicotine (e.g. , 1-15 mg, 1- 10 mg; 1-9 mg, 1-8 mg; 1- 7 mg; 1-6 mg; 1-5 mg; 1-4 mg, and the like); d. if the TNE is < 30,000 mg/mg creatinine, then then administer to the subject a composition comprising kavalactone (e.g. , 26 mg + 10 mg of kavain; 14 mg + 5 mg of dihydrokavain; 8 mg + 5 mg of methysticin; 21 mg + 10 mg of dihydromethysticin; 8 mg + 5 mg of

desmethoxyyangonin) and a high dose of nicotine (e.g. , 1-25 mg, 1-20 mg, 1- 15 mg, 1- 10 mg, 1-5 mg, and the like).

a. obtaining a urine sample from the subject;

b. analyzing the urine sample to determine the total nicotine equivalent (TNE);

d. if the TNE is < 30,000 mg/mg creatinine, then then administer to the subject a composition comprising kavalactone (e.g. , 26 mg + 10 mg of kavain; 14 mg + 5 mg of dihydrokavain; 8 mg + 5 mg of methysticin; 21 mg + 10 mg of dihydromethysticin; 8 mg + 5 mg of

a. obtaining a urine sample from the subject;

b. analyzing the urine sample to determine the total nicotine equivalent (TNE);

c. if the TNE is > 30,000 mg/mg creatinine, then administer to the subject a composition comprising kavalactone (e.g. , 26 mg + 10 mg of kavain; 14 mg + 5 mg of dihydrokavain; 8 mg + 5 mg of methysticin; 21 mg + 10 mg of dihydromethysticin; 8 mg + 5 mg of desmethoxyyangonin) and a low dose of nicotine (e.g. , 1-15 mg, 1- 10 mg; 1-9 mg, 1-8 mg; 1- 7 mg; 1-6 mg; 1-5 mg; 1-4 mg, and the like); d. if the TNE is < 30,000 mg/mg creatinine, then then administer to the subject a composition comprising kavalactone (e.g. , 26 mg + 10 mg of kavain; 14 mg + 5 mg of dihydrokavain; 8 mg + 5 mg of methysticin; 21 mg + 10 mg of dihydromethysticin; 8 mg + 5 mg of

a. obtaining a urine sample from the subject;

b. analyzing the urine sample to determine the total nicotine equivalent (TNE);

In other aspects, the invention provides a treatment regimen for smoking cessation and inhibiting nicotine metabolism in a subject, the regimen comprising: a. obtaining a urine sample from the subject;

b. analyzing the urine sample to determine the total nicotine equivalent (TNE);

c. if the TNE is > 30,000 mg/mg creatinine, then administer to the subject a composition comprising kavalactone (e.g. , 26 mg + 10 mg of kavain; 14 mg + 5 mg of dihydrokavain; 8 mg + 5 mg of methysticin; 21 mg + 10 mg of dihydromethysticin; 8 mg + 5 mg of desmethoxyyangonin) and a low dose of nicotine (e.g. , 1-15 mg, 1- 10 mg; 1-9 mg, 1-8 mg; 1- 7 mg; 1-6 mg; 1-5 mg; 1-4 mg, and the like); d. if the TNE is < 30,000 mg/mg creatinine, then then administer to the subject a composition comprising kavalactone (e.g. , 26 mg + 10 mg of kavain; 14 mg + 5 mg of dihydrokavain; 8 mg + 5 mg of methysticin; 21 mg + 10 mg of dihydromethysticin; 8 mg + 5 mg of desmethoxyyangonin) and a high dose of nicotine (e.g. , 1-25 mg, 1-20 mg, 1- 15 mg, 1- 10 mg, 1-5 mg, and the like).

a. identifying the high risk patient (e.g. , a patient having a total nicotine equivalent (TNE) of > 30,000 mg/mg creatinine); and

b. administering to the patient a composition comprising kavalactone (e.g. , 26 mg + 10 mg of kavain; 14 mg + 5 mg of dihydrokavain; 8 mg + 5 mg of methysticin; 21 mg + 10 mg of dihydromethysticin; 8 mg + 5 mg of desmethoxyyangonin) and a low dose of nicotine (e.g. , 1- 15 mg, 1- 10 mg; 1-9 mg, 1-8 mg; 1-7 mg; 1-6 mg; 1-5 mg; 1-4 mg, and the like).

In other aspects, the invention provides a kit for treating tobacco addiction in a subject with a total nicotine equivalent (TNE) of > 30,000 mg/mg creatinine in the cessation of tobacco use, comprising: 1) a composition comprising kavalactone (e.g. , 26 mg + 10 mg of kavain; 14 mg + 5 mg of dihydrokavain; 8 mg + 5 mg of methysticin; 21 mg + 10 mg of dihydromethysticin; 8 mg + 5 mg of desmethoxyyangonin) and a low dose of nicotine (e.g. , 1-15 mg, 1-10 mg; 1-9 mg, 1- 8 mg; 1-7 mg; 1-6 mg; 1-5 mg; 1-4 mg, and the like); and 2) instructions for use.

In other aspects, the invention provides a method for aiding tobacco cessation in a subject at high risk of lung cancer comprising administering to the subject with a total nicotine equivalent (TNE) of > 30,000 mg/mg creatinine: 1) a composition comprising kavalactone (e.g. , 26 mg + 10 mg of kavain; 14 mg + 5 mg of

In other aspects, the invention provides a method for decreasing nicotine metabolites in a subject at high risk of lung cancer while undergoing nicotine replacement therapy comprising administering to a subject having TNE of > 30,000 mg/ mg creatine a composition comprising: 1) a composition comprising kavalactone (e.g. , 26 mg + 10 mg of kavain; 14 mg + 5 mg of dihydrokavain; 8 mg + 5 mg of methysticin; 21 mg + 10 mg of dihydromethysticin; 8 mg + 5 mg of

desmethoxyyangonin); and 2) a low dose of nicotine (e.g. , 1-15 mg, 1- 10 mg; 1-9 mg, 1-8 mg; 1-7 mg; 1-6 mg; 1-5 mg; 1-4 mg, and the like).

4 mg, and the like).

5 mg of methysticin; 21 mg + 10 mg of dihydromethysticin; 8 mg + 5 mg of desmethoxyyangonin) and a low dose of nicotine (e.g. , 1-15 mg, 1-10 mg; 1-9 mg, 1- 8 mg; 1-7 mg; 1-6 mg; 1-5 mg; 1-4 mg, and the like). In other aspects, the invention provides a method for aiding tobacco cessation in a subject particularly suitable for such treatment comprising administering to a subject having TNE of > 30,000 mg/ mg creatine a composition comprising: 1) a composition comprising kavalactone (e.g. , 26 mg + 10 mg of kavain; 14 mg + 5 mg of dihydrokavain; 8 mg + 5 mg of methysticin; 21 mg + 10 mg of dihydromethysticin; 8 mg + 5 mg of desmethoxyyangonin); and 2) a low dose of nicotine (e.g. , 1- 15 mg, 1- 10 mg; 1-9 mg, 1-8 mg; 1-7 mg; 1-6 mg; 1-5 mg; 1-4 mg, and the like).

In other aspects, the invention provides a method for decreasing nicotine metabolites in a subject particularly suitable for such treatment while undergoing nicotine replacement therapy comprising administering to a subject having TNE of > 30,000 mg/ mg creatine a composition comprising: 1) a composition comprising kavalactone (e.g. , 26 mg + 10 mg of kavain; 14 mg + 5 mg of dihydrokavain; 8 mg + 5 mg of methysticin; 21 mg + 10 mg of dihydromethysticin; 8 mg + 5 mg of desmethoxyyangonin); and 2) a low dose of nicotine (e.g. , 1-15 mg, 1- 10 mg; 1-9 mg, 1-8 mg; 1-7 mg; 1-6 mg; 1-5 mg; 1-4 mg, and the like). Pharmaceutical Compositions

In another aspect, the invention provides a pharmaceutical composition comprising a kava extract and a pharmaceutically acceptable carrier.

In another aspect, the invention provides a pharmaceutical composition comprising an enriched kava extract and a pharmaceutically acceptable carrier. In one aspect the "enriched" kava extract is enriched in one or more kavalactones selected from kavain, dihydrokavain, methysticin, dihydomethysticin, desmethoxyyangonin, yangonin, and their respective salts.

In another aspect, the invention provides a pharmaceutical composition comprising one or more kavalactones and a pharmaceutically acceptable carrier. In another embodiment, the invention provides a pharmaceutical composition further comprising an additional therapeutic agent. In a further embodiment, the additional therapeutic agent is nicotine. In a further embodiment, the additional therapeutic agent is nicotinea nicotine-containing smoking cessation product (e.g., patch, lozenge, gum, and the like).

In one aspect, the invention provides a kit comprising an effective amount of a kava extract composition, enriched active extract, isolated active agents, in unit dosage form, together with instructions for administering the compound to a subject suffering from or susceptible to tobacco addiction and nicotine addiction.

The term "pharmaceutically acceptable salts" or "pharmaceutically acceptable carrier" is meant to include salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present invention contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric,

monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p- tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, e.g., Berge et al., Journal of Pharmaceutical

Science 66: 1-19 (1977)). Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts. Other pharmaceutically acceptable carriers known to those of skill in the art are suitable for the present invention. The neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention.

In addition to salt forms, the present invention provides compounds which are in a prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. Additionally, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.

Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.

The invention also provides a pharmaceutical composition, comprising an effective amount a compound described herein and a pharmaceutically acceptable carrier. In an embodiment, compound is administered to the subject using a pharmaceutically-acceptable formulation, e.g., a pharmaceutically-acceptable formulation that provides sustained delivery of the compound to a subject for at least 12 hours, 24 hours, 36 hours, 48 hours, one week, two weeks, three weeks, or four weeks after the pharmaceutically-acceptable formulation is administered to the subject.

