The Official Publication of the American Herbal Products Association March 2011 www.ahpa.org Volume 26, Number 3

In this issue of the AHPA Report

Inside AHPA 2

• AHPA Board Election: Candidates Represent Impressive Cross Section of Industry • FDA Health Fraud Coordinator and Industry Marketing Expert to Present at Annual Member Meeting • The AHPA Expo West Schedule of Meetings and Events • AHPA Members Eligible for SupplySide East Discount • Savings Opportunities for AHPA Members

Special Topics 7

• Understanding the Complexities of Customs Regulations for Herbal and Dietary Supplements by Adonica-Jo R. Wada and Neil S. Helfand • Kava and the Risk of Liver Toxicity: Past, Current, and Future Aspects by Rolf Teschke

Legal & Regulatory 18

• GAO Calls for FDA Inspection Authority on Food Claims Records by Michael McGuffin • Status of 111th Congressional Legislation in the 112th Congress by Peter Evich • Dear Retailer: There’s a Hole in the cGMP Bucket by Anthony L. Young, Esq. • FDA Issues First Reportable Food Registry Report by Anthony L. Young

Botanical Science Update 25

• NCCAM Strategic Plan Includes “Integration of Alternative Treatment” • Literature Citations by Steven Dentali, PhD, and Francis Brinker, ND English Plantain Shows Ulcer-Healing Properties; Fenugreek Fiber Prevented Heartburn in Humans; Common Herbal Extracts Prevent Bacterial Adhesion; Herbal Traditions in Bosnia and Herzegovina; Cannabis Extracts Fight MS Symptoms in Mice; Passionflower Slightly Improved Sleep; Purple Granadilla Shows Anxiolytic Activity; Passionflower Synergistically Improves SJW Activity; “Toothache Plant” Puts the Hurt on Malarial Parasites; Patented Essential Oils Used to Repel Mosquitoes; Muira Puama Performs Well in Mouse Alzheimer Model; Rhodiola Reviews Well; More Quality Research Needed; Free Fitoterapia Special Edition on Research Since DSHEA; Diet, Supplements, and Mental Energy: A Review; Herb, Drug, and Author Interactions; Considerations Concerning Kids Consuming Caffeine

Calendar of Botanical Events 33 Inside AHPA

AHPA Board Election: Candidates “AHPA is pleased to have such an excellent group of board candi- Represent Impressive Cross Section dates seeking to represent our diverse membership,” says Michael McGuffin, AHPA president. “It’s inspiring to see such a high level of of Industry commitment to the organization. This interest in engagement on the board and in our many committees has been a hallmark of this Absentee ballots are due by March 7 organization for many years and bodes well for its future The 13 candidates running for election or re-election to the Board successes.” of Trustees of the American Herbal Products Association (AHPA), The election will take place at the Annual Member Meeting, the voice of the herbal products industry, represent an impressive Thursday, March 10, in the Avalon Ballroom of the Anaheim Hilton cross section of industry executives that have expressed interest in in Anaheim, Calif. Ballots have already been sent via email to com- joining the governing body of the association. pany representatives, along with candidate statements expressing The group of highly qualified candidates brings valuable skills, lead- their interest in joining the board. Members are encouraged to re- ership, and experience to the board, including scientific and legal view the candidate statements prior to the Annual Member Meeting. expertise, long-term industry experience and knowledge, and herbal (Note: The PDF containing the candidate statements may take 3-4 or integrative medicine backgrounds. minutes to load.)

2011 Candidates for the Board of Trustees Candidate Name Title Company Name Cindy Angerhofer Executive Director of Botanical Research and Aroma Aveda Volker Wypyszyk CEO Azile, LLC Rupa Das VP, Global Quality & Compliance BI Nutraceuticals Jackie Greenfield VP, Global Sourcing & Sustainability Gaia Herbs Daniel Gagnon Owner Herbs, Etc. Skye Sturgeon Quality Assurance Manager Mayway USA Olaf Weitz Head of Business Development, Supplements Group MB North America Steven Yeager QC/Laboratory Manager Mountain Rose Herbs Tim Callahan VP of Quality New Chapter Wilson Lau VP of Sales and Marketing Nuherbs Co. Richard Kaufman Chief Operating Officer Paragon Labs Michael Friedman President Restorative Formulations Stefan Gafner Director of Analytical Chemistry Tom’s of Maine

The AHPA Report, the official voice of the AHPA Staff Send inquiries, comments or American Herbal Products Association Michael McGuffin, President requests to: (AHPA), is published monthly as a service Steven Dentali, PhD, Chief Science Officer American Herbal to AHPA members and friends of the , Chief Operations Officer Devon Powell Products Association herbal products industry. The material Frank Lampe, Director of Communications & Editor, AHPA Report 8630 Fenton Street, Suite 918 contained in this publication is for the Yelena Teterina, Operations Manager information of AHPA members. Although Rosie Ysasi, Certification Program Coordinator Silver Spring, MD 20910 the information is believed to be correct, Merle Zimmermann, Information Analyst Phone: 301-588-1171 AHPA disclaims all responsibility for any Fax: 301-588-1174 Anthony Young, General Counsel, Kleinfeld, Kaplan & Becker damage or liability that may result from Peter Evich, National Legislative Consultant, Van Scoyoc Associates Email: [email protected] any reliance on the information contained Website: www.ahpa.org in this publication. Janice Chika, Graphic Designer, AHPA Report Breyeh Freesol, Media Production Coordinator Articles may not be reproduced or reprinted Monica Emerich, PhD, Copy Editor, AHPA Report © copyright 2011, American without written permission from AHPA. Bill Schoenbart, D.A.O.M., Proofreader, AHPA Report Herbal Products Association

March 2011 • Page  Each candidate will be provided with an opportunity to address The Board of Trustees provides general oversight of the affairs, the membership at the March 10 meeting. In conformity with the business and concerns of the association. Its duties are carried out at AHPA Bylaws and Election Policies, nominations for additional regularly scheduled meetings and at other such times as provided by candidates will not be accepted from the floor and write-in votes association bylaws. The board has the power to admit, suspend or will not be accepted. expel members; to formally approve all operating budgets desirable All active members in good standing are asked to vote for nine of in the conduct of the business of the association; to establish trade the 13 candidates who have declared their intentions to stand for requirements as amendments to the association’s Code of Ethics & election to the board. Members may cast their votes in one of three Business Conduct; and to establish or recommend additional poli- ways: in person at the Member Meeting or via email or via mail-in cies and guidelines that are consistent with the association’s mission: ballots, which were sent to members on Feb. 10, along with candi- to promote the responsible commerce of herbal products, in date statements and complete instructions. Email or mail ballots addition to other responsibilities. are due at the AHPA office by March 7. If you are your company’s primary contact and have not received an Alternately, a member may assign their vote to a proxy by printing email containing the ballot and candidate statements, or if you have the ballot and filling in the “Proxy Assignment for Election of AHPA questions regarding the election process, please contact Devon Trustees, March 10, 2011” and giving it to their proxy, who will Powell, 301.588.1171 x102, or by email. then cast the member’s vote in-person at the Member Meeting. If you have not yet registered for the Annual Member Meeting and Members who will not be attending the Annual Member Meeting are Breakfast, you can do so here. encouraged to take the time to exercise one of the absentee options.

March 2011 • Page  FDA Health Fraud Coordinator and FDA takes enforcement actions, seeks criminal prosecutions and Industry Marketing Expert to Present works to educate consumers to address this serious public health at Annual Member Meeting risk. He will also address how FDA is working with dietary supple- ment trade associations—such as AHPA—to educate the industry As part of its 2011 Member Meeting, AHPA is pleased to welcome and to help develop new strategies to combat this problem. Gary Coody, R.Ph., the Food and Drug Administration’s (FDA) na- Before his appointment as National Health Fraud Coordinator in tional health fraud coordinator in the Office of Enforcement, Office the Office of Enforcement, Mr. Coody dealt with policy issues relat- of Regulatory Affairs, and Steve French, managing partner of the ed to dietary supplements and drugs in the Office of Regulatory Natural Marketing Institute (NMI), who will both make presenta- Affairs’ Division of Compliance Policy. Mr. Coody began his FDA tions to the membership. career in 2000 at the Center for Food Safety and Applied Nutrition’s Office of Nutritional Products, Labeling, and Dietary Supplements. Coody to Discuss Drug Spiking of Supplements Before joining FDA, Mr. Coody served as Senior Pharmacist at the Gary Coody, a registered pharma- Texas Department of Health, and he practiced retail and hospital cist, will address the serious issue of pharmacy. dangerous drugs masquerading as dietary supplements. In recent French to Share Latest Consumer Herb Trends years, FDA has identified more than Steve French, who is an executive with one of the industry’s leading 300 tainted “supplement” products business consulting and market re- that contain undeclared or decep- search firms, will share new data on tively labeled ingredients (i.e., consumer attitudes and purchasing drugs, drug analogs, and other com- habits around herbal products, pounds). These products have been pulled from NMI’s The Health & associated with numerous reports of Wellness Trends Database, a com- injury. Mr. Coody will discuss how Gary Coody prehensive resource for measuring consumer attitudes, behavior pat- terns, product usage, lifestyles, and demographics. French has more than 25 years of strategic marketing, business devel- Steve French opment, market research, and management experience. Complementing a BS and MBA in mar- keting, Mr. French has accumulated extensive insight and knowl- edge into health, wellness, environmentalism, and social responsibility and has unparalleled experience across a wide range of corporate business functions and has pioneered a range of consumer research databases. He is a frequent speaker at many industry events and conferences, and is regularly utilized by television, radio, magazine, newspaper, Internet, and other media sources. He is also an author of numerous published articles and has written research reports used across many industries. Also on the program is a presentation from Richard Griffin, presi- dent of Grifcon Enterprises. Sponsorship of the AHPA Annual Member Meeting & Breakfast is graciously provided by Grifcon Enterprises and RT Specialty Insurance Services, AHPA-endorsed providers of products-liability insurance to the supplement industry, and GreenbergTraurig, a law firm that provides legal services to the herbal products and dietary supplement industry.

March 2011 • Page  The AHPA Expo West Schedule of Meetings and Events

The American Herbal Product Association’s (AHPA) member meet- Government Relations ing, committee meetings, and events schedule for the Natural Friday, March 11, 2:00 – 3:45 p.m., Products Expo West trade show and convention, to be held March Anaheim Marriott Hotel, La Jolla Room 9-13 in Anaheim, Calif., is now available online. Staff Liaison: Michael McGuffin Learn about the committee online. Association-hosted events provide members with excellent networking and educational opportunities during Expo West. The cornerstones of Communications the AHPA activities at the show include the annual member breakfast Friday, March 11, 4:00 – 5:30 p.m., and meeting and the association’s reception. Members can help guide Anaheim Marriott Hotel, La Jolla Room AHPA’s work, learn from colleagues, and stay up to speed about impor- Staff Liaison: Frank Lampe tant developments in the herbal and dietary supplement marketplace. Learn about the committee online.

Register here for the Member Breakfast & Meeting. Education Saturday, March 12, 9:00 – 11:00 a.m., Annual Member Meeting (Thurs., March 10) will take place Anaheim Marriott Hotel, La Jolla Room from 7:30 – 11:45 a.m., in the Avalon Ballroom of the Anaheim Staff Liaison: Devon Powell Hilton and will include the election of AHPA’s Board of Trustees Learn about the committee online. and presentation of the 2011 AHPA Awards. The deadline for re- ceipt of absentee ballots for the election is Monday, March 7 (see Chinese Herbal Products article on page 2). Members are encouraged to review the candi- Saturday, March 12, 11:15 a.m. – 12:45 p.m., date statements prior to the Annual Member Meeting. If you have Anaheim Marriott Hotel, La Jolla Room questions regarding the election process, please contact Devon Staff Liaison: Michael McGuffin Powell, 301.588.1171 x102, or by email. Sponsorship of the AHPA Learn about the committee online. Member Breakfast & Annual Meeting is provided by Grifcon Enterprises, RT Specialty Insurance Services, and GreenbergTraurig. Ayurvedic Products Saturday, March 12, 1:00 – 2:30 p.m., AHPA Member Reception (Fri., March 11) will once again Anaheim Marriott Hotel, La Jolla Room close out the first day of the trade show floor with libations, hors Staff Liaison: Michael McGuffin d’oeuvres, and a great opportunity to reconnect with friends and Learn about the committee online. colleagues. This year, AHPA welcomes to the reception special Sports Nutrition guests the International Alliance of Dietary/Food Supplement Saturday, March 12, 2:45 – 4:15 p.m., Associations (IADSA). The AHPA Member Reception is spon- Anaheim Marriott Hotel, La Jolla Room sored by ChromaDex and Poms & Associates and will Staff Liaison: Devon Powell be held in the Hilton Anaheim Hotel Pacific Ballroom B. Learn about the committee online.

AHPA Committee Meetings (March 10–12) represent the Cannabis heart and soul of the organization. In addition to guiding the ac- Saturday, March 12, 4:30 – 6:00 p.m. tivities and direction of the trade association, becoming a mem- Anaheim Marriott Hotel, La Jolla Room ber of an AHPA committee is a great way to stay abreast of Staff Liaison: Michael McGuffin. industry developments and learn from your peers through dis- cussion and information sharing. The following committees AHPA’s Board of Trustees will meet Wednesday, March 9, from have scheduled meetings at Expo West: noon to 6:00 p.m., and Thursday, March 10, from 12:30 - 2:00 p.m. in the Anaheim Marriott Hotel, La Jolla Room. Joint Meeting: Analytical Labs / Botanical Raw Materials / Standards The AHPA Foundation for Education and Research on Friday, March 11, 9:00 – 11:45 a.m., Botanicals Board will be meeting Friday, March 11, from 12:00 Anaheim Marriott Hotel, La Jolla Room noon - 1:45 p.m. in the Anaheim Marriott Hotel, La Jolla Room. Staff Liaison: Steven Dentali, PhD Contact Michael McGuffin for more information about either of Learn about the committees online. these board meetings.

