encyclopedia of dietary supplements - the-eye.eu · steffany haaz, k. y. williams, kevin r....

Edited by

Paul M. CoatesJoseph M. Betz

Marc R. BlackmanGordon M. Cragg

Mark LevineJoel Moss

Jeffrey D. White

Encyclopedia of Dietary SupplementsSecond Edition

Encyclopedia of Dietary Supplements

Editorial Advisory Board

Stephen BarnesDepartment of Pharmacology and Toxicology, University ofAlabama at Birmingham, Birmingham, Alabama,U.S.A.

John H. Cardellina IIReevesGroup Consultations, Walkersville, Maryland,U.S.A.

Norman H. FarnsworthUIC/NIH Center for Botanical Dietary Supplements Researchfor Women’s Health, Program for Collaborative Research in thePharmaceutical Sciences, College of Pharmacy, University ofIllinois at Chicago, Chicago, Illinois, U.S.A.

Donald B. McCormickDepartment of Biochemistry, School of Medicine, and Programin Nutrition and Health Sciences, Division of BiologicalSciences, Emory University, Atlanta, Georgia, U.S.A.

Robert M. RussellOffice of Dietary Supplements, National Institutes of Health,Bethesda, Maryland, and Jean Mayer USDA HumanNutrition Research Center on Aging, Tufts University,Boston, Massachusetts, U.S.A.

Noel W. SolomonsCenter for Studies of Sensory Impairment, Aging, andMetabolism (CeSSIAM), Guatemala City, Guatemala

Roy UptonAmerican Herbal Pharmacopoeia R©, Scotts Valley, California,U.S.A.

Steven H. ZeiselDirector, Nutrition Research Institute, and Director, Nutritionand Obesity Research Center, UNC Gillings School of PublicHealth, University of North Carolina, Chapel Hill, NorthCarolina, U.S.A.

Encyclopedia of Dietary SupplementsSecond Edition

Edited by

Paul M. CoatesDirector, Office of Dietary Supplements

National Institutes of Health, Bethesda, Maryland, U.S.A.

Joseph M. BetzOffice of Dietary Supplements


Marc R. BlackmanResearch Service, Veterans Affairs Medical Center

Washington, D.C., U.S.A.Departments of Medicine, George Washington University

Johns Hopkins University and University of Maryland Schools of Medicine

Gordon M. CraggNIH Special Volunteer, Natural Products Branch

Developmental Therapeutics ProgramDivision of Cancer Treatment and Diagnosis

National Cancer Institute, National Institutes of Health, Bethesda, Maryland, U.S.A.

Mark LevineMolecular and Clinical Nutrition Section

Digestive Diseases BranchNational Institute of Diabetes and Digestive and Kidney Diseases


Joel MossTranslational Medicine Branch

National Heart, Lung, and Blood InstituteNational Institutes of Health, Bethesda, Maryland, U.S.A.

Jeffrey D. WhiteDirector, Office of Cancer Complementary and Alternative Medicine

Division of Cancer Treatment and DiagnosisNational Cancer Institute, National Institutes of Health

Bethesda, Maryland, U.S.A.

First published in 2005 by Marcel Dekker, New York, NY.This edition published in 2010 by Informa Healthcare, Telephone House, 69-77 Paul Street, LondonEC2A 4LQ, UK.Simultaneously published in the USA by Informa Healthcare, 52 Vanderbilt Avenue, 7th floor, NewYork, NY 10017, USA.

c© 2010 Informa UK Ltd, except as otherwise indicated.No claim to original U.S. Government works.