Actual dosage levels and time course of administration of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic (or unacceptably toxic) to the patient. In use, at least one compound according to the present invention is

administered in a pharmaceutically effective amount to a subject in need thereof in a pharmaceutical carrier by intravenous, intramuscular, subcutaneous, or intracerebro ventricular injection or by oral administration or topical application. In accordance with the present invention, a compound of the invention may be administered alone or in conjunction with a second, different therapeutic. By "in conjunction with" is meant together, substantially simultaneously or sequentially. In one embodiment, a compound of the invention is administered acutely. The compound of the invention may therefore be administered for a short course of treatment, such as for about 1 day to about 1 week. In another embodiment, the compound of the invention may be administered over a longer period of time to ameliorate chronic disorders, such as, for example, for about one week to several months depending upon the condition to be treated.

By "pharmaceutically effective amount" as used herein is meant an amount of a compound of the invention, high enough to significantly positively modify the condition to be treated but low enough to avoid serious side effects (at a reasonable benefit/risk ratio), within the scope of sound medical judgment. A pharmaceutically effective amount of a compound of the invention will vary with the particular goal to be achieved, the age and physical condition of the patient being treated, the severity of the underlying disease, the duration of treatment, the nature of concurrent therapy and the specific organozinc compound employed. For example, a therapeutically effective amount of a compound of the invention administered to a child or a neonate will be reduced proportionately in accordance with sound medical judgment. The effective amount of a compound of the invention will thus be the minimum amount which will provide the desired effect.

A decided practical advantage of the present invention is that the compound may be administered in a convenient manner such as by intravenous, intramuscular, subcutaneous, oral or intra-cerebroventricular injection routes or by topical application, such as in creams or gels. Depending on the route of administration, the active ingredients which comprise a compound of the invention may be required to be coated in a material to protect the compound from the action of enzymes, acids and other natural conditions which may inactivate the compound. In order to administer a compound of the invention by other than parenteral administration, the compound can be coated by, or administered with, a material to prevent inactivation. The compound may be administered parenterally or intraperitoneally.

Dispersions can also be prepared, for example, in glycerol, liquid polyethylene glycols, and mixtures thereof, and in oils.

The pharmaceutical forms suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the

extemporaneous preparation of sterile injectable solutions or dispersions. In all cases the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage. The carrier can be a solvent or dispersion medium containing, for example, water, DMSO, ethanol, polyol (for example, glycerol, propylene glycol, liquid polyethylene glycol, and the like), suitable mixtures thereof and vegetable oils. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion. In many cases it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions are prepared by incorporating the compound of the invention in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization.

Generally, dispersions are prepared by incorporating the various sterilized compounds into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum-drying and the freeze-drying technique which yields a powder of the active ingredient plus any additional desired ingredient from previously sterile-filtered solution thereof.

For oral therapeutic administration, the compound may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. Compositions or preparations according to the present invention are prepared so that an oral dosage unit form contains compound concentration sufficient to treat a disorder in a subject.

Some examples of substances which can serve as pharmaceutical carriers are sugars, such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethycellulose, ethylcellulose and cellulose acetates; powdered tragancanth; malt; gelatin; talc; stearic acids; magnesium stearate; calcium sulfate; vegetable oils, such as peanut oils, cotton seed oil, sesame oil, olive oil, corn oil and oil of theobroma; polyols such as propylene glycol, glycerine, sorbitol, manitol, and polyethylene glycol; agar; alginic acids; pyrogen-free water; isotonic saline; and phosphate buffer solution; skim milk powder; as well as other non-toxic compatible substances used in pharmaceutical formulations such as Vitamin C, estrogen and echinacea, for example. Wetting agents and lubricants such as sodium lauryl sulfate, as well as coloring agents, flavoring agents, lubricants, excipients, tableting agents, stabilizers, anti-oxidants and preservatives, can also be present.

Topical administration of the pharmaceutical compositions of this invention is especially useful when the desired treatment involves areas or organs readily accessible by topical application. For topical application topically to the skin, the pharmaceutical composition should be formulated with a suitable ointment, lotion, or cream containing the active components suspended or dissolved in a carrier. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax, and water.

Alternatively, the pharmaceutical composition can be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water. The pharmaceutical compositions of this invention may also be topically applied to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation. Topically-transdermal patches and iontophoretic administration are also included in this invention.

For topical administration, the active compound(s), extracts, enriched extracts, or prodrug(s) can be formulated as solutions, gels, ointments, creams, suspensions, and the like.

The recitation of a listing of chemical groups in any definition of a variable herein includes definitions of that variable as any single group or combination of listed groups. The recitation of an embodiment for a variable herein includes that embodiment as any single embodiment or in combination with any other

embodiments or portions thereof. The recitation of an embodiment herein includes that embodiment as any single embodiment or in combination with any other embodiments or portions thereof.

Examples

Example 1: UPLC-MS2 Method for Quantifying Kavalactones

To date, a number of analytical methods have been developed to quantify different kavalactones in kava, including high performance liquid chromatography (HPLC), liquid chromatography - mass spectrometry (LC-MS), and nuclear magnetic resonance spectroscopy (NMR) [Martin AC, Johnston E, Xing C, Hegeman AD. Measuring the Chemical and Cytotoxic Variability of Commercially Available Kava (Piper methysticum G. Forster). PLoS One. 2014;9(l l):el 11572. doi: 10.1371/journal.pone.0111572. PubMed PMID: 25365244; PubMed Central PMCJD: PMC4218769; Bilia AR, Bergonzi MC, Lazari D, Vincieri FF. Characterization of commercial kava-kava herbal drug and herbal drug preparations by means of nuclear magnetic resonance spectroscopy. Journal of agricultural and food chemistry. 2002;50(18):5016-25. Epub 2002/08/22. PubMed PMID: 12188601; He XG, Lin LZ, Lian LZ. Electrospray high performance liquid chromatography-mass spectrometry in phytochemical analysis of kava (Piper methysticum) extract. Planta medica. 1997;63(l):70-4. Epub 1997/02/01. doi: 10.1055/s-2006-957608. PubMed PMID: 17252331; Bobeldijk I, Boonzaaijer G, Spies-Faber EJ, Vaes WH. Determination of kava lactones in food supplements by liquid chromatography- atmospheric pressure chemical ionisation tandem mass spectrometry. J Chromatogr A. 2005;1067(1-2): 107- 14.]. Lebot and his colleagues have also developed a UV-vis spectrometry method for kavalactone quantification [Lasme P, Davrieux F, Montet D, Lebot V. Quantification of kavalactones and determination of kava (Piper methysticum) chemotypes using near-infrared reflectance spectroscopy for quality control in Vanuatu. Journal of agricultural and food chemistry. 2008;56(13):4976-81. doi: 10.1021/jf800439g. PubMed PMID: 18540613.]. Recently, the same group developed a high performance thin layer chromatography method to measure three chalcone-based flavokavains in kava [Lebot V, Do TK, Legendre L. Detection of flavokavins (A, B, C) in cultivars of kava (Piper methysticum) using high performance thin layer chromatography (HPTLC). Food Chem. 2014;151:554-60. doi: 10.1016/j.foodchem.2013.11.120. PubMed PMID: 24423570.], which does not require high-end instrumentations and would be more applicable to the on-site testing. Supercritical fluid chromatography has also been employed to quantify the major kavalactones in kava products [Murauer A, Ganzera M. Quantitative Determination of Lactones in Piper methysticum (Kava- Kava) by Supercritical Fluid Chromatography. Planta Med. 2017. doi: 10.1055/s- 0043-100632. PubMed PMID: 28095587.]. The main limitations of these methods are either the lack of structural confirmation or the low detecting sensitivity, which limits the unambiguous and quantitative analyses of different kava products.

Such issues of these analytical methods also limit kava's pharmacokinetic characterizations. Although there have been numerous studies that evaluated the pharmacology of kava for different indications and kava has been widely practiced in humans as an anxiolytic agent and a dietary supplement, there has been very few pharmacokinetic characterizations of kava, even in animal models [Anke J, Ramzan I. Pharmacokinetic and pharmacodynamic drug interactions with Kava (Piper methysticum Forst. f.). Journal of ethnopharmacology. 2004;93(2-3): 153-60. doi: 10.1016/j.jep.2004.04.009. PubMed PMID: 15234747.]. GC-MS [Keledjian J, Duffield PH, Jamieson DD, Lidgard RO, Duffield AM. Uptake into Mouse Brain of Four Compounds Present in the Psychoactive Beverage Kava. Journal of Pharmaceutical Sciences. 1988;77(12): 1003-6.] or HPLC [Mathews JM, Etheridge AS, Valentine JL, Black SR, Coleman DP, Patel P, et al. Pharmacokinetics and disposition of the kavalactone kawain: interaction with kava extract and kavalactones in vivo and in vitro. Drug Metab Dispos. 2005;33(10): 1555-63.] has been employed to study kava's pharmacokinetics in animal models at dosages significantly higher than human relevant exposure [Dams R, Huestis MA, Lambert WE, Murphy CM. Matrix effect in bio-analysis of illicit drugs with LC-MS/MS: influence of ionization type, sample preparation, and biofluid. Journal of the American Society for Mass Spectrometry. 2003;14(l l): 1290-4; King R, Bonfiglio R, Fernandez-Metzler C, Miller-Stein C, Olah T. Mechanistic investigation of ionization suppression in electrospray ionization. Journal of the American Society for Mass Spectrometry. 2000; 11(11):942-50.]. Only one pharmacokinetic study in humans has ever been reported, which used kavain alone at a dose of 800 mg, again much higher than the recommended dose of the total kavalactones in kava for human use (200 - 300 mg/person daily) [Tarbah F, Mahler H, Kardel B, Weinmann W, Hafner D, Daldrup T. Kinetics of kavain and its metabolites after oral application. Journal of chromatography B, Analytical technologies in the biomedical and life sciences. 2003;789(l): 115-30. PubMed PMID: 12726850.]. The lack of the pharmacokinetic knowledge of kava limits its rational pharmacological evaluation and application.