March 2011 • Page  AHPA Members Eligible for Savings Opportunities for AHPA Members SupplySide East Discount Within the pages of this edition of AHPA Report, we are pleased to AHPA members can save $50 on registration for the upcoming provide our members with several valuable money-saving opportu- SupplySide East conference and trade show, to be held May 2-4, nities. The following goods and services are offered at a discount 2011, in Secaucus, N.J. New this year, all AHPA members are eligi- for—or are uniquely available to—AHPA members this month: ble to receive the discount; in the past, this benefit was available only to finished-goods manufacturers. The discount is the result of  American Herbal Pharmacopoeia, 10% off for AHPA a partnership between AHPA and Phoenix, Ariz.-based Virgo members (page 19) Publishing, the producer of SupplySide East.  AuthenTechnologies, 10% off for AHPA members (page 14) Steven Dentali, PhD, AHPA’s chief science officer, will present a ses- sion titled: “Sorting out Identity GMP Requirements: Which Tools  CPG Jobs, 15% off for employers (page 10) and Technologies are Scientifically Valid?” on Tuesday, May 3, as  First National Merchants, members-only offer (page 17) part of the 3-day education program. Call 800.454.5760 or visit www.supplysideshow.com and enter pro-  Herbs of Commerce, $20 discount for members (page 8) mo code “AHPAvip” to take advantage of this offer. The offer does  SupplySide East, save $50 on registration (page 27) not replace a previously paid registration, is non-transferable, and is valid through April 28, 2011.  The Tan Sheet, $360 off of new subscriptions (page 20) Details on the 30-session education program, an exhibitor listing, workshop information, and much more is available at the confer- ence website.

The AHPA NDI Database Your key to future botanicals

The AHPA NDI Database helps companies that have invested in new dietary ingredients increase their knowledge how to submit NDI notifications and speed their time to market. Cut through the confusion

The AHPA NDI Database is the most complete listing and analysis resource for NDI filings, often posting informa- tion well in advance of the FDA website. No need to review lengthy or numerous documents to try to determine the outcome of an NDI submission. “Outcome statements” for each notification summarize FDA’s response.

Easily locate notifications by searching for such key terms as the generic names, brand names, Latin names, the submitting firm or their counsel or other consultant, or the report number assigned by FDA.

Subscribe to and access the database at http://ndi.npicenter.com/ But wait! There’s more … AHPA also offers a practical guidance document to help companies increase their success in filing NDI notifications. AHPA’s Interim Guidance for New Dietary Ingredient Notifications for Manufacturers or Distributors of New Dietary Ingredients explains the NDI regulations, details what information to include (and exclude) in a notifica- tion, and provides three practical hands-on worksheets: ♦ Determination of Requirement to Submit ♦ Submission of NDI Notification ♦ Cover Letter Template for Notification Submission

Available for purchase via the AHPA online bookstore www.ahpa.org

March 2011 • Page  should certainly be part of any manufactur- approximately 8% ad valorem in some cases, Special Topics er’s or importer’s considerations, especially depending on the specific product. The fish when dealing with dietary supplements. oil supplements could also potentially be CPB’s treatment of fish oil supplements, classified under Chapter 21 as dietary sup- Understanding the specifically the classification or country of plements, if the fish oil supplements are im- Complexities of Customs origin marking of fish oil supplements, ported in an encapsulated or softgel form. Regulations for Herbal serves as a bellwether for issues facing the And, if this encapsulation process takes place in either Canada or Mexico, the pro- and Dietary Supplements importation of a number of other supple- ments and supplement ingredients. cess of encapsulating the fish oils there by Adonica-Jo R. Wada and Neil S. Helfand “transforms” the product to make the neces- Classification of any product imported into sary tariff shift from Chapter 15 to Chapter the United States carries with it an atten- With the rising popularity of dietary supple- 21, and thus eligible for duty-free entry un- ments—specifically fish oil supplements, dant duty rate, or “Customs duties.” der the North American Free Trade which have been proven to be beneficial in Customs duties are chargeable upon the im- Agreement (NAFTA). Although it is possi- reducing the risk for heart disease, improv- portation of goods, which are generally ble to take advantage of preferential tariff ing vision and helpful in battling certain grouped into exclusive, similar categories or treatment under NAFTA by encapsulating cases of Alzheimer’s disease—we have wit- classes of goods. the fish oils in Canada or Mexico, the more nessed increasing scrutiny from governmen- In the United States, bulk and unaltered fish important question is: How should these tal agencies. These agencies are challenging oils have always been classified under fish oil supplements be classified? health claims, the legality of claims made on Chapter 15 of the Harmonized Tariff There are provisions in the tariff code that dietary-supplement labels and whether any Schedule of the United States (HTSUS), would allow for the duty-free treatment of one agency can or should regulate the im- which provides, among other things, for an- the fish oil supplements regardless of where port of herbal or dietary supplements. imal and vegetable fats and oils (Chapter that encapsulation process takes place and Among these agencies, The Bureau of 15). The various subheadings in Chapter possibly whether the fish oils even undergo Customs and Border Protection (CBP) 15 used by Customs are dutiable, up to an encapsulation process.

March 2011 • Page  In the case of Inabata Specialty Chems. v. reliever, but rather, found it sufficient that general health and well being. This is strong United States, 29 C.I.T. 419 (Ct. Int’l Trade the marketplace, among other factors, rec- evidence to support the marketing and pub- 2005), the Court of International Trade ad- ognized CS as a therapeutic substance. In lic perception of the efficacy of fish oil sup- dressed the classification of chondroitin sul- Inabata Specialty, the court recognized that plements and, concurrently, that fish oil fate (CS)—processed bovine cartilage the classification of CS depended upon the supplements are medicaments and should imported in a bulk powder form and that “use” of that product and thus took into be treated and classified as such. With the was used for therapeutic purposes such as to consideration each of the factors to deter- importation of fish oil supplements increas- provide relief from osteoarthritis (OA). The mine what that use is in the United States ing from year to year, the savings in duty court found that the evidence overwhelm- at, or immediately prior to, the date of upon a successful appeal to Customs or, fail- ingly, and essentially uncontrovertibly, es- importation of CS. ing that, the Court of International Trade, tablished that CS was prepared for, bought The same argument that was made in would be substantial and may potentially result in an ocean of savings. and sold, and imported for “therapeutic Inabata Specialty can be made for fish oil uses.” In other words, regardless of whether supplements. There are provisions in the Although this article focuses on issues con- substantial evidence existed as to whether tariff for fish oil supplements that are more cerning fish oil supplements, there are many use of CS had a measurable, positive effect relevant and would allow the fish oil supple- additional herbal and dietary supplements on people suffering from OA, it was unde- ments to be imported into the United States, that may be incorrectly classified and sub- niable that CS was being used as a treatment free of duty regardless of the country of ject to Customs duties. Manufacturers and for that particular ailment, rather than for origin or manufacture. importers would be well served to learn purposes of general health or well being. The industry and the commercial under- more about the classification and country of In determining the proper classification of standing of consumers that purchase fish oil origin marking of herbal and dietary supple- the CS, the Inabata Specialty court recog- supplements is clear—use of the fish oil ments and whether such provisions apply to nized that tariff classification relies heavily supplements is intended to both treat and their products. on commercial practice and understand- prevent various and specific ailments and Adonica-Jo R. Wada is partner in the San ings, not just the indications given on labels, diseases. There is a body of scientific evi- Francisco office of Simon Gluck & Kane, LLP. literature, or otherwise. The court reiterated dence that supports the fact that fish oil Ms. Wada’s practice is focused in import, ex- that it was not required to determine how supplements are prepared, bought, and sold port and international trade law. Neil S. effectively CS functioned as an OA pain for such purposes, and not simply for Helfand is an associate at the firm.

What’s In a Name? Herbs of Commerce, 2nd Edition by Michael McGuffin, John Kartesz, Albert Leung and Arthur Tucker

This revised edition, published in 2000, lists 2,048 separate species, including 25 fungi and 23 seaweeds, by their Standardized Common Names and Latin binomials, and includes Indian Ayurvedic names for more than 300 plants and Chinese (pinyin) names for 500 herbs. Also, 639 botanical synonyms are included; older botanical names no longer accepted can be cross-referenced. AHPA published the first edition in 1992 to reduce confusion by establishing “standardized” common names. It was rec- ognized and codified when FDA adopted the original edition in 1997: the common names may be used instead of Latin binomials to identify herbal ingredients in dietary supplements.

Special Member Price: $79.99 U Non-Member Price: $99.00 To order, call: 301-588-1171 or buy online at: http://www.ahpa.org/bookstore.htm

March 2011 • Page  Kava and the Risk of are most safe for human use (8,9). Early pi- kava-related study and each kava product Liver Toxicity: Past, Current, oneering work has established the chemo- should provide the chemotype of the in- and Future Aspects typing of kava plants (6,10-13) that contain volved kava cultivar. 18 kavalactones, but only the six major kav- In 2003, the opinion was expressed that in by Rolf Teschke, Department of Internal alactones are used to define a particular kava the South Pacific islands, consumption of Medicine II, Division of Gastroenterology chemotype. They are: kavain (K), dihy- aqueous kava extracts had a long tradition and Hepatology, Klinikum Hanau, drokavain (DHK), methysticin (M), dihy- of safe usage to include lack of liver injury Teaching Hospital of the Goethe University dromethysticin (DHM), yangonin (Y), and (19,20), even when higher amounts were of Frankfurt/ Main, Germany desmethoxyyangonin (DMY). The individ- consumed daily over many years (19). In ual kava chemotype may be established by a Editor’s Note: In the process of reviewing the litera- the same year, however, case reports ap- ture for the AHPA Report, I found numerous re- system of kavalactone signatures, attribut- peared showing toxic liver disease in two cent papers on the topic of kava and liver toxicity. ing to each lactone a number in the sequence patients originating from New Caledonia Instead of trying to cover them individually I asked of its elution from the High Performance due to kava use in the form of the tradition- the primary author of most of the articles to consider Liquid Chromatography (HPLC) column al aqueous beverages derived from an un- writing a guest article for AHPA. We are proud to (3): DMY corresponds to 1; DHK to 2; Y to feature that article here. –Steven Dentali, PhD, known kava cultivar (21), possibly a Chief Science Officer 3; K to 4; DHM to 5; and M to 6. When non-drink Two-Day cultivar (8), with sub- the figures are sorted in the sequence of de- sequent confirmed causality evaluation Kava refers to both the South Pacific herb creasing quantities of individual lactones in (4,22,23). In these two cases, there were in- (Piper methysticum G. Forster) and the prod- the sample, a signature is formed by this creased levels of two liver values commonly ucts prepared from its rhizomes and roots method of chemotype coding. Based upon known as transaminases, alanine aminotran- that contain the psychoactive kavalactones this assessment, it became evident that kava ferase (ALT) and aspartate aminotransferase (1). Due to their tranquilizing, sedative, and exists in more than 200 variant strains or (AST) (21). The transaminases were mark- anxiolytic properties, kava is widely used all cultivars (9), categorized as noble cultivars, edly elevated between 13 and 42 times the over the world for recreational and medici- medicinal cultivars, Two-Day cultivars, and upper limit of the normal ranges, findings nal purposes. In the South Pacific, tradi- the wild species Piper wichmannii C.DC, an that are in line with severe liver-cell injury. tional aqueous kava extracts are part of the ancestor of the domesticated kava Piper This particular enzyme constellation (21) social and ceremonial life whereas in Western methysticum (14,15). Moreover, the chemo- was quite different from the pattern of cor- countries kava extracts are used as anxiolytic type may vary between roots, rhizomes, and responding liver values reported in other drugs, kava dietary supplements, and as rec- basal stems (8,13). The multiplicity of kava publications after the use of traditional reational drinks (1-3). Various clinical trials cultivars used for medicinal purposes is the aqueous kava beverages (21,24-26). There have shown efficacy of kava for treatment of consequence of fragmentary standards of were either no activity changes of ALT (24- patients with anxiety disorders (2), but a regulatory agencies and manufacturers (14- 26) and of AST (26), or there were only current overarching concern with kava is 18) and rarely allowed causality attribution marginally elevated ALT and AST levels in the rare occurrence of hepatotoxicity (4) to a single kava cultivar (9). Therefore, it is a few heavy kava users (21). These results and the need to determine causation (5). apparent that any clinical or experimental indicated little if any signs of clinically This review presents some highlights of the kava mystery related to the observed Disclaimer adverse reaction of rare toxic liver injury The views presented in this guest article are those of the author and do not necessarily after kava use in a few susceptible patients. reflect those of AHPA or its members. AHPA’s current Code of Ethics expects members An approach is also made to promote future in good standing of the association that offer kava products for sale for internal use and strategies for safe human kava use and im- that contain kava (Piper methysticum) to label such products so they bear the following provement of kava quality standards. or significantly similar statement: Historical Facts Caution: US FDA advises that a potential risk of rare, but severe, liver injury may be associ- ated with kava-containing dietary supplements. Ask a healthcare professional before use if you For centuries, kava has attracted the interest have or have had liver problems, frequently use alcoholic beverages, or are taking any medica- of physicians, pharmacologists, botanists, tion. Stop use and see a doctor if you develop symptoms that may signal liver problems (e.g., and agriculturists, and the obtained results unexplained fatigue, abdominal pain, loss of appetite, fever, vomiting, dark urine, pale stools, of their studies have been summarized in yellow eyes or skin). Not for use by persons under 18 years of age, or by pregnant or breastfeed- excellent reviews (6,7). In the past, major ef- ing women. Not for use with alcoholic beverages. Excessive use, or use with products that forts have been undertaken to identify those cause drowsiness, may impair your ability to operate a vehicle or dangerous equipment. kava varieties, called also cultivars, which