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Preface

Welcome to the second edition of Encyclopedia of DietarySupplements, reflecting the combined efforts of more than100 authors from 13 countries on 97 topics. Response tothe first edition, published in 2005 and then supplementedby a series of online chapters, prompted us to revise andexpand the Encyclopedia. There has been considerableexpansion in research on many dietary supplements andtheir ingredients. We expect that this Encyclopedia willcontinue to be a valuable reference for students and re-searchers in physiology and chemistry, for health careproviders, and for consumers who are interested in un-derstanding the kind of science that is—or is not—behindthe claims that are made for dietary supplements that aresold throughout the world, where standards of govern-ment regulation differ from country to country. In theUnited States, sales of products in the dietary supple-ment market approached $25 billion in 2009. Their formand their labeling are regulated by the Food and DrugAdministration (FDA) as a result of legislation passed in1994 called the Dietary Supplement Health and Educa-tion Act (DSHEA). The dietary supplement category inthe United States includes vitamins, minerals, and otheringredients that are found in foods, as well as ingredientsnot ordinarily found in foods—such as extracts of herbsand other natural products—that are used by consumersfor their potential health-promoting, disease-preventing,or performance-enhancing properties. Many of these arerepresented in the chapters of this book.

The Encyclopedia is not just for consumers in theU.S. market, although we acknowledge that the term “di-etary supplements” is an American expression. We arenot aware of any other single term that describes all of thesubstances that we wish to include in this Encyclopedia,although terms such as food supplements, nutritional sup-plements, or natural health products have been applied aswell. Sometimes the claims for benefit of specific productsare borne out by well-documented scientific studies. Inother cases, they are not, or the science to support theiruse is still at an early stage. Enthusiasm for their use maybe based on popular legend or on longstanding patternsof use in traditional healing systems. In this book, we hopethat readers will be able to examine the types of evidencethat have been used to support claims of benefit and safety.

The goal of this book is to provide readers withcomprehensive, yet accessible, information on the currentstate of science for individual supplement ingredients orextracts. To this end, each entry reviews basic informa-tion available about the ingredient including, where ap-plicable, its chemistry and functions, before detailing thepreclinical and clinical literature. Articles conclude withreferences to the relevant literature.

Given the large number of dietary supplement prod-ucts in commerce, this book covers only a small frac-tion of them, with selection based primarily on the fre-quency of their use and the availability of a sufficient sci-ence base to discuss their efficacy and safety. It is clearthat the level of scientific information available differsmarkedly among the various entries. For many ingredi-ents, the chemistry and physiology, preclinical and clinicalinformation, and mechanism of action are well known. Forothers, by contrast, some or many pieces of these data aremissing. The preparation of some commercial productsis of high quality and follows good agricultural, labo-ratory, and manufacturing practices. Again, by contrast,the preparations for others have not been reliable, mak-ing them subject to high variability in content and pos-sible contamination. As dietary supplement use becomesmore widespread, there are growing concerns about safetyof some ingredients, including possible harmful interac-tions between supplements and prescribed drugs. Whenknown, this information is included in the chapters ofthis book. These issues should form the basis for futureresearch.

The field of dietary supplements is a rich one, andthe science related to this large class of ingredients is ex-panding all the time. All the chapters that appeared inthe first edition have been revised and updated for thisedition. In addition to providing these updated chapters,we have included 12 additional chapters on topics notpreviously covered, reflecting the emergence of dietarysupplements in the marketplace, as well as the science be-hind them. There is also a new chapter on the challenges ofdietary supplement research. Additional changes involvegathering several related chapters under “umbrella” top-ics: Carotenoids and Polyphenols. Two of the chapters in thisedition of the Encyclopedia, on Ephedra and Androstene-dione, were commissioned before their status as dietarysupplements in the U.S. market was changed. In 2004,the FDA banned ephedra-containing products from thedietary supplement market in the United States. Also in2004, the FDA issued warning letters to companies thenmarketing products containing androstenedione; the reg-ulatory status of these products as dietary supplementshas therefore changed. Nevertheless, until recently, bothephedra and androstenedione were widely consumed inthe United States. We felt, therefore, that discussion of thescience of these ingredients was important. The chaptershave been updated to reflect the new regulatory status ofthese ingredients.

Where possible and applicable, chapter names forbotanical ingredients have been adapted to conform tothe standardized common names in the American Herbal

v

vi Preface

Products Association’s Herbs of Commerce, Second Edi-tion (2000). The accepted scientific names (with authority)and additional synonyms may be found in the individualchapters.

We express our thanks to the authors of the individ-ual chapters. This is a challenging and somewhat contro-versial field, but we believe that our authors have pro-vided a balanced and current view of the literature. Wealso acknowledge with gratitude the hard work and guid-ance of Informa Healthcare’s editorial staff, particularlythe project editor, Timothy DeWerff.