To address these issues, an ultraperformance liquid chromatography tandem mass spectrometry (UPLC-MS ) based method has been developed, employing high- resolution accurate mass spectrometric measurement with an Orbitrap mass spectrometer, to unambiguously and sensitively quantify five major kavalactones (kavain, DHK, methysticin, DHM and desmethoxyyangonin) using a deuterium- labeled DHM ( H₂-DHM) as an internal standard. This method quantified these kavalactones in different kava products, characterized the pharmacokinetics and biodistribution of these major kavalactones in C57BL/6 mice when the kava extract was administered via gavage at a dose of 41 mg/kg body weight, relevant to the human clinical dose, and this method successfully detected and quantified these five kavalactones in human urine and plasma samples in human subjects (n = 2). The human results demonstrate the capability of this UPLC-MS based method to characterize kava's pharmacokinetics in humans in the future.

Materials and Methods

One kava product in the ethanolic extract format (standardized to 150 mg/mL total kavalactones) was purchased from Gaia Herbs, Inc. (Brevard, NC). Another dietary supplement kava product in the soft-gel capsule format (75 mg total kavalactone per capsule) was also purchased directly from Gaia Herbs, Inc. Kavain, DHK,

methysticin, DHM and desmethoxyyangonin were isolated from the ethanolic kava with their structures confirmed via NMR and mass spectrometric analyses as reported before [Shaik AA, Hermanson DL, Xing C. Identification of methysticin as a potent and non-toxic NF- kappa B inhibitor from kava, potentially responsible for kava's chemopreventive activity. Bioorganic & medicinal chemistry letters.

2009; 19( 191:5732-6. doi: 10.1()16/j.bmcl.2()09.()8.003. PubMed PMID: 19716299; PubMed Central PMCID: PMC2756981 .]. A deuterium labeled dihydromethysticin (Ήι-ΟΗΜ) was synthesized following our published procedures with slight modifications [Shaik AAT, J.; Lu, J.; Xing, C. Economically viable efficient synthesis of (±)-Methysticin - A component in kava potential responsible for its cancer chemopreventive activity. Arkivoc. 2012; viii: 137-45.], which was used as the internal standard for quantification. LC-MS grade water, formic acid, methanol and acetonitrile were purchased from Sigma- Aldrich (St. Louis, MO). All other chemicals were ACS grade unless stated otherwise. SOLA HRP solid-phase extraction (SPE) cartridges (10 nig) were purchased from Fisher Scientific (Rock ford. 1L).

Animal Studies

All experiments were carried out using male C57BL/6J mice (The Jackson

Laboratory, Bar Harbor, ME) of 10 weeks old. Mice were kept in groups of five in a temperature-controlled room with 12-hour light/dark cycle. Food and water were available ad libitum until the time of the experiment. All mice were housed, tested, and cared for in accordance with the 2011 National Institutes of Health Guide for the Care and Use of Laboratory Animals, and handled according to the animal welfare protocols approved by Institutional Animal Care and Use Committee at the University of Florida.

Mice were administered kava or vehicle (PEG400, 200 μί) through the per os (p.o., or oral) route and euthanized by C0₂ administration at various time points from 0.5, 1.5, 4, 8 or 24 hours post-administration. Urines were collected upon

euthanization. Blood (200 - 250 μί) was collected from mice by cardiac puncture with serum prepared. Tissues, including lung, liver, and brain, were harvested, weighed, flash frozen in liquid nitrogen. All samples were stored at - 80 °C till processing.

Human Studies

Urine and plasma samples were obtained from a clinical trial conducted at the University of Minnesota in which healthy adult cigarette smokers took the

commercial soft-gel formulation of kava manufactured by Gaia Herbs at the manufacturer's recommended dose of 1 capsule three times daily for 7 days. Subjects had normal kidney and liver function. A spot urine sample was collected prior to kava, and a 24 hour urine sample was on day 6-7 of the 7-day kava intervention.

Plasma was obtained prior to kava, and on days 6 or 7 of the 7-day kava intervention. Kava compliance was determined by pill counts and dosing diaries completed by each subject.

Optimized Conditions for Kavalactone Ionization, Detection and Quantification via Ultraperformance Liquid Chromatography-electro spray Ionization-tandem Mass

Spectrometry (UPLC-MS²) Mass spectra of kavain, DHK, methysticin, DHM, and desmethoxyyangonin were first acquired by direct infusion of the pure kavalactones with a Q Exactive Hybrid Quadrupole Orbitrap Mass Spectrometer (Thermo Fisher Scientific, San Jose, CA) and a Heated Electrospray Ionization (HESI-II) (Thermo Fisher Scientific, San Jose, CA) at a flow rate of 5 /jL/min. Instrument tuning parameters have been optimized as follows: sheath gas, 5; auxiliary gas, 0; capillary temperature, 300 °C; spray voltage, 4 kV; maximum injection time, 200 ms for MS .

For kavalactone quantification, the samples were assayed by UPLC-MS employing a Dionex Ultimate 3000 RS and a Q Exactive Hybrid Quadrupole Orbitrap Mass Spectrometer. Briefly, the samples prepared from different kava products, tissues, serum, plasma or urine samples (5 /JL) were resolved through an Atlantis del 8 column (150 x 2.1 mm, 3 μπι particle size, 100 A) with a 25 min linear gradient from 99% A (H₂0 with 1 % CH₃CN and 0.05% HC0₂H) to 99% B (CH₃CN with 5% H₂0 and 0.05% HC0₂H) at a flow rate of 250 ^L/min. Chromeleon 7.2

Chromatography Data System was used for the UPLC management. The parameters for Heated Electrospray Ionization (HESI-II) were set as follows: sheath gas, 50; auxiliary gas, 15; auxiliary gas temperature, 300 °C; capillary temperature, 300 °C; spray voltage, 4 kV; 1 /jscan; maximum injection time, 200 ms for MS ; HCD, 20 for all kavalactones. Resolution was set as 17,500 at m/z 200 for MS . The isolation width

2

was set at m/z 1 for MS scan modes. AGC (automated gain control) was set at 50,000 for Orbitrap (FT) MS . The Orbitrap was routinely calibrated in the positive ion mode using Pierce LTQ Velos ESI Positive Ion Calibration Solution (2 μg/mL caffeine, 1 <g/mL MRFA, 0.001% Ultramark 1621 and 0.00005% n-butylamine). Calibration Curves for Kavalactone Quantification

For the quantification of kavalactones in kava products, a seven-point calibration curve was constructed with DHM in 10% CH₃OH (0, 0.05, 0.10, 0.50, 1.00, 2.50 and 5.00 pg jiL). [ H₂]-DHM was added at a level of 2.50 pg//iL as the internal standard. For the quantitative analyses of kavalactones in mouse samples, a ten-point calibration curve was constructed, adding DHM (0, 2.5, 5, 10, 50, 150, 250, 500,

2500, and 5000 pg/mg tissue) to the processed tissue samples from the control group.

[²H₂]-DHM was added at 50 pg/mg tissue or 100 pg/μ serum (360 nM) as the internal standard. For the quantitative analyses of kavalactones in human samples, a seven-point calibration curve was constructed, adding DHM (0, 0.05, 0.10, 0.20, 0.50, 1.00, and 2.00 pg/£iL sample) to the urine or plasma samples collected before the subject took the kava capsule. [ H₂]-DHM was added at 1 pg//jL urine or plasma (3.6 nM) as the internal standard. DHM and [ 2 H₂]-DHM were measured at the MS 2 scan stage using product ions at mJz 277.1 > 131.0490, 135.0438, 161.0593 and m/z 279.1 > 131.0490, 137.0564, 163.0719 at a mass accuracy window of + 5 ppm, respectively. The amounts of the other four kavalactones were estimated using the DHM

calibration curves but corrected by ratios of ion peak areas of kavalactones to DHM (FIG. 3). Kava Sample Preparation

The ethanolic kava product was dried under vacuum to remove the solvent, resulting in an oil. Such an oil was dissolved in dimethyl sulfoxide (D SO) to make a kava stock solution (1 mg/mL). The stock solution was diluted to a final concentration of 10 pg//iL in 10% CH₃OH in H₂0 for UPLC-MS² analysis. [ H₂J-DHM was post- added as the internal standard at a level of 2.5 pg/juL. For the kava soft-gel capsule product, all materials (kava extract and its carriers) in a capsule were transferred to a clean Eppendorf tube and weighed. Such materials were dissolved in DMSO to make a stock solution (1 mg/mL). The stock solution was diluted to a final concentration of 10 pg/_juL in 10% CH₃OH in H₂0 for UPLC-MS² analysis. [²H₂]-DHM was post- added as the internal standard at a level of 2.5 pg/μh.

Pharmacokinetics of the Ethanolic Kava Extract in C57/BL6J Mice

The ethanolic kava product was dried under vacuum to remove the solvent. The oily residue was dissolved in polyethylene glycol 400 (PEG400) at a concentration of 5 mg/mL. At the age of 10 weeks, male C57BL/6J mice were randomized into six groups (n-3 for each group). The average body weight was 24.5 g/mouse. Mice in the control group were given PEG400 (200 //L) via gavage once. Each mouse in the treatment group was administered kava in PEG400 (5 mg/mL. 200 iL) via gavage once (a dose of -41 mg/kg body weight). Mice were euthanized by C0₂ asphyxation 0.5 - 24 hours after kava administration. Mice in the control group were euthani/cd 24 hours after PEG400 administration. Serum, urine, lung, liver and brain tissues of each mouse were collected and stored at - 80 "C till analysis. Each sample was processed individually. Generally, kavalactones were recovered from the mouse samples by an ethyl acetate liquid extraction followed by a solid phase extraction as reported before [Wang Y, Villalta PW, Peng L, Dingley K, Malfatti MA, Turteltaub KW, et al. Mass Spectrometric Characterization of an Acid-Labile Adduct Formed with 2-Amino-l-methyl-6-phenylimidazo[4,5-b]pyridine and Albumin in Humans. Chemical research in toxicology. 2017. Epub 2016/12/17. doi: 10.1021/acs.chemrestox.6b00426. PubMed PMID: 27984695.].

Briefly, mouse liver, lung or brain tissues (~5 mg wet weight, rinsed once with H₂0) were mechanically homogenized in H₂0 (180 /JL, LC-MS grade) with 0.1% formic acid (HC0₂H) using a Teflon glass tissue grinder (Thomas Scientific). The [ H₂]-DHM internal standard was added at the level of 50 pg/mg tissue. After sonication for 5 min, tissue homogenate (20 μΥ was mixed with methanol (900 /JL, - 20 °C). Mouse serum or urine samples (5 /JL), added with [ H₂]-DHM at the level of 100 pg/juL, were mixed with cold CH₃OH (495 /JL, -20 °C). From here, all samples were processed following the same procedures below.