March 2011 • Page  relevant liver-cell injury (4) in the study Figure 1 groups (21,24-26), as opposed to the two cases from New Caledonia with severe liver toxicity (21). A clinical and scientific highlight was the unexpected observations stemming from five studies (21,24-27) that the use of tradi- tional aqueous kava extracts derived from non-specified kava cultivars caused marked- ly increased levels of γ-glutamyltranspepti- dase (γGT), another liver enzyme commonly used in routine liver-assessment conditions. Among these five reports, three were Australian studies involving Aborigines in Arnhem Land who consumed traditional aqueous kava extracts prepared with kava raw material imported from Pacific Islands (24,25,27). The fourth report studied in- habitants of New Caledonia who consumed traditional aqueous kava beverages prepared from plants imported from Vanuatu (21), and the fifth study provided data of a pre- dominantly Tongan population of Hawaii, Legend to Figure 1: consuming traditional aqueous kava extracts HPLC Chromatogram of the Noble Cultivar Borogu prepared from plants of Hawaii (26). There are six major peaks with retention times of 11.28, 12.28, 15.25, 17.57, 19.57, and 25.75 min- Considering these five studies with increased utes, corresponding to desmethoxyyangonin, dihydrokavain, yangonin, kavain, dihydromethysticin, and γGT levels (21,24-27), serum activities of methysticin, respectively. Details are derived from a previous report (3). another liver enzyme—the alkaline phos- phatase (ALP)—were presented as increased ALP is not found in European cases of kava reports and spontaneous reports communi- (24-26), unchanged (21), or not evaluated liver disease (4,28), the underlying mecha- cated to regulatory health agencies followed, (27). The observed increased levels of both nisms may be different. but again lacking cultivar specifications γGT (21,24-27) and ALP (24-26) deserve There were no case reports of liver disease (4,28,30-32). In 2002, these reports led to further evaluation and are likely to be due to associated with the use of acetonic and eth- withdrawals of kava from various European either malnutrition, alcohol, hepatic en- anolic kava extracts as anxiolytic drugs in countries (1,30,31); to a Food and Drug zyme induction, enzyme adaptation, or Western countries prior to 1998 when the Administration (FDA) consumer advisory cholestasis (4,5) in the investigated study first case of liver disease associated with the in the US (33,34); and to a practitioner groups (21,24-27). Since this particular en- use of a non-specified kava cultivar was alert, consumer advisory, and voluntary zyme constellation of increased γGT and published (29). Consecutively, other case recall in Australia (19). Since 2005, aqueous

March 2011 • Page 10 kava products are available again in Australia as Therapeutic Goods Administration Table 1 (TGA) approved medicinal over-the-coun- Compounds Detected in Kava Roots Extracted with ter products (35,36). Water and Various Organic Solvents Cases of primarily assumed liver disease Compounds Detection in various extracts obtained with caused by kava use (30) have been a matter Water Acetone Ethanol Others of international discussions (31,32,37-41). 1. 10-Methoxyyangonin + - - - Criticisms focused on the poor quality of 2. Hydroxykavain - - - + the regulatory data presented (31,32,37,40), 3. Dihydro-5,6-dehydrokavain + + + + of it being highly selective (42), insufficient- 4. 7,8-Dihydrokavain + + + + ly evaluated (43), and with inappropriate 5. 7,8-Dihydroyangonin - + - + causality-assessment methods used on an 6. Kavain + + + + ad-hoc basis or with the unspecific liver 7. 7,8-Dihydro-5-hydroxykavain - + - + scales of Naranjo and the World Health 8. 5,6-Dihydroyangonin - + - + Organization (WHO) (44). Subsequent 9. 11-Hydroxy-12-methoxydihydrokavain - + - + analysis using a structured, quantitative, 10. 11-Methoxyyangonin - + - + and liver-specific assessment method estab- 11. Desmethoxyyangonin + + + + lished overall causality for kava in only a few 12. 5,6,7,8-Tetrahydroyangonin + + + + patients (4,22,23,28). Surprisingly, liver in- 13. Methysticin - + - + jury observed in these few cases was causally 14. Dihydromethysticin + + + + related to the use of traditional aqueous 15. 11,12-Dimethoxydihydrokavain - - - + kava extracts as well as to the use of acetonic 16. Yangonin + + + + and ethanolic kava drugs. The primary cause 17. 11-Methoxy-12-hydroxydehydrokavain - - - + of the toxic event obviously resides with the 18. 11-Hydroxyyangonin + + - + crude material used to prepare the various 19. 5,6-Dehydromethysticin - + - + kava extracts and may be attributed to poor quality (5), possibly caused also by mold Non-kavalactones hepatotoxins (45,46) rather than to any pri- 1. Flavokavain A - - - + mary constituent of kava (Table 1) (1,47,48) 2. Flavokavain B + + -/+ + as discussed in recent reviews (45,46). 3. Flavokavain C - - - + 4. Cinnamic acid bornyl ester + + + + The Pacific kava paradox—based on kava 5. 5,7-Dimethoxyflavanone - + + + liver disease that was observed following the 6. 2,5,8-Trimethyl-1-naphthol - - - + use of Western acetonic and ethanolic kava 7. 5-Methyl-1-phenylhexen-3-yn-5-ol - - - + drugs but not of traditional aqueous kava 8. 8,11-Octadecadienoic acid-methyl ester + + + + extracts in the Pacific region (19,20)—was 9. Pinostrobin chalcone + + + + suggested in 2003. However, subsequent re- 10. 5-hydroxy-4´-7-Dimethoxyflavanone + + + + ports (4,22,23) and cases of the World 11. 5,7(OH) -4´-one-6,8-dimethylflavone + + - + Health Organization (WHO) (1) revealed 2 12. Cupric acid ? ? + ? that traditional aqueous kava extracts also 13. Pipermethystine ? ? + ? used in New Caledonia, Australia, the US, 14. Glutathione + - - - and Germany may rarely exhibit potential hepatotoxic properties (49). The clinical 15. Chromic acid ? ? ? ? characteristics were similar whether the 16. Aflatoxins of Aspergillus varieties ? ? ? ? hepatotoxic reactions were caused by aque- 17. Hepatotoxic mycotoxins of other fungus var. and other mould hepatotoxins ? ? ? ? ous, acetonic, or ethanolic kava extracts, and identical causality for kava was estab- The data in Table 1 are primarily derived from two reports, mainly from the study of Xuan et al., 2008 (47), lished for all cases and extract varieties but also from the compilation presented by the World Health Organization, 2007 (1). The following details of the assessed kava roots and the used solvents have been communicated: extraction (4,22,23). Since kava hepatotoxicity also of medium water, acetone, 95% ethanol, and others as are chloroform, methanol, and hexane, but occurred after the use of traditional aqueous no details regarding chemotype and part of roots (47); extraction of medium 95% ethanol, and dried, prob- kava extracts in the Pacific region, there is ably unpeeled roots of undeclared chemotype (1). Data for flavokavain B are also derived from the reports no basis to support the previously proposed of Zhou et al., 2010 (48). Details of the table are derived from a previous report (45). Pacific kava paradox (49).

March 2011 • Page 11 Table 2 The Current Situation At present, an abundance of information and proposals are now available regarding Based on current knowledge, the clinical Noble Kava Cultivars of Vanuatu kava quality standardization (3,14-18,33- characteristic of kava-related liver disease is 35,45,55,56) and legislation (14,33-35,56), Noble cultivar Origin Chemotype now fairly well described (4,5,28) and docu- which are prerequisite conditions to im- Ahouia Tanna 426531 mented as possessing features similar to prove both the safety of kava consumers and Amon Tanna 246513 those observed in toxic liver disease due to the quality of kava raw material (1,3,45,55). Asiyai Aneityum 246531 the use of other herbs, dietary supplements, Based on the Republic of Vanuatu Kava Act Bir Kar Santo 246513 and synthetic drugs (4,5,46). Herbal hepa- No. 7 of 2002, only noble kava cultivars are Bir Sul Santo 246531 totoxicity is normally quite difficult to de- to be used as kava drugs or kava dietary sup- Biyai Aneityum 426531 fine regarding its typology, since herbs plements and they must meet various other Borogoru Maewo 425361 represent a combination of various ingredi- quality specifications before export from Borogu Pentecost 423561 ents rather than one single compound as Vanuatu (14). Names and the respective Gegusug Gaua 246531 with synthetic drugs (50-52). In cases of chemotypes of all noble kava cultivars in Ge vemea Vanua Lava 245631 kava liver disease, assignment was made ei- Vanuatu are available (Table 2) (6,8,10,12- Ge wiswisket Gaua 246513 ther to the predictable, intrinsic, and a dose- 15,45). This is useful information for local Kelai Epi 423516 dependent form that requires an farmers, distributors, manufacturers, regu- Leay Tanna 246351 overdose-treatment regimen and is therefore latory agencies, and physicians (3,45,55). Melomelo Ambae 245361 basically preventable, or to the unpredicta- Noble kava cultivars have a long tradition of Melmel Pentecost 246531 ble, idiosyncratic, and a dose-independent safe use (3,6,9,13) and can easily be differ- Miela Emae 426351 form associated with a metabolic subgroup entiated and identified by their characteris- Naga miwok Vanua Lava 246351 that therefore is not preventable (5,46). tic chemotype (3,6,8,9,13) using standard Olitao Emae 245631 Contributing causative factors are overdos- methods that are described in detail (Table Palarasul Santo 246531 es, prolonged kava use, and co-medication 3) (3,6,10,12,45,57). In addition to Vanuatu Palasa Santo 246531 with other herbs and synthetic drugs (5,6). (3,13,14), noble kava cultivars also exist in Paliment Emae 426351 Yet questions still remain that relate to poor other South Pacific islands that lack appro- Pia Tanna 423516 kava quality including adulteration, misi- priate kava legislation (56), a problem at Poivota Santo 243561 dentification, impurities, and mold hepato- least for the present (45). According to the Pualiu Tongoa 246531 toxins (1,3,5,9,15,18,45,46,49). Vanuatu Kava Act, other kava cultivars such Puariki Tongoa 423156 as medicinal cultivars, Two-Day cultivars, Sese Pentecost 245631 Good evidence is now available that the and Wichmannii varieties (14) are now pro- Silese Malekula 423651 kava problem was not limited to the kava hibited for export (14). Urukara Santo 426531 pharmaceutical markets in Germany and Switzerland (22,28,30,32) but may have Another kava quality standard pertains to Table 2 presents an alphabetical order of noble also extended to the kava dietary supple- kava cultivars in Vanuatu with their place of origin the strict use of peeled subaerial rhizomes according to the Republic of Vanuatu Kava Act ment markets with polyherbal kava mix- and roots (3,34,45,55). In the past, kava No. 7 of 2002 (14) and Food Standards Australia tures such as in the Unites States (22,23,53), products occasionally contained aerial parts New Zealand Technical Report, 2005 (15) with Australia (22,23,54), and the traditional of kava plants (1,5,8,9,15,18,55) that con- their chemotypes assessed in their roots as re- kava markets such as New Caledonia in the tain the hepatotoxic compound piperme- ported previously (45). The numbers of the chem- South Pacific Islands (21-23). thystine (1). Aerial parts include in particular otypes correspond to the following kavalactones: 1, desmethoxyyangonin; 2, dihydrokavain; 3, yangonin; 4, kavain; 5, dihydromethysticin; and Table 3 6, methysticin. The data are based on original Standard Method to Assess Chemotype of Kava Cultivars studies of Lebot and Lévesque, 1996 (10), Lebot et al., 1997 (6), and Siméoni and Lebot, 2002 Analytical Approach (12), substantiated by recent reports of Lebot, 1. The kava plant to be assessed should have been dried for at least 2 weeks at 12% room 2006 (8) and Lasme et al., 2008 (13). As far as a humidity cultivar keeps its chemotype fingerprint 42 … or 2. Use of peeled plant organ: both rhizome and roots 24 … , then it is a “noble” cultivar. Other require- ments are that there are no parts exposed to light 3. Absolute ethanol as the solvent of primary choice in the raw material, it is organically grown, all the 4. The previously described standard method of Siméoni and Lebot, 2002 (12) is the primary parts are well identified and separated, it is suf- choice to assess the chemotype of kava cultivar ficiently old (5 yrs. for export), and the village or Other details are presented in additional references (6,10,45,57). Details of the table are derived from origin is known (traceability) (14). Details of the a previous report (45). table are derived from a previous report (45).