Finally, we wish to emphasize that the inclusion ofchapters on particular dietary supplements in this Ency-clopedia does not imply that we endorse them.

Paul M. CoatesJoseph M. Betz

Marc R. BlackmanGordon M. Cragg

Mark LevineJoel Moss

Jeffrey D. White

Contents

Preface . . . . vContributors . . . . xThe Challenges of Dietary Supplement Research andConsiderations for Future Studies . . . . xvi

S-Adenosylmethionine 1José M. Mato and Shelly C. Lu

Aloe Vera 7Santiago Rodriguez, Steven Dentali, andDevon Powell

Androstenedione 15Benjamin Z. Leder

L-Arginine 21Mauro Maccario, Guglielmo Beccuti, Valentina Gasco,Mariangela Seardo, Gianluca Aimaretti, EmanuelaArvat, Fabio Lanfranco, and Ezio Ghigo

Astragalus 29Roy Upton

Bilberry 37Marilyn Barrett

Biotin 43Donald M. Mock

Bitter Orange 52Steffany Haaz, K. Y. Williams, Kevin R. Fontaine, andDavid B. Allison

Black Cohosh 60Daniel S. Fabricant, Elizabeth C. Krause, andNorman R. Farnsworth

Blue-Green Algae (Cyanobacteria) 75Wayne W. Carmichael and Mary Stukenberg withJoseph M. Betz

Boron 82Curtiss Hunt

Caffeine 90Harris R. Lieberman, Christina E. Carvey, andLauren A. Thompson

Calcium 101Robert P. Heaney

L-Carnitine, Acetyl-L-Carnitine, andPropionyl-L-Carnitine 107Charles J. Rebouche

β-Carotene 115Elizabeth J. Johnson and Robert M. Russell

Carotenoids Overview 121Elizabeth J. Johnson and Robert M. Russell

Cascara Sagrada 124Kapil K. Soni and Gail B. Mahady

Chaste Tree 129Gail B. Mahady, Joanna L. Michel, and Kapil K. Soni

Choline 136Steven H. Zeisel

Chondroitin Sulfate 144Karla L. Miller and Daniel O. Clegg

Chromium 149Richard A. Anderson and William T. Cefalu

Coenzyme Q10 157Gustav Dallner and Roland Stocker

Conjugated Linoleic Acid 166Kristina B. Martinez, Arion J. Kennedy, andMichael K. McIntosh

Copper 175Leslie M. Klevay

Cordyceps 185John Holliday, Matt Cleaver, Mojca Tajnik, Joseph M.Cerecedes, and Solomon P. Wasser

Cranberry 193Marguerite A. Klein

Creatine 202G. S. Salomons, C. Jakobs, and M. Wyss

Dong Quai 208Roy Upton

Dehydroepiandrosterone 217Salvatore Alesci, Irini Manoli, and Marc R. Blackman

vii

viii Contents

Echinacea Species 226Rudolf Bauer and Karin Woelkart

Elderberry 235Madeleine Mumcuoglu, Daniel Safirman, andMina Ferne

Eleuthero 241Josef A. Brinckmann

Ephedra 250Anne L. Thurn with Joseph M. Betz

Evening Primrose 256Fereidoon Shahidi and Homan Miraliakbari

Feverfew 267Dennis V. C. Awang

Flaxseed 274Lilian U. Thompson and Julie K. Mason

Folate 288Pamela Bagley and Barry Shane

French Maritime Pine 298Peter J. Rohdewald

Garcinia 307Frank Greenway

Garlic 314J. A. Milner

Ginger 325Tieraona Low Dog

Ginkgo 332Kristian Strømgaard, Stine B. Vogensen, Joseph Steet,and Koji Nakanishi

Ginseng, American 339Chong-Zhi Wang and Chun-Su Yuan

Ginseng, Asian 348Lee Jia and Fabio Soldati

Glucosamine 363Karla L. Miller and Daniel O. Clegg

Glutamine 370Steven F. Abcouwer

Goldenseal 379Dennis J. McKenna and Gregory A. Plotnikoff

Grape Seed Extract 391Dallas L. Clouatre, Chithan Kandaswami, andKevin M. Connolly