After vortexing, the mixture was kept at -20 °C for 30 min, and centrifuged at 13,000 g for 20 min to remove the proteins and debris. The supernatant was transferred to a clean Eppendorf tube, vacuum centrifuged to dryness, and

resuspended in H₂0 (100 μΥ . Kavalactones were extracted by a liquid extraction with ethyl acetate (600 /JL). After vortexing, the ethyl acetate layer was transferred to a clean Eppendorf tube, vacuum centrifuged to dryness, and resuspended in 10% CH₃OH in H₂0 (1 mL). The mixture was then applied to a SOLA HRP cartridge

(Thermo Fisher) (10 mg), which was pre-conditioned with CH₃OH (1 mL) and H₂0 (1 mL). Upon rinsing with 10% CH₃OH in H₂0 (2 mL), kavalactones were eluted with 100% CH₃OH (1 mL). The elute was vacuum centrifuged to dryness. The residue was resuspended in 10% CH₃OH in H₂0 with 0.1% HC0₂H (100 /JL), transferred to an HPLC vial (Chrom Tech, Apple Valley, MN), and analyzed with the same targeted UP LC- S method for kavalactone quantification.

Pharmacokinetics Calculations

Peak plasma concentration (C_max) of kavain, DHK, methysticin, DHM and desmethoxyyangonin and time to reach the C_max (t_max) in serum/tissue homogenates were recorded directly from the raw data of concentration-time profile. The mean concentration-time data of serum (ng/mL) and tissue (liver, lung and brain) homogenates (ng/g) were subjected to non-compartmental analysis using Phoenix™, version 6.4.0.768 (Certara Inc, Missouri, USA). The area under the serum/tissue concentration-time up to the last observation (AUCo-t) was calculated using the linear trapezoidal method. Mean residence time (MRT) was calculated as AUMCo AUCo-t ratio, where AUMCo-t is the area under the first moment curve up to the last observation. Oral clearance (Cl/F) was determined as Cl/F= Dose/ AUCo-t-

Quantification of Kavalactones in Human Plasma and Urine

r¾]-DHM was added as the internal standard at a level of 1 pg//jL (3.6 nM) urine or plasma. To the plasma samples (100 /JL), CH₃OH (1 mL, -20 °C) was added to precipitate proteins. The mixture was centrifuged at 13,000 g for 20 min. The supernatant was transferred to a 2-mL Eppendorf tube, vacuum centrifuged to dryness, resuspended in 10% CH₃OH in H₂0 (100 μΥ followed by the addition of ethyl acetate (600 /JL). The urine sample (100 μΥ was directly mixed with ethyl acetate (600 μΥ . The ethyl acetate extraction, solid phase extraction and the targeted UPLC-MS" methods were the same as described above for the mouse

pharmacokinetic studies.

Method Validation

For the mouse study, the method was validated based on the accuracy, within- day and between-day reproducibility using mouse liver tissues of the control group added with DHM at a level of 50 pg/mg tissue. For the human study, the method was validated based on the accuracy, within-day and between-day reproducibility using the pre-kava urine sample added with DHM at a level of 1 pg//jL (3.6 nM) urine. The reproducibility studies were based on three independent measurements on three different days. The accuracy and percent coefficient of variation (CV%) were used as the criteria for the precision and reproducibility of the method.

Statistical Analysis

Data were presented as mean + standard deviation (SD). Differences were evaluated by two-tailed student i-test analysis at 95% confidence interval using SigmaPlot 12.0 (Systat Software Inc., San Jose, CA, USA).

Mass Spectral Analysis of Kavalactones

The mass spectra of kavain, DHK, methysticin, DHM, and desmethoxyyangonin

₂

at the full MS and MS scan stages were acquired by direction infusion of the pure standards. The observed ions [M+H]⁺ of all five kavalactones at the full MS scan stage had excellent agreement with the calculated m/z values (within 1 ppm, data not shown). The reconstructed ion chromatograms and product ion spectra of the kavalactone standards were also assayed online by UPLC-MS (FIG. 3). The product ion spectra of these kavalactones acquired by online UPLC-MS had excellent agreement with the spectra acquired by direct infusion. The product ion mass spectrum of kavain showed major ions at m/z 115.0541 (observed vs. calculated 115.0542, Δ0.9 ppm), m/z 153.0693 (observed vs. calculated 153.0699, Δ3.9 ppm) and m/z 185.0954 (observed vs. calculated 185.0961, Δ3.8 ppm). The product ion mass spectrum of DHK displayed ions at m/z 91.0545 (observed vs. calculated

91.0542, Δ3.3 ppm), m/z 117.0698 (observed vs. calculated 117.0699, Δ0.9 ppm), m/z 155.0849 (observed vs. calculated 155.0855, Δ3.9 ppm), and m/z 187.1113 (observed vs. calculated 187.1117, Δ2.1 ppm). A major ion at m/z 159.0435 (observed vs.

calculated 159.0435, Δ0 ppm) was detected in the mass spectrum of methysticin at the MS scan stage. The product ion mass spectrum of DHM showed major product ions at m/z 131.0488 (observed vs. calculated 131.0491 , Δ2.3 ppm), m/z 135.0437

(observed vs. calculated 135.0441, Δ3.0 ppm) and m/z 161.0591 (observed vs.

calculated 161.0597, Δ3.7 ppm). The parent ion of desmethoxyyangonin underwent fragmentation to produce product ions at m/z 131.0488 (observed vs. calculated 131.0491, Δ2.3 ppm), m/z 141.0693 (observed vs. calculated 141.0699, Δ4.3 ppm) and m/z 201.0901 (observed vs. calculated 201.0910, Δ4.5 ppm). Through these high- resolution based MS features, the chemical structures of these five kavalactones in different samples were confirmed. Kavalactone Composition of Two Commercial Forms of Kava

The targeted UPLC-MS method was utilized to quantify kavain, DHK, methysticin, DHM, and desmethoxyyangonin in two kava products (FIG. 4). The linearity of the calibration curve of DHM with [ ¾]-DHM was confirmed by the slope (s = 1.0165 + 0.0093) and the linear regression value (r² = 0.9996) (FIG. 5). The ions at m/z 131.0491, m/z 135.0441 and m/z 161.0597 were used to determine the limit of detection (LOD) and the limit of quantification (LOQ) of DHM. The LOD and LOQ were estimated by the 3.3a/s and ΙΟσ/s, respectively (σ is the standard deviation of the slope (s) of the calibration curve) [Fan H, Shao ZY, Xiao YY, Xie ZH, Chen W, Xie H, et al. Incidence and survival of non-small cell lung cancer in Shanghai: a population-based cohort study. BMJ open. 2015;5(12):e009419. doi: 10.1136/bmjopen-2015-009419. PubMed PMID: 26700282; PubMed Central PMCID: PMC4691760.]. The LOD and LOQ of DHM were estimated at 0.027 pg/^L and 0.081 pg _juL, respectively. Since kavain, DHK, methysticin and desmethoxyyangonin are structurally similar to DHM, LOD and LOQ of kavain, DHK, methysticin and desmethoxyyangonin were estimated using [ ¾]-DHM as the internal standard by the ratios of the ion peak areas of individual kavalactones to the ion peak area of [ 2 ¾]-DHM when the same amounts of these kavalactones and [ 2 ¾]- DHM were analyzed by UPLC-MS² analysis (FIG. 3) [Stokvis E, Rosing H, Beijnen JH. Stable isotopically labeled internal standards in quantitative bioanalysis using liquid chromatography/mass spectrometry: necessity or not? Rapid communications in mass spectrometry : RCM. 2005;19(3):401-7. Epub 2005/01/13. doi: 10.1002/rcm.l790. PubMed PMID: 15645520.]. LOD values of kavain, DHK, methysticin and desmethoxyyangonin were estimated at 0.118 pg/_juL, 0.026 pg/_juL, 0.155 pg/_juL and 0.081 pg/_juL, respectively. LOQ values of kavain, DHK, methysticin and desmethoxyyangonin were estimated at 0.353 pg/_juL, 0.077 pg//jL, 0.464 pg/μh and 0.243 pg/_juL, respectively.

For the ethanolic kava extract, DHK (0.247 + 0.018 g/ g kava; 39.1%) and kavain (0.172 + 0.030 g/ g kava; 27.2%) were the most abundant kavalactones, followed by desmethoxyyangonin (0.103 + 0.011 g/ g kava; 16.2%), DHM (0.089 + 0.008 g/ g kava; 14.1%), and methysticin (0.021 + 0.009 g/ g kava; 3.4%) (FIG. 4). These five kavalactones account for ~ 63% of the mass balance of the ethannolic kava extract. Their abundance was generally higher than that determined previously via the large-scale silica gel chromatography-based isolation except for methysticin (DHK, 0.156 g/g kava; kavain, 0.150 g/g kava; desmethoxyyangonin, 0.064 g/g kava; DHM, 0.075 g/g kava; and methysticin, 0.033 g/g kava) [Leitzman P, Narayanapillai SC, Balbo S, Zhou B, Upadhyaya P, Shaik AA, et al. Kava blocks 4-(methylnitrosamino)- l-(3-pyridyl)-l-butanone-induced lung tumorigenesis in association with reducing 06-methylguanine DNA adduct in A/J mice. Cancer prevention research

(Philadelphia, Pa). 2014;7(l):86-96. doi: 10.1158/1940-6207.CAPR- 13-0301.