March 2011 • Page 12 the lower stems (1,5), adventitious roots Currently, there continues to be kava culti- err on the side of caution and to ensure originating from the stems and extending vation, harvest, consumption, and export in against liver injury, kava-consuming inhab- into the soil (5,18), and upper, not uphilled the South Pacific islands (56). Traditional itants of the kava-producing and -importing parts of rhizomes (45). Of note, peeled and aqueous kava beverages are consumed in the South Pacific islands should undergo clini- unpeeled kava rhizomes and roots are the South Pacific islands for social and cultural cal assessment of their liver function in rela- form of kava raw material used for kava purposes as usual (1,56). While kava legisla- tion to their consumption of kava cultivar, preparations in Australia (35), and peeled tion to ensure good kava quality is available their daily kavalactone intake, and duration rhizomes were required by the German reg- for Vanuatu (14), it is lacking for the other of kava use (45). Overall, the results of these ulatory agency for kava drugs before the South Pacific islands (56); and, this is reason new studies should facilitate further regula- kava ban in 2002 (16,17). for concern (45). The overall demand for tory recommendations and decisions re- Various recent reports advocate that kava kava raw material has decreased since 2002 garding kava use. (1,8,56) because of the European regulatory products to be used as kava drugs or as kava Other novel strategies will be developed to ban (30). Kava-producing countries of the dietary supplements should be water-based minimize hepatotoxic risks due to the use of South Pacific region export part of their (1-3,34-36,55,58-60), as are the traditional kava products. Some proposals have been kava raw material to regional countries such kava beverages of the South Pacific islands made in the past (1,8,9,22,32,50,58), and as Fiji, Kiribati, and New Caledonia (56). (1). This specification has already been ap- new ones are presently emerging in the Kava is also sold in various amounts to plied to medicinal kava products licensed by course of additional analyses (3,45,55,60). countries such as the United States, Canada, the Australian TGA (35) and was suggested Future safety requirements for kava will Europe, China, Japan, New Zealand, and (34) to be included in FDA’s consumer ad- have to take into account previous tradi- Australia (1,56), partly via the Internet (1). visory in the United States (33). The princi- tional experience (6) including farming In the United States, kava is available as a ples of these recommendations are based on practices (6,18) and manufacturer expertise kava dietary supplement (33,34). Medicinal the understanding going back to the safe (1,15). Kava is an effective anxiolytic herb aqueous kava extracts are available in form of aqueous kava extracts used tradi- (1,36,40,41,61) with a high potential for Australia as over-the-counter medicine to be tionally for at least a millennium in the worldwide use (60). However, a prerequisite used for treatment of anxiety (2,35,36), South Pacific region (1,3,19,20). There have will be good-quality kava raw material cre- with a limitation of 125 mg kavalactones been no regulatory reports or published case ated by following Good Agricultural per individual dosage and 250 mg kavalac- reports of liver injury associated with the Practices (GAP) for kava cultivation, farm- tones per day (35). Previous regulatory lim- use of medicinal aqueous kava products in ing, and harvesting followed by manufac- its of 120 mg kavalactones per day were the Australian market since their return in turing sites operating under cGMP standard in Europe for acetonic and ethano- 2005 for the treatment of anxiety symptoms (3,45,55). Updates to previous kava quality- lic kava drugs (16). (35). Lack of liver toxicity was also evident standardization approaches (14-18) are nec- in a short-term clinical trial with aqueous Future Requirements essary, and ethnobotanical studies associated medicinal kava (1,36), but results of already with local expertise and surveillance are re- planned long-term treatment are necessary Long-tem safety and efficacy will be tested quired to achieve good quality of kava raw to confirm these findings (60). to evaluate the risk/benefit ratio in new clin- material (45). Presumably, the principles of Good ical trials with kava extracts for the treat- Key issues for the future also include appro- Manufactural Practice (cGMP) are applied ment of anxiety disorders (1,45,60). The priate kava legislation in order to assure in the course of manufacturing kava dietary use of traditional aqueous extracts obtained good kava quality standards (3,45,55). An supplements in the United States (33) as from peeled rhizomes and peeled roots of a update of the Vanuatu Kava Act (14) is re- well as in Australia for the preparation of noble kava cultivar such as Borogu has been quired to make the kava standards for local medicinal kava products (35). There are, recommended for these studies (3,45,55,60). and export use the same. Pan-Pacific kava however, open questions whether and to As a highlight, for the first time, recent legislation should be the primary aim with what extent these principles have always short-term studies have shown efficacy and the involvement of all kava-producing been followed in the South Pacific islands safety for aqueous kava extracts (36,59,62), South Pacific islands (3,45,55,56), using an (1,21). Shortcomings of kava quality related which confirms previous reports from trials updated version of the Vanuatu Kava Act to adulteration, misidentification, and con- done with acetonic and ethanolic kava ex- (14) as a basis (3). tamination were apparent (1,3,8,9,15,18, tracts (1,40,41,61). One of these new long- 45,55), and elimination of these problems is term studies has been started in Australia Novel experimental studies are required likely due to new legislation, regulatory (60), where aqueous kava extracts are fully to elucidate theoretical pathogenetic guidance, and improved standards of pro- licensed (35), and hopefully other studies, mechanism(s) underlying reported kava-as- cessing and manufacturing. including multi-center ones, will follow. To sociated adverse events (45) in face of the

March 2011 • Page 13 present uncertainty of their culprit(s) tones. Concomitantly, more research should age conditions are so poor that mold may (5,45,46). Available data of numerous re- be conducted on the bioavailability of kava- develop rapidly on the roots only one week ports recently summarized suggests that lactones and non-kavalactones derived from after harvest. In Pacific countries such as causation appears to be multifactorial (45), aqueous kava extracts. Fiji, Tonga, and Samoa, where the beverage which presents a particular challenge for Early theories of kava-associated hepatotox- is prepared from dried raw material, the agrobotanists, botanists, toxicologists, phar- icity focused on the possibility that raw ma- parts can be stored for a longer period, but macologists, farmers, and manufacturers. terial could have been contaminated by oil, mold is still a problem. When dried kava Most importantly, however, there is so far fertilizers, pesticides, nematodes, bacteria, was exported in bags and containers to no clear evidence for a causative role of kav- fungi, and specific plant diseases such as Europe, mold sometimes developed in the alactones (5) or non-kavalactone constitu- kava dieback (18). However, in the past, vir- bags, and if proper inspection did not occur ents such as pipermethystine (45,46,63) tually none of these possible causes have before grinding and extraction, it is likely and flavokavain B (45,46) identified from been explicitly evaluated in detail (1,5). that hepatotoxins, including aflatoxins, kava (Table 1) (1,45). Therefore, additional Future identification of possible hepatotoxic could be present. In fact, a moldy taste of studies should address enzymatic, analyti- kava constituents is desired (45,46,49). the beverage served in local kava bars of cal, and toxicological issues, using aqueous, Recently, inquiries center on the question of Nouméa (New Caledonia) has been recog- acetonic, and ethanolic kava extracts (45). whether kava hepatotoxicity might have nized as a problem (Lebot, personal field These extracts should be derived from dif- been caused by the use of moldy kava raw observation) (45). ferent plant parts such as peeled and un- material (45,46,49). Post-harvest storage of There are few data about kava contamination peeled rhizomes and roots, and their kava material is the major constraint in the by bacteria (18,46,64) and Aspergillus species peelings, from both noble and non-noble warm, humid climate of the Pacific islands producing mycotoxins such as ochratoxin A kava cultivars with clear identification of (18). In Vanuatu and Pohnpei (Micronesia), (45,46,64) and aflatoxins (45,46,65), which their chemotypes. Suggestions for new re- where kava is always consumed fresh, the may be represented as the sum of aflatoxin search activities have also been made with raw material has a maximum shelf life of B1, B2, G1, and G2 (45). In three aqueous respect to enzymatic degradation of kavalac- three to four weeks (45). However, the stor- extracts prepared from the internal part of

March 2011 • Page 14 the kava rhizome (minimizing soil contami- the first step in clarifying whether reported use. Establishing certainty related to rare re- nation) various bacteria species were isolated: kava hepatotoxicity could be due to aflatoxi- ports of kava-associated liver disease awaits Bacillus, Cellulomonas, Enterococcus, cosis, similar to epidemic toxic hepatitis a definitive answer for their final causality Pectobacterium, and Staphylococcus. The caused by food contaminated with aflatox- attribution(s). With the proposed research conclusion was reached that the Bacillus ins that has been reported from India and activities and qualifying measures, it is hoped cereus group and Staphylococcus species may Kenya (67-69). If causally related to aflatox- that the safety of individuals consuming produce toxins and cause foodborne illness ins or other mold-created hepatotoxins, kava will substantially be improved. (64). At present, however, we urgently need kava hepatotoxicity may be regarded as a bacteriological studies using peeled rhi- preventable disease both in the Pacific re- Conclusions zomes and roots, as well as their peelings, gion and in Western countries with respect derived from moldy kava plants, and this to both traditional aqueous and solvent- Kava-related liver disease is a well-defined would possibly provide evidence for addi- based kava extracts. clinical entity that occurred in a few patients after the worldwide use of kava. Toxicity tional bacteria species in sufficient quanti- Some uncertainties remain regarding the ties to elicit hepatotoxicity (45). was associated with ingestion of traditional safety of kava use with respect to various aqueous kava extracts, acetonic and eth- Of greater concern than bacteria are kava quality standards (70). Of particular anolic kava drugs, and kava dietary supple- mycotoxin contaminants (45,46,65,66). interest is the use of aqueous versus organic ments in kava-herb mixtures. These adverse Kava roots obtained from a botanical sup- solvents (1). Ethanolic extracts of kava are reactions emerged unexpectedly in face of plier were found to contain ochratoxin A at manufactured and distributed in New the apparent safe traditional use of kava for a level of 10.3 ng/g. Corrected for about 50 Zealand and in the United States. New thousands of years; these reactions were percent recovery obtained with the analyti- Zealand kava manufacturers supply TGA- most probably a consequence of poor-quali- cal, the actual concentration of ochratoxin compliant aqueous liquid kava extracts as ty raw kava material employed in the manu- was likely closer to 20 ng/g (66). In other well as 90% ethanol/water extracted solid facture of a few kava extracts. Further studies, kava has been found to be contami- kava products and 60% ethanol/water liq- clinical trials and experimental research is nated with least 0.5 ng/g (65) of aflatoxins uid kava extracts, as reported in 2005 (71). necessary to evaluate whether kava hepato- that are known human liver toxins (67-69). The situation in the United States is similar toxicity may be due to mold-produced hep- Other mycotoxins are likely to have similar as manufacturers are not restricted to aque- atotoxins. To minimize hepatotoxic risks hepatotoxicity potency, and an overall as- ous-only extracts and are free to manufac- due to kava use, efforts have to be undertak- sessment has to include examinations of ture hydro-ethanolic (ethanol/water) en to improve kava quality standards and to moldy kava plant rhizomes and roots with extracted products. Labelling of kava prod- establish strict regulations for kava cultiva- their peelings considered separately. It is ucts should provide information regarding tors, farmers, harvesters, manufacturers, and presently unclear whether peeled rhizomes kava cultivar, place of origin, and the used physicians treating patients for anxiety, ten- and roots are to be preferred over the un- plant part and solvent. sion, and restlessness. Thorough national peeled parts. An approach evaluating poten- It is apparent that we need more details on regulatory measures and Pan-Pacific kava tial aflatoxin contamination would represent the multiple facets of kava production and legislation are mandatory.

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Kava: herbal pana- safety and risks including rare hepatotoxici- netic aspects and prospective considerations. cea or liver poison? Med J Aust 2003; 178: ty. Phytomedicine 2003; 10: 440-446 Liver Int 2010; 30: 1270-1279 451-453 32. Schmidt M, Morgan M, Bone K, McMillan 6. Lebot V, Merlin M, Lindstrom L. Kava, the 21. Russmann S, Barguil Y, Cabalion P, J. Kava: a risk-benefit assessment. In: Mills Pacific elixir. New Haven: Yale University Kritsanida M, Duhet D, Lauterburg BH. M, Bone K (Eds). The essential guide to Press; 1997 Hepatic injury due to traditional aqueous herbal safety. Elsevier Churchill Livingstone, 7. Singh YN, Blumenthal M. Kava: An over- extracts of kava root in New Caledonia. St. Louis (Missouri), 2005; 155-221 view. Distribution, mythology, botany, cul- Eur J Gastroenterol Hepatol 2003; 15: 33. FDA (U.S. Food and Drug Administration): ture, chemistry, and pharmacology of the 1033-1036 Consumer advisory: Kava-containing di- South Pacific’s most revered herb. Herbal 22. Teschke, R, Schwarzenboeck A, Akinci A. etary supplements may be associated with Gram 1997; 39: 33-55 Kava hepatotoxicity: a European view. New severe liver injury. Issued March 25, 2002. 8. Lebot V. The quality of kava consumed in Zeal Med J 2008; 121: 1283. Available at: Available at: http://www.fda.gov/Food/ the South Pacific. HerbalGram 2006; 71: http://www.nzma.org.nz/journal/121- ResourcesForYou/Consumers/ucm085482. 34-37 1283/3296/ Accessed February 17, 2011 htm Accessed February 17, 2011 9. Schmidt M. Quality criteria for kava. 23. Teschke R, Genthner A, Wolff A. Kava 34. Teschke R, Schulze J. Risk of kava hepato- HerbalGram 2007; 73: 45-49 hepatotoxicity: Comparison of aqueous, toxicity and the FDA consumer advisory. J 10. Lebot V, Lévesque J. Genetic control of ka- ethanolic, acetonic kava extracts and kava- Am Med Ass 2010; 304: 2174-2175 valactone chemotypes in Piper methysticum herbs mixtures. J Ethnopharmacol 2009; 35. Therapeutic Goods Administration (TGA), cultivars. Phytochemistry 1996; 43: 397-403. 123: 378-384 Australian Government, Department of 11. Lebot V, Johnston E, Zheng QY, McKern 24. Clough AR, Bailie RS, Currie B. Liver func- Health and Aging. Kava fact sheet, April 2005. D, McKenna D. Morphological, phyto- tion test abnormalities in users of aqueous Web page last updated September 20, 2010. chemical and genetic variation in Hawaiian kava extracts. J Toxicol Clin Toxicol 2003; Available at: http://www.tga.gov.au/cm/ka- cultivars of ‘Awa (Kava, Piper methysticum, 41: 821-829 vafs0504.htm Accessed February 17, 2011 Piperaceae). Economic Botany 1999; 53: 25. Clough AR, Jacups SP, Wang Z, Burns CB, 36. Sarris J, Kavanagh DJ, Byrne G, Bone KM, 407-418 Bailie RS, Carney SJ, Collie A, Guyula T, Adams J, Deed G. The Kava Anxiety 12. Siméoni P, Lebot V. Identification of factors McDonald SP, Currie BJ. Health effects of Depression Spectrum Study (KADSS): a determining kavalactone content in Kava kava use in an eastern Arnhem Land com- randomized, placebo-controlled crossover (Piper methysticum Forst. F.). Biochem munity. Intern Med 2003; 33: 336-340 trial using an aqueous extract of Piper me- System Ecol 2002; 30: 413-424 26. Brown AC, Onopa JO, Holck P, Kaufusi P, thysticum. Psychopharmacol 2009b; 205: 13. Lasme P, Davrieux F, Montet D, Lebot V. Kabasawa D, Craig WJ, Dragull K, Levine 399-407 Quantification of kavalactones and deter- AM, Baker JD. Traditional kava beverage 37. Denham A, McIntyre M, Whitehouse J. mination of kava (Piper methysticum) che- consumption and liver function tests in a Kava – the unfolding story: report on a motypes using near-infrared reflectance predominantly Tongan population in work-in-progress. J Altern Complement spectroscopy for quality control in Vanuatu. Hawaii. Clin Toxicol 2007; 45: 549-556 Med 2002; 8: 237-263 J Agric Food Chem 2008; 56: 4976-4981 27. Mathews JD, Riley MD, Fejo L, Munoz E, 38. Schulze J, Raasch W, Siegers CP. Toxicity of 14. Vanuatu Legislation: Republic of Vanuatu Milns NR, Gardner ID, Powers JR, kava pyrones, drug safety and precautions- a Kava Act No. 7 of 2002. Available at: Ganygulpa E, Gununuwawuy BJ. Effects of case study. Phytomedicine 2003; 10, Suppl http://www.paclii.org/vu/legis/num_act/toc- the heavy usage of kava on physical health: IV: 68-73 K.html Accessed February 17, 2011 summary of a pilot survey in an aboriginal 39. Clouatre DL. Kava kava: examining new re- 15. Food Standards Australia New Zealand. community. Med J Aust 1988; 148: ports of toxicity. Toxicol Lett 2004; 150: Kava. A human health risk assessment. 548-555 85-96 Technical report Series No.30. 2005. 28. Teschke R, Schwarzenboeck A, Hennermann 40. Ulbricht C, Basch E, Boon H, Ernst E, Available at: http://www.foodstandards.gov. KH. Kava hepatotoxicity: a clinical survey Hammerness P, Sollars D, Tsourounis C. au/scienceandeducation/publications/techni- and critical analysis of 26 suspected cases. Safety review of kava (Piper methysticum) by the calreportserie1338.cfm Accessed February Eur J Gastroenterol Hepatol 2008; 20: Natural Standard Research Collaboration. 17, 2011 1182-1193 Exp Opin Drug Saf 2005; 4: 779-794