Green Tea Polyphenols 402Shengmin Sang, Joshua D. Lambert, Chi-Tang Ho, andChung S. Yang

Hawthorn 411Egon Koch, Werner R. Busse, Wiltrud Juretzek, andVitali Chevts

5-Hydroxytryptophan 423Pedro Del Corral, Kathryn S. King, and Karel Pacak

Iron 432Laura E. Murray-Kolb and John Beard

Isoflavones 439Mark Messina

Isothiocyanates 450Elizabeth H. Jeffery and Anna-Sigrid Keck

Kava 459Michael J. Balick, Katherine Herrera, andSteven M. Musser

Lactobacilli and Bifidobacteria 469Linda C. Duffy, Stephen Sporn, Patricia Hibberd,Carol Pontzer, Gloria Solano-Aguilar, Susan V. Lynch,and Crystal McDade-Ngutter

Licorice 479Decio Armanini, Cristina Fiore, Jens Bielenberg, andEugenio Ragazzi

α-Lipoic Acid/Thioctic Acid 487Donald B. McCormick

Lutein 493John Paul SanGiovanni, Emily Y. Chew, andElizabeth J. Johnson

Lycopene 504Rachel Kopec, Steven J. Schwartz, and Craig Hadley

Maca 518Ilias Muhammad, Jianping Zhao, and Ikhlas A. Khan

Magnesium 527Robert K. Rude

Melatonin 538Amnon Brzezinski and Richard J. Wurtman

Milk Thistle 550Elena Ladas, David J. Kroll, and Kara M. Kelly

Niacin 562Christelle Bourgeois and Joel Moss

Noni 570Alison D. Pawlus, Bao-Ning Su, Ye Deng, andA. Douglas Kinghorn

Omega-3 Fatty Acids 577William S. Harris

Contents ix

Omega-6 Fatty Acids 587William L. Smith and Bill Lands

Pancreatic Enzymes 598Naresh Sundaresan, Unwanaobong Nseyo, andJoel Moss

Pantothenic Acid 604Lawrence Sweetman

Pau d’Arco 612Memory P. F. Elvin-Lewis and Walter H. Lewis

Phosphorus 626John J. B. Anderson and Sanford C. Garner

Polyphenols Overview 632Navindra P. Seeram

Proanthocyanidins 635Catherine Kwik-Uribe, Rebecca Robbins, andGary Beecher

Pygeum 650François G. Brackman and Alan Edgar withPaul M. Coates

Quercetin 656Jae B. Park

Red Clover 665Elizabeth C. Krause, Nancy L. Booth, Colleen E.Piersen, and Norman R. Farnsworth

Reishi 680Solomon P. Wasser

Riboflavin 691Richard S. Rivlin

Saw Palmetto 700Edward M. Croom and Michael Chan

Selenium 711Roger A. Sunde

Shiitake 719Solomon P. Wasser

St. John’s Wort 727Jerry M. Cott

Taurine 738Robin J. Marles, Valerie A. Assinewe, Julia A. Fogg,Milosz Kaczmarek, and Michael C. W. Sek

Thiamin 748Hamid M. Said

Turmeric 754Janet L. Funk

Valerian 766Dennis V. C. Awang

Vitamin A 778A. Catharine Ross

Vitamin B6 792James E. Leklem

Vitamin B12 812Lindsay H. Allen

Vitamin C 821Sebastian Padayatty, Michael Graham Espey, andMark Levine

Vitamin D 832Patsy Brannon, Mary Frances Picciano, andMichelle K. McGuire

Vitamin E 841Maret G. Traber

Vitamin K 851J. W. Suttie

Yohimbe 861Joseph M. Betz

Zinc 869Carolyn S. Chung and Janet C. King

Index . . . . 877

Contributors

Steven F. Abcouwer Departments of Surgery, Cellularand Molecular Physiology, and Ophthalmology, PennState University College of Medicine, Milton S. HersheyMedical Center, Hershey, Pennsylvania, U.S.A.