PubMed PMID: 24403291; PubMed Central PMCID: PMC3888881.]. The lower value determined via isolation was at least partially due to the inevitable loss of materials during the isolation processes. Overall, the abundance determined by both methods demonstrated that these five kavalactones were highly abundant in the ethanolic extract form of kava from Gaia Herbs. For the soft-gel kava capsule, the estimated total amount of these five major kavalactones was 77 + 4 mg/capsule, consistent with the labeled 75 mg total kavalactones per capsule. However, the relative abundance of these five kavalactones in the kava capsule was quite different from that in the ethanolic kava extract. In the capsule, kavain (33.7%) and DHM (27.3%) were the most abundant kavalactones, followed by DHK (18.2%), desmethoxyyangonin (10.4%) and methysticin (10.4%) (FIG. 3). The relative abundance of methysticin was 3.1 times in the kava capsule in comparison to the ethanolic kava extract. The abundance of DHM was 1.9 times in the kava capsule relative to the ethanolic kava extract. On the other hand, the abundance of DHK in the kava capsule was less than half of that in the ethanolic kava extract while the abundance of kavain is comparable in both forms of kava products. There is a significant difference of desmethoxyyangonin with respect to its relative abundance in these two kava products as well. Through the comparison of the five major

kavalactones in two kava products from the same company, our results substantiate the fact that dietary supplement kava products on the market can differ significantly in their chemical compositions. Such products are expected to induce different pharmacology and potentially reveal different safety profiles. The current

standardization, the abundance of total kavalactone, therefore, is likely not sufficient.

Method Validation and Pharmacokinetic Studies in C57BL/6J Mice

The linearity of the calibration curve of DHM with [ H₂]-DHM was confirmed by the slope (s = 1.0487 + 0.0048) and the linear regression value (r² = 0.9994) (FIG. 6). The LOD and LOQ of the five kavalactones were estimated by following the same procedures above. The LOD values of kavain, DHK, methysticin, DHM and desmethoxyyangonin in the tissues were estimated at 3.32 pg/mg tissue, 0.71 pg/mg tissue, 4.32 pg/mg tissue, 0.76 pg/mg tissue, and 2.28 pg/mg tissue, respectively; and the LOQs were estimated at 9.99 pg/mg tissue, 2.13 pg/mg tissue, 13.11 pg/mg tissue, 2.29 pg/mg tissue and 6.87 pg/mg tissue, respectively. For the serum and urine samples, the LOD values of kavain, DHK, methysticin, DHM, and desmethoxyyangonin were estimated at 24 nM, 5.1 nM, 31.5 nM, 5.5 nM and 16.5 nM, respectively. The LOQ values were estimated at 75.9 nM, 16.2 nM, 99.6 nM, 17.4 nM and 52.2 nM, respectively. To validate the method, three independent measurements were performed to quantify spiked kavalactones (kavain, DHK, methysticin, DHM and

desmethoxyyangonin, each 50 pg/mg of tissue) in the control mouse liver tissues on three different days. The accuracy values of DHM were 106.2%, 101.8% and 93.2% respectively on three different days with the standard deviation of 3.6-6.5%. The coefficient of variation (CV%) values for the intraday and interday precision were 10.5% and 11.8%, respectively. Similar results were obtained for the other four kavalactones (FIG. 7). The reproducibility of the method was evaluated by three independent measurements on three different days of the five kavalactones in the mouse liver tissues collected 1.5-hours after kava treatment. The CV% values for the intraday and interday precision for DHM were 6.8% and 8.7%. Similar data were obtained for the other four kavalactones. The mass spectrum of DHM in the mouse liver tissue had an excellent agreement with the DHM standard.

Upon validation, this targeted UPLC-MS method was used to quantify the five major kavalactones in the mouse serum, liver, lung, and brain tissues at different time points (0.5, 1.5, 4, 8 and 24 h) after the single oral gavage administration of the ethanolic extract kava at a dose of 41 mg/kg body weight. Given that kavalactones account for around 60% of the mass of this kava extract (FIG. 4), such a dose would be comparable to a dose of 150 mg total kavalactone for a human of 75 kg bodyweight according to the body surface area normalization method [Reagan-Shaw S, Nihal M, Ahmad N. Dose translation from animal to human studies revisited. FASEB J. 2008;22(3):659-61. doi: 10.1096/fj.07-9574LSF. PubMed PMID: 17942826.], within the range of the recommended human daily dosage of kava (typically between 200 - 300 mg total kavalactones daily)[Savage KM, Stough CK, Byrne GJ, Scholey A, Bousman C, Murphy J, et al. Kava for the treatment of generalised anxiety disorder (K-GAD): study protocol for a randomised controlled trial. Trials. 2015;16:493. doi: 10.1186/sl3063-015-0986-5. PubMed PMID: 26527536; PubMed Central PMCID: PMC4630875.]. The results of the pharmacokinetics and biodistribution of these kavalactones are shown in FIG. 8. For the mice without kava treatment, kavalactones were below the LOD in all of the serum and tissue samples. In kava-treated mice, kavain, DHK, methysticin and DHM were all above the LOD in all samples at all of the time points. The amount of desmethoxyyangonin was generally less than the other four kavalactones, particularly at the later-time point samples and it was below the LOD in the lung samples at the 4- hour time point and in the serum samples at the 8- and 24-hour time points. Interestingly, considerate amount of desmethoxyyangonin was detected in the urine samples (FIG. 9E), suggesting that desmethoxyyangonin was quickly secreted via the urine. As expected, the highest concentrations of these kavalactones were achieved in the liver tissues, reaching their maximum concentrations 0.5 hours after kava oral administration and decreasing thereafter (FIG. 8A). The concentrations of kavain and dihydrokavain in the liver tissues could reach 10 - 15 ng/mg tissues, equivalent to a concentration of 40 - 60 μΜ. The highest abundance of the other three kavalactones in the liver tissues were 2 - 4 ng/mg tissues, equivalent to 10 - 15 μΜ. In the lung tissues (FIGs. 10A-10D), kavalactones were readily detected 0.5 hours after kava administration as well. However their concentrations reached the maximum levels at the 1.5-hour time point. The maximum abundance of kavain, DHK, methysticin, DHM and desmethoxyyangonin in the lung tissues were ~3, 2.3, 0.5, 1.0 and 0.4 ng/mg tissue, roughly equivalent to the concentrations of 12, 10, 2, 4 and 1.5 μΜ respectively. The biodistribution and pharmacokinetics of these five kavalactones in the brain tissues (FIG. 8C) were similar to the lung tissues with their maximum abundance reached at the 1.5 -hour time point as well except that their abundance were lower in the brain relative to the lung tissues, particularly at the 0.5 and 1.5-hour time points. The pharmacokinetics of these five kavalactones in the serum samples, however, were quite different from those in the tissues (FIG. 8D). Although the maximum abundance of these kavalactones were detected in the samples collected at the 1.5-hour time point, there were relatively smaller dynamic changes of their abundance over the 24-hour time period in comparison to the liver, lung and brain tissues, particularly for DHK and DHM that their concentrations remained at ~1 μΜ even 24 hours after the single dose kava exposure. The maximum concentrations of these kavalactones were between 2 - 4 μΜ except for desmethoxyyangonin, which is below 0.5 μΜ.

These data overall demonstrate that all of the five kavalactones are orally available and can cross the blood-brain barrier. They, kinetically, reached the liver tissues first followed by the serum, lung and brains tissues, consistent with its oral route of administration [Turner PV, Brabb T, Pekow C, Vasbinder MA. Administration of substances to laboratory animals: routes of administration and factors to consider. Journal of the American Association for Laboratory Animal Science : JAALAS. 2011;50(5):600-13. Epub 2012/02/15. PubMed PMID: 22330705; PubMed Central PMCID: PMCPMC3189662.]. These kavalactones, except desmethoxyyangonin, were in the sub μΜ concentrations in all tissues even 24 hours after the single oral dose of kava. Given their relatively slow clearance, it is possible that a single-dose of kava may result in long-term pharmacodynamics, particularly if DHM and DHK are the bioactive ingredients. Further investigation is warranted to determine whether one dose of kava daily is sufficient or whether kava needs to be taken 3 times daily as currently recommended. The concentrations of these kavalactones in different mouse tissues also provided information for future ex vivo experiments in the context of the in vivo relevance. On the other hand, these five kavalactones also appeared to have differential preference towards tissues. The ratios of individual kavalactone to total kavalactones in the serum, urine and tissues at different time point after kava oral gavage are shown in FIGs. 9A-9E. Kavain, DHK, and DHM, particularly DHK, appeared to have no significant tissue preference (FIGs. 9A, 9B and 9D). Less methysticin was detected in the urine at all the time point and relative more methysticin was retained in the brain (FIG. 9C). On the other hand, the relative abundance of desmethoxyyangonin in serum and tissues was lower than its natural abundance while its abundance in the urine was higher than its natural abundance (FIG. 9E), suggesting a quick clearance of desmethoxyyangonin in vivo.

Serum/tissue pharmacokinetic parameters of kavain, DHK, methysticin, DHM and desmethoxyyangonin in male C57BL/6 mice are shown in FIG. 11. Tissue-to- serum AUCo-t ratios were highest for liver, suggesting that maximum distribution of kavalactones in liver. They also showed adequate exposure to brain with brain-to- serum AUCo-t ratio of 0.44 to 2.25. Among the studied kavalactones, kavain showed maximum affinity to brain with brain-to-serum AUCo-t ratio of 2.25. The volume of distribution (VyF, 11.0-41.6 L/h/kg) of kavain, dihydrokavain, methysticin and dihydromethysticin is larger than the total blood volume of mouse (0.085 L/kg;

Davies and Morris, 1993). Moderate tissue-to-serum _Auco-t ratio, large Vd/F and long MRT (5.6-9.2 h) indicate the extensive affinity of kavalactones to the tissues. Method Validation and Pharmacokinetic Studies in Human Plasma and Urine

Since there has been no pharmacokinetic characterization of kava in humans, the ability of the targeted UPLC-MS method in detecting and quantifying these five kavalactones were tested in the human plasma and urine samples. The urine and plasma samples were collected from a clinical trial conducted at the University of Minnesota, in which subjects took a commercially available soft-capsule kava supplement from Gaia Herb, one capsule three times a day, for 7 days. The plasma and urine samples from two subjects before and after the kava intervention were analyzed herein.