March 2011 • Page 16 41. Ernst E. A re-evaluation of kava (Piper 55. Teschke R, Sarris J, Glass X, Schulze J. 64. Kandukuru P, Huang AS, Dong J, methysticum). Br J Clin Pharmacol 2007; Kava, the anxiolytic herb: back to basics to Bittenbender HC, Li Y. Rapid identifica- 64: 415-417 prevent liver injury? Br J Clin Pharmacol tion of bacterial isolates from aqueous kava 42. Teschke R, Wolff A. Kava hepatotoxicity: 2011; 71: 445-448 (Piper methysticum) extracts by polymerase Regulatory data selection and causality as- 56. Codex alimentarius. Commission E. chain reaction and DNA sequencing. sessment. Dig Liv Dis 2009; 41: 891-901 Discussion Paper on the Development of a Applied Microbiol 2009; 49: 764-768 43. Teschke R, Fuchs J, Bahre R, Genthner A, Standard for Kava. JOINT FAO/WHO 65. Weaver CM, Trucksess MW. Determination Wolff A. Kava hepatotoxicity: comparative FOOD STANDARDS PROGRAMME, of aflatoxins in botanical roots by a modifi- study of two structured quantitative meth- September 2010, eleventh session, CX/ cation of AOAC Official Method 991.31: ods for causality assessment. J Clin Pharm NASWP 10/11/8. Available at: ftp://ftp.fao. single-laboratory validation. J AOAC Int Ther 2010; 35: 545-563 org/codex/ccnaswp11/na11_08e.pdf Accessed 2010; 93: 184-189 February 1, 2011 44. Teschke R, Wolff A. Regulatory causality 66. Trucksess M, Weaver C, Oles C, D’Ovidio 57. Lebot V, Lévesque J. The origin and distri- evaluation methods applied in kava hepato- K, Rader J. Determination of aflatoxins and bution of kava ( Forst. F. toxicity: Are they appropriate? Reg Toxicol Piper methysticum ochratoxin A in ginseng and other botanical Piperaceae): A phytochemical approach. Pharmacol 2011; 59: 1-7 roots by immunoaffinity column cleanup Allertonia 1989; 5: 223-281 45. Teschke R, Qiu SX, Xuan TD, Lebot V. and liquid chromatography with fluores- 58. Sarris J, Adams J, Wardle JL. Time for a re- Kava and kava hepatotoxicity: requirements cence detection. J AOAC Int 2006; 89: assessment of the use of kava in anxiety? for novel experimental, ethnobotanical, and 624-630 Compl Ther Med 2009; 17: 121-122 clinical studies based on a review of the evi- 67. Krishnamachari KA, Bhat RV, Nagarajan V, dence. Phytother Res 2011; in press 59. Sarris J, Adams J, Kavanagh D. An explora- Tilak TB. Hepatitis due to aflatoxicosis. An tive qualitative analysis of participants’ ex- 46. Teschke R, Qiu SX, Lebot V. Herbal hepa- outbreak in Western India. Lancet 1975; perience of using kava versus placebo in an 7915: 1061-1063 totoxicity by kava: update on pipermethys- RCT. Aust J Med Herbalism 2010a; 22: tine, flavokavain B, and mould hepatotoxins 12-16 68. Tandon HD, Tandon BN, Ramalingaswami as primarily assumed culprits. Dig Liv Dis V. Epidemic of toxic hepatitis in India of 60. Sarris J, Teschke R, Stough C, Scholey A, 2011; in press possible mycotoxic origin. Arch Pathol Lab Schweitzer I. Re-introduction of kava (Piper Med 1978; 102: 372-376 47. Xuan TD, Fukuta AA, Wie AC, Elzaawely methysticum) to the EU: Is there a way for- AA, Khanh TD, Tawata S. Efficacy of ex- ward? Planta Med 2011; 77: 107-110 69. Ngindu A, Johnson BK, Ngira JA, Nandwa tracting solvents to chemical compounds of 61. Pittler M H, Ernst E. Kava extract for treat- H, Jansen AJ, Kaviti JN, Siongok TA. kava (Piper methysticum) root. J Nat Med ing anxiety (Cochrane Review). Cochrane Outbreak of acute hepatitis caused by 2008; 62: 188-194 Database Syst Rev 2003; Issue 1: CD003383. aflatoxin poisoning in Kenya. Lancet 1982; 48. Zhou P, Gross S, Liu JH, Yu BY, Feng LL, Wiley Interscience. DOI: 10.1002/ 319: 1346-1348 Nolta J, Sharma V, Piwnica-Worms D, Qiu 14651858 70. Teschke R, Lebot V. Kava Quality SX. Flavokawain B, the hepatotoxic constit- 62. Sarris J, Kavanagh DJ. Kava and St. John’s Standardization Code. Submitted for uent from kava root, induces GSH-sensitive wort: Current evidence for use in mood and publication oxidative stress trough modulation of IKK/ anxiety disorders. J Altern Complement 71. Rasmussen, P. New Zealand Association of NF-κB and MAPK signaling pathways. Med 2009; 15: 827-836 Medical Herbalists. Submission on pro- FASEB J 2010; 24: 4722-4732 63. Lechtenberg M, Quandt B, Schmidt M, posed reclassification of kava as a prescrip- 49. Teschke R, Sarris J, Schweitzer I. Kava Nahrstedt A. Is the alkaloid pipermethys- tion medicine – Medicines classification hepatotoxicity in traditional and modern tine connected with the claimed liver toxici- committee, June 2005. Available at: http:// use: The presumed Pacific kava paradox ty of kava products? Pharmazie 2008; 63: nzamh.org.nz/downloads/kavamay05.pdf hypothesis revisited. Submitted for 71-74 Accessed: February 17, 2011 publication 50. Richardson WN, Henderson L. The safety of kava – a regulatory perspective. Br J Clin Pharmcol 2007; 64: 418-420 51. Teschke R, Bahre R. Severe hepatotoxicity by Indian Ayurvedic herbal products: A structured causality assessment. Ann Hepatol 2009; 8: 258-266 52. Navarro VJ. Herbal and dietary supplement hepatotoxicity. Semin Liver Dis 2009; 29: 373-382 53. Humberston CL, Akhtar J, Krenzelok EP. Acute hepatitis induced by kava kava. J Toxicol / Clin Toxicol 2003; 41: 109-113 54. Gow PJ, Connelly NJ, Hill RL, Crowley P, Angus PW. Fatal fulminant hepatic failure induced by a natural therapy containing kava. Med J Aust 2003; 178: 442-443

March 2011 • Page 17 Legal & Regulatory

The GAO report is focused entirely on claims made on conventional foods and does not address dietary-supplement claims. It discusses GAO Calls for FDA Inspection Authority the issue of qualified health claims in great detail, and in fact may be on Food Claims Records worth reading for no other reason than for its thorough treatment of this subject. In reviewing the use of structure/function claims on by Michael McGuffin, AHPA President conventional foods, the report notes FDA’s position that such claims In a report issued in January, the Government Accountability Office may only be based on a food’s nutritive value, and reiterates that, (GAO) recommended that the Food and Drug Administration unlike the stricter requirements for dietary supplements, food com- (FDA) request Congress amend current law to provide FDA with panies are not required to notify FDA or use disclaimers when they the authorities needed to inspect the evidence that companies use to make structure/function claims. support structure/function and other claims made on food. GAO In recommending that FDA seek congressional authority to inspect made the recommendation so that FDA could “establish whether claim-substantiation records, GAO notes that the Federal Trade there is scientific support for the claims.” In the report, GAO also Commission (FTC) already has such authority for advertising recommends that FDA provide guidance to industry on the type claims. GAO also reports that FTC has “taken enforcement actions and strength of scientific evidence needed to prevent false or mis- for alleged false structure/function claims on food labels and in ad- leading information in a structure/function claim for a food, and vertisements.” The GAO report does not address why FDA should that the agency provide direction to its inspectors so that they can also have authority to inspect food company records since FTC has better identify potentially false or misleading structure/function shown that it is willing to act against companies for claims made not claims on food products. only in advertising but also on product labels. The GAO report is titled: FDA Needs to Reassess its Approach to GAO reports that FDA stated that it would work to determine Protecting Consumers from False or Misleading Claims. It is addressed whether it needs additional statutory authority to inspect food- to Sens. Daniel Inouye, D-HI, and Thad Cochran, R-MS, the chair- claims records and that it would consider providing guidance to the man and ranking member of the Senate Committee on food industry on the type of evidence needed to substantiate struc- Appropriations, respectively; and to Reps. Harold Rogers, R-KY, ture/function claims. On this last point, GAO notes that FDA al- and Norman Dicks, D-WA, who hold these positions on the U.S. ready has such guidance for dietary supplements, and that the agency House of Representatives’ Committee on Appropriations. “could issue a statement that the same principles apply to foods.”

Support Safety by Supporting the Botanical Safety Handbook Revision

AHPA’s Botanical Safety Handbook is a reference book that provides safety information on more than 600 species in trade as ingredients in dietary supplements. An essential reference for health- care providers, consumers, retailers and manufacturers of herbal products, its safety classifications are frequently cited in other publications. Time for an update v Significant herbal research has been published since the BSH was published in 1997 v A number of new ingredients are now on the market.

The revision will be based upon comprehensive literature reviews for each herb, historical uses and traditional knowledge, and case reports of adverse reactions and herb-drug interactions, herb-drug interaction studies, metabolism studies, toxicol- ogy studies and clinical trials. The BSH revision is to be completed over a three-year period, and seed money for the project has been pledged by the Office of Dietary Supplements at the National Institutes of Health, the University of Massachusetts, and individual and corporate contributions to the AHPA-ERB Foundation. Pledge your tax-deductible contribution today! Contact Michael McGuffin at [email protected].