The linearity of calibration curve was confirmed by the slope (s = 0.9987 +

0.0074) and linear regression value (r² = 0.9997) (FIG. 12). The LOD and LOQ values of DHM, estimated by the 3.3o/s and ΙΟσΑ·, were 0.09 nM and 0.26 nM, respectively in human body fluids. The LODs of kavain, DHK, methysticin and desmethoxyyangonin were estimated to be 0.46 nM, 0.08 nM, 0.50 nM, and 0.32 nM, and their LOQs were estimated to be 1.39 nM, 0.24 nM, 1.52 nM, and 0.97 nM, respectively. The precision and reproducibility tests of the method are shown in FIGs. 13A-13D based on the quantification of DHM in the human urines. The accuracy values were 90%, 96% and 81% respectively on three different days based on the spiked DHM at 1 pg/μh (3.6 nM). The coefficient of variation (CV%) values for the intraday and interday precision were 7.7% and 10.6%, respectively (FIG. 13A). The CV% values of the reproducibility of the method for the intraday and interday precision were 2.9% and 4.8%, respectively, based on the quantification of DHM in the urine sample from one subject (FIG. 13B).

Upon validation, this method was applied to quantify the five kavalactones in the plasma and urine samples from two subjects before and after the kava intervention (FIGs. 14 and 15). None of the five kavalactones was above the LODs in the urine or plasma samples of the two subjects before they started taking kava capsules, consistent with the fact that these kavalactones are unique to kava. Kavain, DHK, DHM and desmethoxyyangonin were above their LOQs in both urine samples after the subjects took kava while methysticin was below its LOD. Kavain (44.4% and

31.3%), desmethoxyyangonin (24.1% and 35.0%), and DHK (19.3% and 23.6%) were the most abundant kavalactones in the urine samples with considerable amounts of DHM (12.2% and 10.1%) as well. All five kavalactones were above their LOQs in plasma samples in both subjects after taking kava. DHM (50.3% and 44.3%) was the most abundant kavalactone followed by DHK (31.8% and 35.5%) and kavain (10.6% and 13.1%). Unlike the urine samples, methysticin (6.5% and 6.9%) was well above the LOQ in both subjects, while desmethoxyyangonin was barely above the LOQ (0.8% and 0.2%) in both subjects. Consistent with the observation in C57BL/6 mice, these five kavalactones appeared to have different pharmacokinetics and biodistributions in humans (FIG. 11). The relative abundance of DHM/total kavalactones were considerably greater in the plasma (50.3% and 44.3%) than that in the urine (12.2% and 10.1%). Desmethoxyyangonin was dominantly detected in the urine samples (24.1% and 35.0%) with minimal quantity detected in the plasma samples (0.8% and 0.2%). Methysticin, which was of comparable abundance as desmethoxyyangonin in the soft-gel kava capsule, on the other hand, was readily detectable in the plasma (6.5% and 6.9%) while it was below its LOD in the urine samples. Kavain had a higher relative abundance in the urine relative to plasma while DHK was exactly opposite that higher abundance was detected in the plasma relative to the urine. These data also demonstrate that this UPLC-MS method has the capability to characterize the pharmacokinetics of kava extracts and individual kavalactones in humans.

Example 2: Treatment of Smokers with Kava

Kava Treatment Reduces Tobacco Use

Healthy adult smokers of at least 5 cigarettes per day for the past year were recruited at University of Minnesota. A screening blood sample was analyzed to ensure normal organ function, followed by a brief physical exam by a medical doctor. Eligible subjects, after signing the consent form, were asked to collect 24-hour urine sample for baseline analysis. Baseline blood and Cigarette Evaluation Scale (CES) questionnaire were collected as well. Subjects then consumed three kava capsules daily for seven days. 24-hour urine samples were collected on Days 4 and 7. Blood samples were collected on Days 4 and 7 for clinical chemistry. CES questionnaire was collected on Day 7. In this pilot trial, enrolled individuals were advised not to take other medications/dietary supplements to minimize the potential of drug-herb interactions. No adverse events were self-reported/diagnosed during the trial and kava usage had no detectable impact on liver/kidney function. The urine and plasma samples were stored at -80°C till analysis.

Since kava capsules were self-administered, an LC-MS/MS based DHM detection method was employed to monitor kava compliance because DHM has been only reported in kava and is the chemopreventive ingredient with an isotope-labeled DHM, [D₂]-DHM, as the internal standard. DHM was detected in all urine samples from subjects after they were supposed to have taken kava and it was not detected in any of the urine collected pre-kava exposure. These results demonstrate that the trial was properly implemented with high kava compliance and the samples collected warrant further analyses.

The Cigarette Evaluation Questionnaire (CEQ) and urinary nicotine metabolite analysis have been well-established to measure Smoking Satisfaction, Psychological Rewards and Aversion [Cappelleri JC, Bushmakin AG, Baker CL, Merikle E, Olufade AO, Gilbert DG. Confirmatory factor analyses and reliability of the modified cigarette evaluation questionnaire. Addictive behaviors. 2007;32(5):912-23.] and has been widely used. As shown in FIG. 16, dietary kava usage significantly reduced smoking satisfaction score and nearly significantly reduced the total score and enjoy sensation, indicating the potential of dietary kava to promote tobacco cessation.

Nicotine is the addictive chemical in tobacco products and its metabolism has been well characterized [Murphy SE. Nicotine Metabolism and Smoking: Ethnic Differences in the Role of P450 2A6. Chemical research in toxicology.

2017;30(l):410-9.]. The sum of the seven major nicotine metabolites, Total Nicotine Equivalent (TNE), including free nicotine, nicotine glucuronide, cotinine, cotinine glucuronide, 3-hydroxycotinine, 3-hydroxycotinine glucuronide and nicotine N-oxide, in the 24-hour urine is an established biomarker to access daily tobacco use [Murphy SE. Nicotine Metabolism and Smoking: Ethnic Differences in the Role of P450 2A6. Chemical research in toxicology. 2017;30(l):410-9.]. TNE was quantified in the urine samples from the 21 subjects before kava ingestion and on Day 7 of kava ingestion by following the reported LC-MS/MS based quantification. The short-term kava ingestion significantly reduced the urinary TNE (FIG. 17A), suggesting the reduction in tobacco use among these smokers, even with no tobacco cessation promotion during this trial. In addition, the extent of TNE reduction was higher in AA smokers (a 33.2% reduction, FIG. 17B) in comparison to Caucasian American (CA) smokers (a 26.8% reduction, FIG. 17C), although the reduction in AAs was not statistically significant, likely due to the low number of AA subjects in the study (n=7). These data provide strong evidence that kava, as a dietary supplement, can help smokers reduce tobacco use and such a benefit might be greater among AA smokers.

Impact of Kava on NNAL Excretion and DNA Damage

To explore the potential of kava to enhance NNAL detoxification, the urinary total NNAL (the sum of free NNAL and glucuronidated NNALs) were quantified in the urine samples from the 21 subjects before kava ingestion and on Day 7 of kava ingestion by following the established LC-MS/MS based method [NarayanapiUai SC, von Weymarn LB, Carmella SG, Leitzman P, Paladino J, Upadhyaya P, et al. Dietary Dihydromethysticin Increases Glucuronidation of 4-(Methylnitrosamino)-l-(3- Pyridyl)-l-Butanol in A/J Mice, Potentially Enhancing Its Detoxification. Drug metabolism and disposition: the biological fate of chemicals. 2016;44(3):422-7.]. As shown in FIG. 18 A, kava usage increased the relative amount of NNAL in the urine, consistent with our in vivo data [NarayanapiUai SC, von Weymarn LB, Carmella SG, Leitzman P, Paladino J, Upadhyaya P, et al. Dietary Dihydromethysticin Increases Glucuronidation of 4-(Methylnitrosamino)-l-(3-Pyridyl)-l-Butanol in A/J Mice, Potentially Enhancing Its Detoxification. Drug metabolism and disposition: the biological fate of chemicals. 2016;44(3):422-7.], supporting its promotion of carcinogen detoxification. Such an increase also appeared to be more pronounced in AAs (117% increase, FIG. 18B) relative to CAs (86% increase, FIG. 18C), again supporting the potential greater benefit of kava usage among AA smokers relative to CA smokers. Given that DNA damage and its associated carcinogenesis is the root cause of lung cancer, we also investigated the impact of dietary kava towards DNA damage. Due to the challenge to retrieve DNA samples from the lung tissues, urinary 3 -methyl adenine is one of the best surrogate biomarkers for tobacco-induced DNA damage [Feng S, Roethig HJ, Liang Q, Kinser R, Jin Y, Scherer G, et al. Evaluation of urinary 1-hydroxypyrene, S-phenylmercapturic acid, trans,trans-muconic acid, 3- methyladenine, 3-ethyladenine, 8-hydroxy-2'-deoxyguanosine and thioethers as biomarkers of exposure to cigarette smoke. Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals. 2006;l l(l):28-52.] and potentially the best biomarker for NNK/NNAL- induced DNA methylation, given NNK and NNAL are the major known carcinogens in tobacco to induce DNA methylation. The LC-MS/MS method was used to quantified the urinary 3-mA in the urine samples (FIGs. 19A-19C). Consistent with the increase in urinary excretion of NNAL, kava ingestion led to significant reduction of urinary 3-mA, indicating the reduction of methyl DNA damage in the body and supporting the reduction of cancer risk. Also consistently the magnitude of reduction in urinary 3-mA was more pronounced in AA smokers relative to CA smokers.

NNAL Excretion Correlated With CYP2A6 Enzymatic Activity As the addictive ingredient in tobacco product, nicotine metabolism is an important determinant of smoking dose and lung cancer risk [Patel YM, Park SL, Han Y, Wilkens LR, Bickeboller H, Rosenberger A, et al. Novel Association of Genetic Markers Affecting CYP2A6 Activity and Lung Cancer Risk. Cancer research.

2016;76(19):5768-76; Murphy SE. Nicotine Metabolism and Smoking: Ethnic Differences in the Role of P450 2A6. Chemical research in toxicology.

2017;30(l):410-9; Wang H, Park SL, Stram DO, Haiman CA, Wilkens LR, Hecht SS, et al. Associations Between Genetic Ancestries and Nicotine Metabolism Biomarkers in the Multiethnic Cohort Study. American journal of epidemiology.