March 2011 • Page 18 A Look Back Provides a Glimpse of Sen. Orrin Hatch, R-UT, worked with Leahy to eliminate a Legislative Action to Come section of the bill that tied these enhanced penalties to viola- tions surrounding new dietary ingredient (NDI) applica- by Peter Evich, National Legislative Consultant, tions. Leahy has reintroduced this legislation (not applicable Van Scoyoc Associates to NDIs) on January 27 as S.216. th The 112 Congress is now in full-operation mode. Congressional  Dietary Supplement Safety Act of 2010 (S.3002): Introduced committee assignments have been finalized in both the House and by Sen. John McCain, R-AZ, this legislation would have Senate and legislative workings such as hearings, debate, and votes placed several onerous regulations and requirements on di- have begun in earnest. etary supplements. For more information on this legislation, click here to see the AHPA Update of February 3, 2010. The Recent Past as Prologue?  Dietary Supplement Full Implementation and Enforcement Act In an attempt to determine what may be in store on the legislative (S.3414 and H.R.3236): Introduced in the Senate by Sens. front for the supplement industry in 2011, one barometer is to ex- Hatch and Tom Harkin, D-IA, and in the House by Rep. amine some of the key bills from the 111th Congress that would have Dan Burton, R-IN, this legislation would have provided the impacted this trade, but were not enacted. Here are five such “left- Food and Drug Administration (FDA) with additional re- over” measures, along with a brief explanation of each: sources to implement the Dietary Supplement Health and  The Food Safety Accountability Act (S.3767): Introduced by Education Act (DSHEA). It would also have required FDA Sen. Patrick Leahy, D-VT, chairman of the Senate Judiciary to annually account for how its supplement-related funds are Committee, this bill would have increased the sentences that used and to report and quantify its enforcement actions in prosecutors can seek, to up to ten years imprisonment for this category. food-safety violations where there is a conscious or reckless  Dietary Supplement Tax Fairness Act (H.R.3263): Introduced disregard of a risk of death or serious bodily injury. Last year, by Burton, this bill would have amended the IRS tax code to American Herbal Pharmacopoeia®

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March 2011 • Page 19 allow food for special dietary use and dietary supplements to Supplement Full Implementation and Enforcement Act and the Dietary be tax-deductible medical expenses. Supplement Tax Fairness Act. He also requested feedback and recom- mendations on updating these bills “so that they address the realities  Designer Anabolic Steroid Control Act (S.4032): Introduced at the end of the 111th Congress by now-retired Sen. Arlen of today’s dietary supplement industry.” A later letter to other com- Specter, D-PA, this measure would have added a number of panies is now reportedly planned and will not include mention of steroid analogs to the list of controlled substances regulated these bills, so that there is no sense that Burton has determined to by the Drug Enforcement Agency. reintroduce either of these any time soon. Given Hatch’s new perch as the ranking member of the Senate Reintroduction Not Seen as Likely Finance Committee and Harkin’s continued role as the chairman of the Senate Committee on Health, Education, Labor, & Pensions To date, except for The Food Safety Accountability Act, none of the (HELP), both clearly will have their congressional plates full this bills have been re-introduced in the 112th Congress. Recall that year. However, they are both likely to be interested in any industry McCain last year pulled his support for his own Dietary Supplement position that develops related to whether the Dietary Supplement Safety Act and instead collaborated with Harkin and Hatch on in- Full Implementation and Enforcement Act or the Designer Anabolic cluding several consensus provisions (i.e., mandatory recall for FDA; Steroid Control Act should be reintroduced. a deadline for FDA to issue guidance of compliance with NDI regu- lations; and converting the current food-facility registration from a Key Factors in the Political Climate one-time process to a biennial renewal) into the food safety bill en- acted at the end of the last Congress. Not surprisingly, McCain has As we look at these bills or any potential new piece of legislation, it is not signaled any interest in resurrecting a reconstituted S.3002 in important to assess the realities of the current climate in Washington the 112th Congress. as well as other factors driving the agenda in the 112th Congress. In a recent letter sent by Burton to a number of U.S. companies in For instance, in regard to the Dietary Supplement Full Implementation the supplement industry, he solicited their opinions on regulations and Enforcement Act, given the overwhelming mood in Washington that impact their businesses and also asked for feedback on the two to reduce federal government spending across the board, any bill supplement-related bills he introduced last year: the Dietary that seeks additional funding will face a nearly impossible uphill Fresh New Look! ‘‘The Tan Sheet’’ NONPRESCRIPTION PHARMACEUTICALS AND NUTRITIONALS Elsevier Business Intelligence is proud to partner with the American Herbal Products Association

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March 2011 • Page 20 climb. Since this bill, as introduced in the prior Congress, boosts These developments do not mean we can or should lower our guard. federal funding for FDA, it would likely be “dead on arrival.” We know from the past that it only takes one or two high-profile In addition to addressing the federal deficit, other priority items news articles to lead to congressional scrutiny, which will be accom- emanating from this Congress will be seen through the lenses of jobs panied by misplaced calls to add further regulatory burdens to the creation and unraveling restrictive regulatory burdens. On the latter supplement industry. Therefore, we can never succumb to compla- point, we know that the chairman of the House Oversight and cency and we will maintain our vigilance. Conversely, though, the Government Reform Committee, Rep. Darrell Issa, R-CA, will be situation at hand may present a unique opportunity for the supple- holding several hearings in the coming months on how federal regu- ment community to—for the very first time—take an offensive pos- latory agencies have been working with stakeholders and the entities ture as it relates to public policy. For example, is it time to consider that they are charged with regulating. We will also see similar hear- advancing a DSHEA-type statutory framework for animal ings conducted by the House Energy and Commerce Committee’s supplements? Oversight and Investigations Subcommittee. The 112th Congress has resulted in several new faces on the congres- sional committees that are key to our trade, such as policy jurisdic- Time for a Non-Defensive Posture? tion and oversight for FDA, the Federal Trade Commission (FTC), and the U.S. Department of Agriculture (USDA), as well as 96 re- As I indicated in my last AHPA Report article (see the January 2011 cently inaugurated members of the House and 16 new senators. AHPA Report), due to the Republican takeover of the lower cham- ber, the House leadership and committee power brokers have With that as a backdrop, AHPA President Michael McGuffin and I changed from the last Congress. Reps. Henry Waxman, D-CA, and have begun to meet with congressional offices to educate members John Dingell, D-MI, who have been formidable critics of supple- and staff about the herbal supplement trade, the strong federal regula- ments, are no longer controlling the policy strings at the House tory structure that currently governs this industry, and our current Energy and Commerce Committee. And the Senate is once again on collaborations with federal agencies. As always, we value and welcome firm terrain, with Harkin as the chairman of HELP, along with your input related to AHPA’s federal advocacy efforts. We ask that you Hatch as ranking member of Senate Finance—in addition to also let us know if there are topics of particular interest to you and look having a seat on Senate HELP. forward to being your advocates during our congressional visits.

March 2011 • Page 21 Dear Retailer: this part of the cGMP, among others. In its petition, AHPA ex- There’s a Hole in the cGMP Bucket pressed concern that this section would invite “for example, an un- scrupulous packaging company to attempt to skirt the Final Rule by Industry needs to fix the problems in the hiding their responsibility to be certain of the identity, purity, regulations regulating repackaged supplements, strength and composition of the dietary supplements that they sell or we can expect FDA to fix them—badly behind this paragraph, or a manufacturing company to take advan- by Anthony L. Young, Esq., Partner, Kleinfeld, Kaplan and Becker, LLP, tage of their knowledge that their customers’ obligations to ensure and AHPA General Counsel product quality is limited by this paragraph.” When the Food and Drug Administration (FDA) promulgated The continuing concerns about products spiked with prescription Good Manufacturing Practice (cGMP) for dietary supplements, it weight-loss or erectile-dysfunction drugs, illegal steroids, or their provided special treatment for those who “package or label a product analogs highlight the size of the hole in this bucket. Labelers and that [is received] for packaging or labeling as a dietary supplement packagers in the United States can receive finished product for label- (and for distribution rather than for return to the supplier) … ” [21 ing or packaging, set minimum specifications, package, label, and CFR §111.75(e)]. This section of the regulation establishes the im- ship a product and claim: “we had no idea” the product was spiked. portant requirements for determining whether dietary-supplement So what is the solution? Perhaps it is time for the retail community to manufacturing specifications have been met. In §111.75(c) and (d) use its powers to assure that products in these classes meet the stan- there are specific requirements for accomplishing this. But for those dards intended by FDA in its guidance regarding dietary supple- who package or label already-manufactured dietary supplement ments. Retailers can and should ask hard questions about products products, all that is required is for the packager or labeler to “visually ex- that are in the categories that FDA identified in the December 15, 2010, amine the product and have documentation to determine whether the letter to industry as the most likely candidates for spiking—those specifications that you established under §111.70(f) are met.” In promoted “for weight loss, sexual enhancement, and body building.” turn, all that the section requires are specifications “to provide suffi- cient assurance that the product you receive is adequately identified Questions to ask: Where were the capsules or tablets manufactured? and is consistent with your purchase order.” If the answer is a US manufacturer, then follow-up would be appro- priate. If the answer is an offshore manufacturer, then the packager In a Petition for Reconsideration filed July 25, 2007, the American or labeler should be quizzed on how it was established that the prod- Herbal Products Association (AHPA) sought reconsideration for uct is not spiked. And there are a myriad of other questions that might be asked. Why should retailers take these steps? The easiest and most obvious answer is to demonstrate the industry’s responsibility to ensure that consumers receive dietary supplements that are not adulterated or misbranded and that deliver what they claim to deliver—and not less than they claim—and certainly in the case of these highly scru- tinized categories, not more than they claim. But what about the products that are marketed as supplements and sold in back rooms, on disappearing and reappearing websites, and out on the streets? These marketers are not representative of or even a part of our industry, and they should remain isolated in their illegal pursuits. What might FDA do? There already exist special cGMPs for low- acid canned foods, juice products, and seafood because these prod- ucts can pose special risks to consumers. Where products pose special risks, FDA can and has established special cGMPs. The di- etary supplement industry’s goal should be to address the problem so FDA does not find it necessary to create a solution that sweeps up, for example, multivitamins formulated for men’s special health needs, weight-loss supplements that have a long track record of safety, and sports- nutrition products generally. As is and has been the case in many other industries and classes of consumer products, the best solution to any problem in our indus- try is the solution we impose on ourselves. Self-regulation certainly beats the alternative.

March 2011 • Page 22 FDA Issues First Reportable Food Registry Report by Anthony L. Young, Esq., Partner, Kleinfeld, Kaplan and Becker, LLP, important tool for targeting our inspection resources, bringing and AHPA General Counsel high-risk commodities into focus, and driving positive change in industry practices—all of which will better protect the public The Food and Drug Administration (FDA) has released a new re- health. port detailing its experience with its Reportable Food Registry (RFR) during the Registry’s first year of existence. The annual re- Reporting under the RFR has mainly related to the presence of port, the Reportable Food Registry Annual Report, is a synopsis of the pathogens. During the period of this first annual report, FDA re- one-year reporting period from Sept. 8, 2009, through Sept. 7, ceived 2,240 reportable submissions. Of those, 229 were primary 2010. It is an extension of the Reportable Food Registry Interim Seven- reports (226 were industry primary reports and three were regulato- Month Report issued in July 2010, which covered the reporting peri- ry primary reports submitted voluntarily by federal and state regula- od Sept. 8, 2009, through March 31, 2010. tory officials); 1,872 weresubsequent reports as a result of a primary report; and 139 were amendments to previously submitted primary The RFR was part of the FDA Amendments of 2007. A reportable or subsequent reports. The 229 primary RFR entries included 201 food is an article of food/feed for which there is a reasonable proba- concerning human food and 28 concerning pet food and animal bility that the use of, or exposure to, such article of food will cause feed. serious adverse health consequences or death to humans or animals. All foods under FDA’s jurisdiction, including animal feed/food and Of note to the botanical industry, 17 of the primary RFR entries in- pet food, may be reportable foods, except for dietary supplements volved spices and seasonings, 16 involved nut and seed products, 14 and infant formula. related to raw agricultural commodities, and eight involved stabiliz- ers, emulsifiers, flavors and colors—all ingredients that are used or On its website, FDA characterizes the report as: are similar to those that are used in botanical dietary supplements. … a measure of our success in receiving early warning on prob- Salmonella was the safety hazard predominantly reported in all these lems with food and feed. The data in this report represent an categories.

March 2011 • Page 23 The largest RFR incident involved hydrolyzed vegetable protein. Here is what FDA reported: Hydrolyzed Vegetable Protein (HVP): A food manufacturing facility received a shipment of a flavor enhancer, HVP, which tests showed to be positive for Salmonella Tennessee. The facility submitted a reportable food report to FDA identifying the prob- lem and its supplier. FDA conducted a risk control review analy- sis and consulted with both the primary report submitter and the supplier. The supplier voluntarily recalled the product and sub- mitted a reportable food report. FDA requested that the supplier notify the immediate subsequent recipients of the reported HVP, which helped FDA identify the many other recipients of the in- gredient. FDA worked with the recipients to address their specific situations. This resulted in: 177 products containing the recalled HVP being removed from commerce as of the date of this report. No illnesses associated with the recalled ingredient have been reported. The HVP recall was responsible for 1001 RFR entries, most of them in March 2010 involving at least 11 different commodity categories. What is noteworthy regarding this HVP situation is that no illnesses were reported, and 117 products were removed from commerce. This involved FDA tracking all users of the HVP in question and then pressuring them to either recall the product or face press releas- es from FDA stating that they were not cooperating with the agency. The net conclusion of FDA and the food industry is that this law is working to address food safety issues before they reach the consumer.

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March 2011 • Page 24 Botanical Science Update

NCCAM Strategic Plan Includes emphasis on basic herbal research as proposed in the new plan will “Integration of Alternative Treatment” yield useful information that will benefit industry and the US popu- lation as a whole.” st At the 41 meeting of the National Advisory Council for NCCAM’s 2011-2015 strategic plan begins with the organization’s Complementary and Alternative Medicine, held in Bethesda, Md., current mission “to define, through rigorous scientific investigation, on February 4, the National Center for Complementary and the usefulness and safety of complementary and alternative medi- Alternative Medicine (NCCAM) announced the release of its cine interventions and their roles in improving health and health Exploring the Science of Complementary and Alternative Medicine: care” and includes among its strategic objectives advancing research Third Strategic Plan 2011-2015. on mind and body interventions, practices, and disciplines, and ad- Josephine Briggs, MD, NCCAM’s director, made a point of high- vancing research on complementary and alternative medicine natural lighting the inclusion, in the legislative mandate that established products. NCCAM, of the director’s responsibility “to study the integration of NCCAM’s approximately equal commitment to mind-body re- alternative treatment ... with the practice of conventional medicine search and natural product research is demonstrated through its as a complement to such medicine and into health care delivery sys- funding of significant research dollars into grants focusing on each tems in the United States.” (Emphasis added) of these areas. In the natural products arena, NCCAM has identified “I think Dr. Briggs’ comment is highly significant because it indi- the following herbs as high-priority topics for grant applications: cates that the Center is looking beyond the success of the newly an- ashwagandha (Withania somnifera), astragalus (Astragalus membra- nounced strategic plan,” says Steven Dentali, PhD, AHPA’s chief naceus), devil’s claw (Harpagophytum procumbens), Echinacea pur- science officer, who attended the meeting. “I have confidence that purea, Asian and American ginseng (Panax ginseng and Panax

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March 2011 • Page 25 quinquefolius), hops (Humulus lupulus), milk thistle (Silybum mari- LITERATURE CITATIONS anum), tripterygium (Tripterygium wilfordii), and turmeric (Curcuma by Steven Dentali, PhD, and Francis Brinker, ND longa). See http://nccam.nih.gov/grants/CAMNP/priorities/ for the complete list. English Plantain Shows Ulcer-Healing Properties

Dentali has been invited to serve on the NCCAM review panel to Melese E, Asres K, Asad M, Engidawork E. Evaluation of help evaluate the first round of natural-product-program applica- the antipeptic ulcer activity of the leaf extract of Plantago tions that NCCAM has received in response to its request for lanceolata L. in rodents. Phytother Res. 2011 Feb 7. doi: applications. 10.1002/ptr.3411. [Epub ahead of print] “Focusing on basic research has always been the foundation for the These researchers evaluated the effects of a water extract of English scientific discovery of what herbs do and how they work,” says plantain leaf in rodent peptic-ulcer models. They based their deci- Dentali. “NCCAM’s direction to determine mechanisms of action sion to study this use from personal communications with tradi- for botanical materials is the right way to go.” Dentali added that he tional healers—they could find no documented report for this use. is pleased to have been able to contribute to the discussion that For the study, the researchers decocted and vacuum-dried fresh plant helped NCCAM codify its current strategic plan during its Think leaves and prepared mucilage from the extract using acetone and Tank Day last March and to be a part of the rigorous evaluation of methanol. They tested the extract against a standard anti-secretory applications proposing to study mechanisms of actions for agent and a cytoprotective agent, ranitidine and misoprostol, botanicals. respectively. “In this way, researchers should be able to point the way to further The extract did not exhibit acute toxicity at a 2,000 mg/kg dose. study, including eventual clinical trial evaluations based on a foun- Both the extract and mucilage conferred benefit, with the high-dose dation of what herbs are known to do,” he adds. extract (400 mg/kg) yielding results on par with those of ranitidine. NCCAM’s strategic plan can be viewed in its entirety at Test results from several animal models led the authors to recognize http://nccam.nih.gov/about/plans/2011/. anti-ulcerogenic effects from this plant material with the inescapable

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March 2011 • Page 26 conclusion that English plantain appears to hold promise as an inex- pensive treatment with little, if any, side effects. Taken as a whole, their research showed better ulcer-healing activity from the water extract of this plant than from the over-the-counter drug ranitidine. While not yet validated in human subjects, this study represents the use of a simple herb as an important healing agent. The cutting-edge ingredient show Fenugreek Fiber Prevented Heartburn in Humans

DiSilvestro RA, Verbruggen MA, Offutt EJ. Anti-heartburn effects of a fenugreek fiber product. Phytother Res. 2011 Jan;25(1):88-91. This study also used the antacid ranitidine (Zantac 75®) as a positive Where control, this time against the use of soluble fiber from fenugreek for the treatment of heartburn symptoms. The authors described the fenugreek-fiber material as a Frutarom Belgium product made from Innovation tempered seeds after roller-milling and sifting to produce an 85% fi- ber fraction, predominantly galactomannan, described as “a (1-4)- linked beta-d mannopyranose backbone with branchpoints from Begins their 6-positions linked to alpha-d-galactose, i.e. 1-6-linked alpha- d-galactopyranose” with a mannose:galactose ratio of approximately ■ MEET hundreds 1:1. The fun of polysaccharide descriptions! of exhibitors offering This was a human study with 45 participants who followed a two- thousands of healthy and week regimen to completion. Interestingly, the placebo faired well innovative ingredients! during the second week of treatment. Even so, the authors stated “that the fenugreek treatment still showed differences from placebo ■ DEVELOP your next for various measures in each of the two intervention weeks.” This best seller was also true for ranitidine, but not as often as with the fiber. This is not an indication that fenugreek fiber worked better than ranitidine ■ LEARN about the latest because in this study they did not give statistically different results ingredient technologies from one another. However, the fenugreek-fiber product performed at least as well as ranitidine over the two weeks of the study. A copy of the full article is available for free download here. Special offer Common Herbal Extracts Prevent Bacterial for AHPA members: Adhesion Register by 3/31 and

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March 2011 • Page 27 subjects; it involved only human colon cells in an anti-adhesion as- they answered but overall were consistent with previous investiga- say. The strongest inhibitors of bacterial binding to the human cells tions that showed efficacy of cannabinoids on motor impairment were licorice (Glycyrrhiza glabra), cayenne (Capsicum annuum) and in MS. ginger (Zingiber officinale). Cytotoxic and antibacterial effects of the extracts were also determined. Passionflower Slightly Improved Sleep Herbal Traditions in Bosnia and Herzegovina Ngan A, Conduit R. A double-blind, placebo-controlled investigation of the effects of Passiflora incarnata (passionflow- Sari -Kundali B, Dobeš C, Klatte-Asselmeyer V, Saukel J. ć ć er) herbal tea on subjective sleep quality. Phytother Res. 2011 Ethnobotanical survey of traditionally used plants in human Feb 3. doi: 10.1002/ptr.3400. [Epub ahead of print] therapy of east, north and north-east Bosnia and Herzegovina. J Ethnopharmacol. 2011 Feb 16;133(3):1051-1076. The results of this clinical trial on 41 individuals showed an im- provement in subjective sleep quality over placebo. The volunteers If you want to take advantage of the herbal knowledge of traditional served as their own controls where they drank passionflower healers it helps if that information is recorded. Someone has to ask (Passiflora incarnata) herb tea, or a placebo tea made of parsley, for a those with the knowledge and then record it. This ethnobotanical week, took a week off, and then consumed the tea that they did not survey of traditionally used plants of east, north and north-east drink during week one. The researchers had the subjects venture a Bosnia and Herzegovina complements an earlier one done for mid- guess as to which tea was which. The subjects didn’t do much better dle, southern and western Bosnia and Herzegovina. This time the than chance in identifying which tea they were drinking. They must identity, location, and indications for 254 plants used in 1,655 dif- not have been herbalists. The authors appear to have done a good ferent preparations were gleaned from interviewing 84 people in 45 job in analyzing the results, including providing reasons why the locations. The plants, preparation forms, and indications were com- other sleep measures they recorded were not impacted in this study. pared with those of the earlier study. Knowledge was typically passed down from mother to daughter, and this had been done for over six generations in some cases. Purple Granadilla Shows Anxiolytic Activity

Li H, Zhou P, Yang Q, Shen Y, Deng J, Li L, Zhao D. Cannabis Extracts Fight MS Symptoms in Mice Comparative studies on anxiolytic activities and flavonoid Buccellato E, Carretta D, Utan A, Cavina C, Speroni E, compositions of Passiflora edulis ‘edulis’ and Passiflora edulis Grassi G, Candeletti S, Romualdi P. Acute and chronic ‘flavicarpa’. J Ethnopharmacol. 2011 Feb cannabinoid extracts administration affects motor function in 16;133(3):1085-1090. a CREAE model of multiple sclerosis. J Ethnopharmacol. 2011 This study reported on the chemical composition and anti-anxiety Feb 16;133(3):1033 -1038. activities of two varieties of members of the passionflower genus Some users of medical cannabis (marijuana) do so to help manage known as Passiflora edulis, namely Passiflora edulis ‘edulis’ with purple symptoms of multiple sclerosis (MS). This knowledge prompted in- fruit and Passiflora edulis ‘flavicarpa’ with yellow fruit. After discuss- terest in investigating the body’s cannabinoids system and cannabi- ing possible taxonomic differences, the authors found reason to be- noid receptors to see if cannabinoid compounds may be effective in lieve that there was more than the color of the fruit rind to distinguish treating MS symptoms. This group tested various cannabis extracts these varieties. Four samples of the leaves of each were collected on a mouse model of MS. They employed three different genotypes from wild Chinese populations, prepared as ethanolic extracts, and of Cannabis sativa, one rich in delta9-tetrahydrocannabinol (del- administered to mice in anxiolytic testing with a median dose equiv- ta9THC), another rich in cannabidiol (CBD), and a third, cannabi- alent to 10 grams of leaf for a person weighing 60 kg (132 lbs). noid-free extract containing mainly bioactive, non-psychoactive Phytochemical analyses of the extracts were also performed. flavonoids. Distinct chemical and pharmacological differences were found be- The researchers found that the different extracts were effective in tween the two varieties with Passiflora edulis ‘flavicarpa’ showing sed- their mouse model, but the results were not consistent in regards to ative and anxiolytic activities. The authors reported that Passiflora the various extracts’ effects on MS; different activity was recorded incarnata (passionflower) is generally specified in pharmacopoeials during different phases of the disease. A clinical effect was seen with and Passiflora edulis generally excluded as the source material for pas- the cannabinoid-free, flavonoid-rich extract during acute treatment. sionflower extracts. Their research showed that a variety ofPassiflora The authors postulated that this may be due to an anti-inflammato- edulis may be an acceptable substitute for Passiflora incarnata but ry effect. Their complex results may have raised more questions than only if its identity as an appropriate variety can be confirmed.

March 2011 • Page 28 Passionflower Synergistically Improves which the alkylamide spilanthol was isolated. This compound dem- SJW Activity onstrated anti-malarial activity against a couple of strains of malaria in vitro. The whole extract and spilanthol were also found to inhibit Fiebich BL, Knörle R, Appel K, Kammler T, Weiss G. the growth of malarial parasites in mice. Somewhat surprisingly, a Pharmacological studies in an herbal drug combination of St. water extract of the plant was found to be more active than the etha- John’s wort (Hypericum perforatum) and passion flower nolic one. The authors noted that Spilanthes oleracea is a component (Passiflora incarnata): In vitro and in vivo evidence of synergy in a formula produced and sanctioned by the National Institute of between Hypericum and Passiflora in antidepressant pharma- Public Health in Mali for the treatment of malaria. Further work is cological models. Fitoterapia. 2011 April;82(3):474-480. needed to determine the viability of Spilanthes acmella for this This study is part of a series of pharmacological investigations into a application. proprietary European formulation (Neurapas® balance) composed of special extracts of Hypericum perforatum (St. John’s wort), Passiflora Patented Essential Oils Used to Repel Mosquitoes incarnata (passionflower), andValeriana officinalis(valerian) used to treat mild depression, anxiety, and sleep disorders. It was conducted Pohlit AM, Lopes NP, Gama RA, Tadei WP, de Andrade- to see if there was a synergistic effect between passionflower extract Neto VF. Patent literature on mosquito repellent inventions and St. John’s wort extract that could support lowering the dose of which contain plant essential oils – A review. Planta Med. St. John’s wort extract to achieve the same results as would be ob- 2011 Feb 15. doi: 10.1055/s-0030-1270723. [Epub ahead tained from St. John’s wort extract alone. of print] The researchers found that the passionflower extract alone had little Preventing mosquito bites can sometimes obviate the need to treat potency in a serotonin re-uptake model, but exhibited a synergistic malaria. This review reported on a search of the literature from 1991 reaction that increased the potency of both low- and high-hyperfo- through May 2010 for patents involving essential oils and mosquito rin St. John’s wort extracts with the effect more pronounced for the repellency and analyzed them according to which country they were low-hyperforin materials. This research suggests that low-dose hy- from, what language is utilized, the essential oils mentioned, and perforin St. John’s wort extracts may perform as well as high-dose what type of patents they represent. It also provides text and tables hyperforin St. John’s wort extracts when combined with a passion- that include information on the essential oils, extraction methods, flower extract, a result that was demonstrated in a rodent model scientific evidence for mosquito repellency, and the repellency or screen for antidepressant activity. Such a preparation could be ex- deterrent effects of individual essential oil components used in the pected to have less impact on St. John’s wort herb-drug interactions patent inventions. The authors point out that the best formulation than single-ingredient St. John’s wort preparations. results will likely be achieved by targeting local and regional mosqui- toes for the repellant properties of the product. “Toothache Plant” Puts the Hurt on Malarial Parasites Muira Puama Performs Well in Mouse Spelman K, Depoix D, McCray M, Mouray E, Grellier P. Alzheimer Model The traditional medicine Spilanthes acmella, and the alkyl- Figueiró M, Ilha J, Linck VM, Herrmann AP, Nardin P, amides spilanthol and undeca-2E-ene-8,10-diynoic acid Menezes CB, Achaval M, Gonçalves CA, Porciúncula LO, isobutylamide, demonstrate in vitro and in vivo antimalarial Nunes DS, Elisabetsky E. The Amazonian herbal marapua- activity. Phytother Res. 2011 Jan 20. [Epub ahead of print] ma attenuates cognitive impairment and neuroglial degenera- About 30 years ago, before everyone knew about echinacea (after we tion in a mouse Alzheimer model. Phytomedicine. 2011 Feb all forgot about it a few decades before that), US herbalists were well 15;18(4):327-333. aware of it, and those who grew herbs, or were close to those who This study reported on the effects of an ethanolic extract of “mar- did, knew about spilanthes, also called toothache plant. Two species, apuama” (muira puama or Ptychopetalum olacoides) at an 800 mg/kg Spilanthes acmella and Spilanthes oleracea, both gave that familiar dose for 14 days in mice with induced neurotoxicity caused by amy- echinacea tingle when you chewed the leaves because they too con- loid plaque deposits. The mice were protected from mental impair- tain alkylamides that create that sensation. These researchers looked ment relative to controls and showed reductions in plaque at potential antimalarial activity of Spilanthes acmella, an application accumulation. This promising research was limited due to the deci- known to traditional herbalists in Africa and India. sion to use the same lot of material that had been previously tested. Whole, fresh, one-year-old plants grown at Horizon Herbs in This highlights the need for standardized controls to assure a consis- Williams, Ore., (where I first chewed on a fresh plant some 30 years tent extract so that the results of future trials can be compared to ago) were harvested and used to prepare an ethanolic extract from those already conducted.