2015;182(11):945-51.] . Smokers with quick nicotine metabolism tend to use more tobacco products, in order to sustain the needed level of nicotine. They are less likely to succeed in quitting. CYP2A6 is the key enzyme in metabolizing nicotine and its enzymatic activity has been found to positively correlate with the amount of tobacco use and lung cancer risk in smokers. Since the enzymatic activity of CYP2A6 can be estimated based on the urinary ratio of total 3-hydroxycotinine (the sum of 3- hydroxycotinine and its glucuronide) to cotinine, the potential impact of CYP2A6 status to kava's effect was explored among the 21 subjects (FIGs. 20A-20C).

Consistent with literature reports, CYP2A6 activity correlates positively with the amount of tobacco usage (FIG. 20A). When the 21 subjects were roughly classified into two groups, 2A6 high and 2A6 low, and the impact of kava on TNE was analyzed, it appeared that the reduction of tobacco use induced by kava was mostly among individuals with high CYP2A6 activity (FIG. 20B, heavy smokers) while its benefit was minimal among individuals with low CYP2A6 activity (FIG. 20C). These data suggest that the CYP2A6 status of the smokers might be a surrogate to predict the potential benefit of kava use.

Kava Inhibits Nicotine Metabolism

TNE is the total of free nicotine, nicotine N-oxide, nicotine glucuronide, cotinine, cotinine glucuronide, 3-hydroxycotinine and 3-hydroxycotinine glucuronide. As shown in FIG. 21, kava use reduced nicotine N-oxide, nicotine glucuronide, cotinine, cotinine glucuronide, 3-hydroxycotinine and 3-hydroxycotinine glucuronide but not free nicotine. These data strongly support that kava inhibits nicotine metabolism, which is consistent with the results above: 1) AA smokers may benefit more from kava in relative to CA smokers (FIGs. 17A-17C, 18A-18C, and 19A-19C). individuals with high level of CYP2A6 will metabolize nicotine faster and kava inhibits this process, that is probably why the impact is more on smokers with high levels of CYP2A6 (FIGs. 20A-20C); and 2) given that kava likely inhibits nicotine metabolism, kava may enhance the efficacy of nicotine replacement therapy, particularly subjects that use nicotine for tobacco replacement.

Incorporation by Reference

The contents of all references (including literature references, issued patents, published patent applications, and co-pending patent applications) cited throughout this application are hereby expressly incorporated herein in their entireties by reference.

Equivalents

Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents of the specific embodiments of the invention described herein. Such equivalents are intended with be encompassed by the following claims.

Claims

What is claimed:

1. A composition comprising at least one compound selected from kavain, wherein the amount of kavain in the composition is 26 mg + 10 mg; dihydrokavain, wherein the amount of dihydrokavain in the composition is 14 mg + 5 mg;

desmethoxyyangonin in the composition is 8 mg + 5 mg.

2. A composition comprising at least one compound selected from kavain, wherein the amount of kavain in the composition is 26 mg + 10 mg; dihydrokavain, wherein the amount of dihydrokavain in the composition is 14 mg + 5 mg;

3. A composition comprising: 1) at least one compound selected from kavain, wherein the amount of kavain in the composition is 26 mg + 10 mg; dihydrokavain, wherein the amount of dihydrokavain in the composition is 14 mg + 5 mg;

desmethoxyyangonin in the composition is 8 mg + 5 mg; and 2) nicotine, wherein the amount of nicotine in the composition is 1-25 mg.

4. A composition comprising: 1) at least one compound selected from kavain, wherein the amount of kavain in the composition is 26 mg + 10 mg; dihydrokavain, wherein the amount of dihydrokavain in the composition is 14 mg + 5 mg;

methysticin, wherein the amount of methysticin in the composition is 8 mg + 5 mg; dihydromethysticin, wherein the amount of dihydromethysticin in the composition is 21 mg + 10 mg; and desmethoxyyangonin, wherein the amount of desmethoxyyangonin in the composition is 8 mg + 5 mg; and 2) nicotine, wherein the amount of nicotine in the composition is 1-15 mg.

5. A method of aiding a subject in the cessation of tobacco use, the method comprising the administration of a composition of any one of claims 1-3 to the subject.

6. A method of treating tobacco addiction in a subject, the method comprising the administration of a composition of any one of claims 1-3 to the subject.

7. A method of treating nicotine addiction in a subject, the method comprising the administration of a composition of any one of claims 1-3 to the subject.

8. A method of inhibiting nicotine metabolism in a subject, the method comprising the administration of a composition of any one of claims 1-3 to the subject.

9. A treatment regimen for smoking cessation, the regimen comprising the administration of a composition of any one of claims 1-3 to the subject.

10. A treatment regimen for smoking cessation and inhibiting nicotine metabolism, the regimen comprising the administration of a composition of any one of claims 1-3 to the subject.

11. A method of aiding a subject in the cessation of tobacco use, the method comprising the administration of one or more of the group consisting of 75 mg + 25 mg of kavain per day, 40 mg + 20 mg of dihydrokavain per day, 25 mg + 15 mg of methysticin per day, 60 mg + 30 mg of dihydromethysticin per day, and 25 mg + 15 mg of desmethoxyyangonin per day, to the subject.

12. A method of treating tobacco addiction in a subject, the method comprising the administration of one or more of the group consisting of 75 mg + 25 mg of kavain per day, 40 mg + 20 mg of dihydrokavain per day, 25 mg + 15 mg of methysticin per day, 60 mg + 30 mg of dihydromethysticin per day, and 25 mg + 15 mg of desmethoxyyangonin per day to the subject.

13. A method of treating nicotine addiction in a subject, the method comprising the administration of one or more of the group consisting of 75 mg + 25 mg of kavain per day, 40 mg + 20 mg of dihydrokavain per day, 25 mg + 15 mg of methysticin per day, 60 mg + 30 mg of dihydromethysticin per day, and 25 mg + 15 mg of

desmethoxyyangonin per day to the subject.

14. A treatment regimen for smoking cessation, the regimen comprising the administration of one or more of the group consisting of 75 mg + 25 mg of kavain per day, 40 mg + 20 mg of dihydrokavain per day, 25 mg + 15 mg of methysticin per day, 60 mg + 30 mg of dihydromethysticin per day, and 25 mg + 15 mg of

desmethoxyyangonin per day.

15. A treatment regimen for smoking cessation and inhibiting nicotine

metabolism, the regimen comprising the administration of one or more of the group consisting of 75 mg + 25 mg of kavain per day, 40 mg + 20 mg of dihydrokavain per day, 25 mg + 15 mg of methysticin per day, 60 mg + 30 mg of dihydromethysticin per day, and 25 mg + 15 mg of desmethoxyyangonin per day.

16. A method of inhibiting nicotine metabolism in a subject, the method comprising the administration of one or more of the group consisting of 75 mg + 25 mg of kavain per day, 40 mg + 20 mg of dihydrokavain per day, 25 mg + 15 mg of methysticin per day, 60 mg + 30 mg of dihydromethysticin per day, and 25 mg + 15 mg of desmethoxyyangonin per day to the subject.

17. A method of aiding a subject in the cessation of tobacco use, the method comprising the administration of one or more of the group consisting of 75 mg + 25 mg of kavain per day, 40 mg + 20 mg of dihydrokavain per day, 25 mg + 15 mg of methysticin per day, 60 mg + 30 mg of dihydromethysticin per day, and 25 mg + 15 mg of desmethoxyyangonin per day; and 1-50 mg of nicotine per day to the subject.

18. A method of treating tobacco addiction in a subject, the method comprising the administration of one or more of the group consisting of 75 mg + 25 mg of kavain per day, 40 mg + 20 mg of dihydrokavain per day, 25 mg + 15 mg of methysticin per day, 60 mg + 30 mg of dihydromethysticin per day, and 25 mg + 15 mg of

desmethoxyyangonin per day; and 1-50 mg of nicotine per day to the subject.

19. A method of treating nicotine addiction in a subject, the method comprising the administration of one or more of the group consisting of 75 mg + 25 mg of kavain per day, 40 mg + 20 mg of dihydrokavain per day, 25 mg + 15 mg of methysticin per day, 60 mg + 30 mg of dihydromethysticin per day, and 25 mg + 15 mg of

desmethoxyyangonin per day; and 1-50 mg of nicotine per day to the subject.

20. A treatment regimen for smoking cessation, the regimen comprising the administration of one or more of the group consisting of 75 mg + 25 mg of kavain per day, 40 mg + 20 mg of dihydrokavain per day, 25 mg + 15 mg of methysticin per day, 60 mg + 30 mg of dihydromethysticin per day, and 25 mg + 15 mg of

desmethoxyyangonin per day; and 1-50 mg of nicotine per day.

21. A treatment regimen for smoking cessation and inhibiting nicotine

metabolism, the regimen comprising the administration of one or more of the group consisting of 75 mg + 25 mg of kavain per day, 40 mg + 20 mg of dihydrokavain per day, 25 mg + 15 mg of methysticin per day, 60 mg + 30 mg of dihydromethysticin per day, and 25 mg + 15 mg of desmethoxyyangonin per day; and 1-50 mg of nicotine per day.

22. The method of any one of claims 5-8, 11-13, and 16-19, wherein the subject is an African American.

23. The treatment regimen of any one of claims 9, 10, 14, 15, 20, and 21, wherein the subject is an African American.

24. A method for aiding a subject with a total nicotine equivalent (TNE) of > 30,000 mg/mg creatinine in the cessation of tobacco use, the method comprising administering to the subject a composition of any one of claims 1, 2, and 4.

25. A method for treating tobacco addiction in a subject with a total nicotine equivalent (TNE) of > 30,000 mg/mg creatinine in the cessation of tobacco use, the method comprising administering to the subject a composition of any one of claims 1, 2, and 4.

26. A method for treating nicotine addiction in a subject with a total nicotine equivalent (TNE) of > 30,000 mg/mg creatinine in the cessation of tobacco use, the method comprising administering to the subject a composition of any one of claims 1, 2, and 4.

27. A kit for aiding a subject with a total nicotine equivalent (TNE) of > 30,000 mg/mg creatinine in the cessation of tobacco use, comprising a composition of any one of claims 1, 2, and 4; and instructions for use.

28. A kit for treating tobacco addiction in a subject with a total nicotine equivalent (TNE) of > 30,000 mg/mg creatinine in the cessation of tobacco use, comprising a composition of any one of claims 1, 2, and 4; and instructions for use.

29. A kit for treating nicotine addiction in a subject with a total nicotine equivalent (TNE) of > 30,000 mg/mg creatinine in the cessation of tobacco use, comprising a composition of any one of claims 1, 2, and 4; and instructions for use.

30. A method for aiding a subject with a total nicotine equivalent (TNE) of > 30,000 mg/mg creatinine in the cessation of tobacco use, the method comprising administering to the subject: 1) a composition comprising at least one compound selected from kavain, wherein the amount of kavain in the composition is 26 mg + 10 mg; dihydrokavain, wherein the amount of dihydrokavain in the composition is 14 mg + 5 mg; methysticin, wherein the amount of methysticin in the composition is 8 mg + 5 mg; dihydromethysticin, wherein the amount of dihydromethysticin in the composition is 21 mg + 10 mg; and desmethoxyyangonin, wherein the amount of desmethoxyyangonin in the composition is 8 mg + 5 mg; and 2) nicotine, wherein the amount of nicotine in the composition is 1-15 mg.

31. A method for treating tobacco addiction in a subject with a total nicotine equivalent (TNE) of > 30,000 mg/mg creatinine in the cessation of tobacco use, the method comprising administering to the subject: 1) a composition comprising at least one compound selected from kavain, wherein the amount of kavain in the

composition is 26 mg + 10 mg; dihydrokavain, wherein the amount of dihydrokavain in the composition is 14 mg + 5 mg; methysticin, wherein the amount of methysticin in the composition is 8 mg + 5 mg; dihydromethysticin, wherein the amount of dihydromethysticin in the composition is 21 mg + 10 mg; and desmethoxyyangonin, wherein the amount of desmethoxyyangonin in the composition is 8 mg + 5 mg; and 2) nicotine, wherein the amount of nicotine in the composition is 1-15 mg.

32. A method for treating nicotine addiction in a subject with a total nicotine equivalent (TNE) of > 30,000 mg/mg creatinine in the cessation of tobacco use, the method comprising administering to the subject: 1) a composition comprising at least one compound selected from kavain wherein the amount of kavain in the

33. A kit for aiding a subject with a total nicotine equivalent (TNE) of > 30,000 mg/mg creatinine in the cessation of tobacco use, comprising: 1) a composition comprising at least one compound selected from kavain wherein the amount of kavain in the composition is 26 mg + 10 mg; dihydrokavain, wherein the amount of dihydrokavain in the composition is 14 mg + 5 mg; methysticin, wherein the amount of methysticin in the composition is 8 mg + 5 mg; dihydromethysticin, wherein the amount of dihydromethysticin in the composition is 21 mg + 10 mg; and

desmethoxyyangonin, wherein the amount of desmethoxyyangonin in the

composition is 8 mg + 5 mg; 2) nicotine, wherein the amount of nicotine in the composition is 1-15 mg; and 3) instructions for use.

34. A kit for treating tobacco addiction in a subject with a total nicotine equivalent (TNE) of > 30,000 mg/mg creatinine in the cessation of tobacco use, comprising: 1) a composition comprising at least one compound selected from kavain wherein the amount of kavain in the composition is 26 mg + 10 mg; dihydrokavain, wherein the amount of dihydrokavain in the composition is 14 mg + 5 mg; methysticin, wherein the amount of methysticin in the composition is 8 mg + 5 mg; dihydromethysticin, wherein the amount of dihydromethysticin in the composition is 21 mg + 10 mg; and desmethoxyyangonin, wherein the amount of desmethoxyyangonin in the

35. A kit for treating nicotine addiction in a subject with a total nicotine equivalent (TNE) of > 30,000 mg/mg creatinine in the cessation of tobacco use, comprising: 1) a composition comprising at least one compound selected from kavain, wherein the amount of kavain in the composition is 26 mg + 10 mg;

dihydrokavain, wherein the amount of dihydrokavain in the composition is 14 mg + 5 mg; methysticin, wherein the amount of methysticin in the composition is 8 mg + 5 mg; dihydromethysticin, wherein the amount of dihydromethysticin in the composition is 21 mg + 10 mg; and desmethoxyyangonin, wherein the amount of desmethoxyyangonin in the composition is 8 mg + 5 mg; 2) nicotine, wherein the amount of nicotine in the composition is 1-15 mg; and 3) instructions for use.

36. A method for aiding tobacco cessation in a subject at high risk of lung cancer comprising administering to a subject having TNE of > 30,000 mg/mg creatine a composition of any one of claims 1, 2, and 4.

37. A method for aiding tobacco cessation in a subject identified as having TNE of > 30,000 mg/ mg creatine comprising administering to the subject a composition of any one of claims 1, 2, and 4.

38. A method for decreasing nicotine metabolites in a subject at high risk of lung cancer while undergoing nicotine replacement therapy comprising administering to a subject having TNE of > 30,000 mg/ mg creatine a composition of any one of claims 1, 2, and 4.

39. A method for decreasing nicotine metabolites in a subject identified as having TNE of > 30,000 mg/ mg creatine while undergoing nicotine replacement therapy comprising administering to the subject a composition of any one of claims 1, 2, and 4.

40. A method for aiding tobacco cessation in a subject particularly suitable for such treatment comprising administering to a subject having TNE of > 30,000 mg/ mg creatine a composition of any one of claims 1, 2, and 4.

41. A method for decreasing nicotine metabolites in a subject particularly suitable for such treatment while undergoing nicotine replacement therapy comprising administering to a subject having TNE of > 30,000 mg/ mg creatine a composition of any one of claims 1, 2, and 4.

42. A method for aiding tobacco cessation in a subject at high risk of lung cancer comprising administering to a subject having TNE of > 30,000 mg/mg creatine: 1) a composition comprising at least one compound selected from kavain, wherein the amount of kavain in the composition is 26 mg + 10 mg; dihydrokavain, wherein the amount of dihydrokavain in the composition is 14 mg + 5 mg; methysticin, wherein the amount of methysticin in the composition is 8 mg + 5 mg; dihydromethysticin, wherein the amount of dihydromethysticin in the composition is 21 mg + 10 mg; and desmethoxyyangonin, wherein the amount of desmethoxyyangonin in the

composition is 8 mg + 5 mg; and 2) nicotine, wherein the amount of nicotine in the composition is 1-15 mg.

43. A method for aiding tobacco cessation in a subject identified as having TNE of > 30,000 mg/ mg creatine comprising administering to the subject: 1) a composition comprising at least one compound selected from kavain, wherein the amount of kavain in the composition is 26 mg + 10 mg; dihydrokavain, wherein the amount of dihydrokavain in the composition is 14 mg + 5 mg; methysticin, wherein the amount of methysticin in the composition is 8 mg + 5 mg; dihydromethysticin, wherein the amount of dihydromethysticin in the composition is 21 mg + 10 mg; and desmethoxyyangonin, wherein the amount of desmethoxyyangonin in the

44. A method for decreasing nicotine metabolites in a subject at high risk of lung cancer while undergoing nicotine replacement therapy comprising administering to a subject having TNE of > 30,000 mg/ mg creatine: 1) a composition comprising at least one compound selected from kavain, wherein the amount of kavain in the composition is 26 mg + 10 mg; dihydrokavain, wherein the amount of dihydrokavain in the composition is 14 mg + 5 mg; methysticin, wherein the amount of methysticin in the composition is 8 mg + 5 mg; dihydromethysticin, wherein the amount of dihydromethysticin in the composition is 21 mg + 10 mg; and desmethoxyyangonin, wherein the amount of desmethoxyyangonin in the composition is 8 mg + 5 mg; and 2) nicotine, wherein the amount of nicotine in the composition is 1-15 mg.

45. A method for decreasing nicotine metabolites in a subject identified as having TNE of > 30,000 mg/ mg creatine while undergoing nicotine replacement therapy comprising administering to the subject: 1) a composition comprising at least one compound selected from kavain, wherein the amount of kavain in the composition is 26 mg + 10 mg; dihydrokavain, wherein the amount of dihydrokavain in the composition is 14 mg + 5 mg; methysticin, wherein the amount of methysticin in the composition is 8 mg + 5 mg; dihydromethysticin, wherein the amount of

dihydromethysticin in the composition is 21 mg + 10 mg; and desmethoxyyangonin, wherein the amount of desmethoxyyangonin in the composition is 8 mg + 5 mg; and 2) nicotine, wherein the amount of nicotine in the composition is 1-15 mg.

46. A method for aiding tobacco cessation in a subject particularly suitable for such treatment comprising administering to a subject having TNE of > 30,000 mg/ mg creatine: 1) a composition comprising at least one compound selected from kavain, wherein the amount of kavain in the composition is 26 mg + 10 mg;

dihydrokavain, wherein the amount of dihydrokavain in the composition is 14 mg + 5 mg; methysticin, wherein the amount of methysticin in the composition is 8 mg + 5 mg; dihydromethysticin, wherein the amount of dihydromethysticin in the composition is 21 mg + 10 mg; and desmethoxyyangonin, wherein the amount of desmethoxyyangonin in the composition is 8 mg + 5 mg; and 2) nicotine, wherein the amount of nicotine in the composition is 1-15 mg.

47. A method for decreasing nicotine metabolites in a subject particularly suitable for such treatment while undergoing nicotine replacement therapy comprising administering to a subject having TNE of > 30,000 mg/ mg creatine: 1) a

composition comprising at least one compound selected from kavain, wherein the amount of kavain in the composition is 26 mg + 10 mg; dihydrokavain, wherein the amount of dihydrokavain in the composition is 14 mg + 5 mg; methysticin, wherein the amount of methysticin in the composition is 8 mg + 5 mg; dihydromethysticin, wherein the amount of dihydromethysticin in the composition is 21 mg + 10 mg; and desmethoxyyangonin, wherein the amount of desmethoxyyangonin in the composition is 8 mg + 5 mg; and 2) nicotine, wherein the amount of nicotine in the composition is 1- 15 mg.