March 2011 • Page 29 Rhodiola Reviews Well; and variable results were found from examination of the studies on More Quality Research Needed cognition. Potential improvements on attention were suggested after short-term administration in young and old, and a positive effect on Hung SK, Perry R, Ernst E. The effectiveness and efficacy of memory was suggested in several other studies, although on the Rhodiola rosea L.: A systematic review of randomized clinical whole the authors concluded that there is insufficient evidence to trials. Phytomedicine. 2011 Feb 15;18(4):235-244. determine if ginkgo improves memory. One way to evaluate the effectiveness of a treatment is to systemati- The research on ginseng (Panax ginseng) and glucose was also con- cally evaluate literature reports of randomized clinical trials that flicted. The available evidence on omega-3 polyunsaturated fatty ac- meet specific criteria. This review found 11 reports that met estab- ids suggests the possibility of delaying or reducing cognitive decline lished quality criteria involving the oral consumption of rhodiola in the elderly, though more research is needed to determine when (Rhodiola rosea) preparations for treating any condition or that used and how much of this material needs to be taken to impact cognitive healthy volunteers. Of the 11 reports, only one met more than 10 of decline and which types of tasks may be affected. The article con- the 15 recommended items of the Consolidated Standards of cludes by pointing out the difficulties in evaluating the data in part Reporting Trials (CONSORT) checklist for herbal medicines inter- due to the “immense variety of testing instruments,” variations in ventions. Regarding the need for future studies to replicate the trial design, and the need for relevant biomarkers that could be mea- promising findings for rhodiola, the authors state: “trials should be sured in future studies. of sufficient sample size, describe their test medication in full detail, and conform with all other requirements laid down in the CONSORT guidelines.” Herb, Drug, and Author Interactions Colalto C. Herbal interactions on absorption of drugs: Free Fitoterapia Special Edition on Research Mechanisms of action and clinical risk assessment. Pharmacol Since DSHEA Res. 2010 Sep;62(3):207-227.

Papers from the 2010 DSHEA Symposium, Chicago, Il, USA, Vlachojannis J, Cameron M, Chrubasik S. Drug interactions DSHEA 2010 Symposium Chicago. Edited by Pauli G. with St. John’s wort products. Pharmacol Res. 2011 Fitoterapia 2011 Jan;82(1):1-92. Mar;63(3):254-256. I reported on this symposium in the April 2010 AHPA Report (vol- Colalto C. Response to the letter “Drug interactions with St. ume 25, number 4, pages 24-29) under the title, Developments in John’s wort products”. Pharmacol Res. 2011 Botanical Dietary Supplements Research 1994 to Today. It was held to Mar;63(3):257-258. celebrate the 80th birthday of Norman Farnsworth, PhD, the guest The first citation is a review of how herbal materials may impact the of honor. The journal Fitoterapia has made the complete proceed- absorption of drugs and what that may mean in clinical settings. It ings available. It was a remarkably well-rounded and informative is interesting, fairly comprehensive, and concludes, among other symposium with the sessions now available for free download from things, that there is good documentation that St. John’s wort the journal’s website. (Hypericum perforatum), grapefruit juice, black pepper, and fiber may cause herb-drug interactions. Its publication provoked a letter Diet, Supplements, and Mental Energy: A Review to the editor (the second citation) that presents a very good descrip- tion of the evidence for St. John’s wort-drug interactions to date, Gorby HE, Brownawell AM, Falk MC. Do specific dietary complete with an extensive table. This provided the author of the constituents and supplements affect mental energy? Review of original article with the opportunity to reply in a way some readers the evidence. Nutr Rev. 2010 Dec;68(12):697-718. might consider as snippy. The effects of ginkgo, ginseng, glucose, and omega-3 polyunsatu- However, in discussing how pharmacologists can contribute to the rated fatty acids on the three aspects of mental energy identified as safety and efficacy of herbal products in a way that translates to best mood, motivation, and cognition are described in this review article clinical practices, Dr. Colalto invoked a mnemonic from another written by the Life Sciences Research Organization (LSRO) of article (Glisson JK, Walker LA. How physicians should evaluate Bethesda, Md. This work evaluated the scientific literature through dietary supplements. Am J Med 2010 May 20;123:577–582) known May of 2010, after the creation of a scientific definition of mental as CARE where “the authors proposed the following challenges: energy that followed a series of workshops hosted by the North a ‘free’ but attentive [C]ommunication with the patients in a American branch of the International Life Sciences Institute (ILSI). ‘non-confrontational manner,’ [A]cquiring knowledge and reference The LSRO review contains tables of published studies of these four about supplements, becoming a [R]eporter of adverse events and materials on mental energy and an analysis of those studies. Definite managing possible interactions, examining and [E]valuating conclusions could not be drawn regarding ginkgo’s effect on mood, literature objectively.”

March 2011 • Page 30 A more complete review of the original article is below. The review ent alkamides with immunomodulatory properties.” That general- was written by Francis Brinker, ND, author of Herbal ization may be about half accurate in regard to roots, but when Contraindications and Drug Interactions plus Herbal Adjuncts with addressing E. purpurea aerial or whole-plant extracts it is mostly Medicines, Fourth Edition (2010 Eclectic Medical Publications, wrong, and does not apply to E. pallida root products at all. Sure Sandy, Ore.). enough, when quoting negligible CYP results from the whole-plant Overall, the coverage of drug-herb interactions in this review article extract that conflict with root-extract positive findings, the author is thorough and relatively balanced, but it becomes typically cloudy fails to make the connection, even though the Gurley et al. 2004 ar- in addressing some important differences in studying botanicals in ticle he cites points this out in the discussion section of that article. comparison to pharmaceutical isolates. The author extensively dis- The attempts to treat herbs like single-compound drugs will contin- cusses in vitro studies that do not represent systemic exposure to the ue to be a problem for those who fail to acknowledge the fact that phytochemical content of complex extracts, which is how herbal the inherent variability in content is part of the challenge in the in- preparations most influence function in humans. However, the ex- terpretation of botanical data that reviewers must learn to discern. amination of the in vitro studies in this review may be more appro- The desire to impose drug standards on herbal preparations will in- priate as it is associated with the author’s emphasis on drug absorption evitably be achieved for a few pharmaceutically manufactured bo- that involves localized exposure to intestinal transporters and meta- tanical products with standardized conformity and significantly bolic enzymes, in contrast to post-absorption effects on the liver. reduced complexity. The rest of the herbal marketplace may be sub- Nonetheless, there have commonly been inconsistencies between jected to attempts to harness or suppress traditional and innovative findings from in vitro, animal, and/or human drug studies of me- processes, but since herbs grow in variable soils and are processed in tabolizing enzymes (cytochrome P-450 or CYP) for herbs and herbal many acceptable but differing ways, ultimately well-intentioned but extracts in these different contexts. To his credit, Dr. Colalto pri- misinformed attempts to constrain the spectrum of effective herbal marily limits his conclusions for each herb to higher-quality evi- preparations will fail. dence from human study outcomes. The other failure of the review in botanical terms was an inadequate Considerations Concerning Kids analysis of particular phytochemical differences in distinctive prepa- Consuming Caffeine rations of the same herb that can result in conflicting data. The au- thor attributes various contrasting human results from some herbal Seifert SM, Schaechter JL, Hershorin ER, Lipshultz SE. preparations to genetic polymorphisms, which would be due to dif- Health effects of energy drinks on children, adolescents, and ferences in individual humans. While genetically determined differ- young adults. Pediatrics 2011 Feb 4. doi:10.1542/peds.2009- ences in how humans react to drugs (pharmacogenetics) are an 3592. [Epub ahead of print] important aspect of variations in human response to herbs, so is the This review article searched one medical database (PubMed) and phytochemical variability between different herbal preparations. Google for studies and information regarding “energy drinks” and Aside from noting the example of differing outcomes obtained from their health effects on humans aged 25 and under. Eighty-one stu- high-hyperforin vs. low-hyperforin St. John’s wort preparations, the dies were found, none of which were systematic reviews. Forty other author inappropriately suggested that a 12-week study with 52 pa- sources of information were reviewed, including twelve websites and tients “failed to confirm a garlic-warfarin interaction” when in fact ten government agency reports. Common ingredients, their thera- that study utilized an aged garlic extract (stated explicitly in the title peutic uses, and adverse effects were reviewed. Product-reported caf- of the article) which is distinctively different in content and CYP feine content and selected additional ingredients of selected products impact from fresh garlic or garlic oil. were also reported (I didn’t know that anyone still misspelled gink- Checking Echinacea species (spp.) discussions is often a good indica- go). Poison Control Centers’ data on caffeine toxicity is reported for tor as to whether the author knows about important differences be- the years 2006 – 2008, national and international regulations are tween products. This author did occasionally specify E. purpurea covered, and more. The authors concluded that these products “have and once acknowledges use of its root extract, but states of Echinacea no therapeutic benefit, and many ingredients are understudied and spp. in general: “The extract consists mainly of lipophilic constitu- not regulated.” It made the news and is available here at no charge.

March 2011 • Page 31 AHPA MEETING SCHEDULE • EXPO WEST 2011 Anaheim Convention Center, Anaheim, California

Except as noted, all meetings will be in the Marriott Anaheim Hotel’s La Jolla Room

WEDNESDAY, MARCH 9

12:00 – 6:00 PM BOARD OF TRUSTEES LUNCHEON & MEETING (HILTON ANAHEIM, PALOS VERDES A/B)

THURSDAY, MARCH 10

7:30 – 8:30 AM REGISTRATION / BREAKFAST (HILTON ANAHEIM, AVALON BALLROOM) 8:30 – NOON ANNUAL MEMBER MEETING: (HILTON ANAHEIM, AVALON BALLROOM) BOARD OF TRUSTEES ELECTION 2011 AHPA AWARDS PRESENTATION 12:30 – 2:00 PM BOARD MEETING / WORKING LUNCH (HILTON ANAHEIM, PALOS VERDES A/B)

FRIDAY, MARCH 11

9:00 – 11:45 AM JOINT MEETING: BOTANICAL RAW MATERIALS, STANDARDS, AND ANALYTICAL LABS COMMITTEES 12:00 – 1:45 PM AHPA-ERB FOUNDATION BOARD MEETING 2:00 – 3:45 PM GOVERNMENT RELATIONS COMMITTEE 4:00 – 5:30 PM COMMUNICATIONS COMMITTEE 6:00 – 8:00 PM AHPA MEMBER RECEPTION W/SPECIAL GUESTS IADSA (HILTON ANAHEIM, PACIFIC BALLROOM B)

SATURDAY, MARCH 12

9:00 – 11:00 AM EDUCATION COMMITTEE 11:15 – 12:45 PM CHINESE HERBAL PRODUCTS COMMITTEE 1:00 – 2:30 PM AYURVEDIC PRODUCTS COMMITTEE 2:45 – 4:15 PM SPORTS NUTRITION COMMITTEE 4:30 – 6:00 PM CANNABIS COMMITTEE

SUNDAY, MARCH 13

10:00 – 11:00 AM AMERICAN HERBAL PHARMACOPOEIA ANNUAL MEETING

SHOW FLOOR SCHEDULE: y FRIDAY, MARCH 11 / SATURDAY, MARCH 12: 10 AM – 6 PM y SUNDAY, MARCH 13: 10 AM – 4 PM

March 2011 • Page 32 Calendar of Botanical Events

 Integrative Healthcare Symposium  International Symposium for High-Performance Thin- March 4 - 6 • New York, N.Y. Layer Chromatography http://www.ihsymposium.com/11/public/enter.aspx July 6 – 8 • Basel, Switzerland http://www.hptlc.com/  Natural Products Expo West & Supply Expo March 10 - 13 • Anaheim, Calif.  27th International Symposium on the Chemistry of http://newhope360. Natural Products com/tradeshows/natural-products-expo-west-2011 July 10 - 15 • Brisbane, Australia http://www.ccm.com.au/home-welcome.php  Institute of Food Technologists Wellness 11 March 23 – 24 • Rosemont, Ill.  American Society of Pharmacognosy http://www.ift.org/meetings-and-events/wellness.aspx July 30 – August 3 San Diego, Calif.  Joint Institute for Food Safety and Nutrition: Microscopic http://www.asp2011.com/ Identification and Characterization of Botanicals March 28 - April 1 • University of Maryland, College Park, Md.  American Association of Naturopathic Physicians http://www.jifsan.umd.edu/events/event_record.php?id=45 Convention August 17 – 20 • Phoenix, Ariz.  International Conference on the Science of Botanicals http://www.naturopathic.org/content.asp?contentid=422 April 11 – 15 • Oxford, Miss. http://www.oxfordicsb.org  Society for Medicinal Plant and Natural Product Research September 4 – 9 • Antalya, Turkey  Institute for Functional Medicine International Symposium: http://www.ga2011.org/ The Challenge of Emerging Infections in the 21st Century: Terrain, Tolerance, and Susceptibility  International Symposium of Essential Oils April 28 - 30 • Bellevue, Wash. September 11 – 14 • Antalya, Turkey http://www.functionalmedicine.org/ifm_ecommerce/Symp18Home.aspx http://www.iseo2011.org/

 SupplySide East  Natural Products Expo East May 2 - 4 • Secaucus, N.J. September 21 - 24 • Baltimore, Md. http://www.supplysideshow.com/2011/east/ http://newhope360. com/tradeshows/natural-products-expo-east-2011  NHP Research Society of Canada May 24 – 27 • Montreal, Canada  Phytochemical Society of North America, http://www.nhprs.ca/?q=node/9 50th Anniversary Meeting December 10 – 15 • The Island of  Institute of Food Technology Food Expo Hawai`i, Hawaii June 11 – 14 • New Orleans, La. http://uhhconferencecenter.com/psna.html http://www.am-fe.ift.org/cms/  International Symposium on Medicinal and  Natural MarketPlace 2011 Aromatic Plants June 23 - 25, 2011 • Las Vegas, Nev. November 15 – 18, 2012 • Chiang Mai, Thailand http://newhope360.com/tradeshows/natural-marketplace-2011 http://www.royalflora2011.com/images/Medicinal.pdf

March 2011 • Page 33