Gianluca Aimaretti Division of Endocrinology,Diabetes and Metabolism, Department of InternalMedicine, University of Turin, Turin, Italy

Salvatore Alesci Discovery Translational Medicine,Pfizer, Collegeville, Pennsylvania, U.S.A.

Lindsay H. Allen United States Department ofAgriculture, Agricultural Research Service—WesternHuman Nutrition Research Center, Davis, California,U.S.A.

David B. Allison Department of Biostatistics/NutritionObesity Research Center, The University of Alabama atBirmingham, Birmingham, Alabama, U.S.A.

John J. B. Anderson Schools of Public Health andMedicine, University of North Carolina, Chapel Hill,North Carolina, U.S.A.

Richard A. Anderson Diet, Genomics, andImmunology Laboratory, Beltsville Human NutritionResearch Center, Beltsville, Maryland, U.S.A.

Decio Armanini Department of Medical and SurgicalSciences, University of Padua, Padua, Italy

Emanuela Arvat Division of Endocrinology, Diabetesand Metabolism, Department of Internal Medicine,University of Turin, Turin, Italy

Valerie A. Assinewe Natural Health ProductsDirectorate, Health Canada, Ottawa, Ontario, Canada

Dennis V. C. Awang MediPlant Consulting Services,White Rock, British Columbia, Canada

Pamela Bagley Biomedical Libraries, DartmouthCollege, Hanover, New Hampshire, U.S.A.

Michael J. Balick Institute of Economic Botany, TheNew York Botanical Garden, Bronx, New York, U.S.A.

Marilyn Barrett Pharmacognosy Consulting, MillValley, California, U.S.A.

Rudolf Bauer Institute of Pharmaceutical Sciences,Department of Pharmacognosy, Karl-Franzens-University Graz, Graz, Austria

John Beard Department of Nutritional Sciences,The Pennsylvania State University, University Park,Pennsylvania, U.S.A. (Deceased).

Guglielmo Beccuti Division of Endocrinology,Diabetes and Metabolism, Department of InternalMedicine, University of Turin, Turin, Italy

Gary Beecher Consultant, Lothian, Maryland, U.S.A.

Joseph M. Betz Office of Dietary Supplements,National Institutes of Health, Bethesda, Maryland,U.S.A.

Jens Bielenberg Department of Medical and SurgicalSciences, University of Padua, Padua, Italy

Marc R. Blackman Research Service, Veterans AffairsMedical Center, Washington, D.C., U.S.A., andDepartments of Medicine, George WashingtonUniversity, Johns Hopkins University, and University ofMaryland Schools of Medicine

Nancy L. Booth Spherix Consulting, Inc, Bethesda,Maryland, U.S.A.

Christelle Bourgeois Max F. Perutz Laboratories,Institute of Medical Biochemistry, Medical University ofVienna, Vienna, Austria

François G. Brackman Fournier Pharma, Garches,France

Patsy Brannon Division of Nutritional Sciences,Cornell University, Ithaca, New York, U.S.A.

Josef A. Brinckmann Traditional Medicinals,Sebastopol, California, U.S.A.

Amnon Brzezinski Department of Obstetrics andGynecology, The Hebrew University–Hadassah MedicalSchool, Jerusalem, Israel

Werner R. Busse Dr. Willmar Schwabe GmbH & Co.KG, Karlsruhe, Germany

Wayne W. Carmichael Department of BiologicalSciences, Wright State University, Dayton, Ohio, U.S.A.

Christina E. Carvey Military Nutrition Division, U.S.Army Research Institute of Environmental Medicine,Natick, Massachusetts, U.S.A.

William T. Cefalu Pennington Biomedical ResearchCenter, Louisiana State University, Baton Rouge,Louisiana, U.S.A.

Joseph M. Cerecedes Mycoverse Unlimited Inc.,Ashland, Oregon, U.S.A.

Michael Chan British Columbia Institute ofTechnology, Burnaby, British Columbia, Canada

x

Contributors xi

Vitali Chevts Dr. Willmar Schwabe GmbH & Co. KG,Karlsruhe, Germany

Emily Y. Chew Division of Epidemiology and ClinicalApplications, National Eye Institute, National Institutesof Health, Bethesda, Maryland, U.S.A.

Carolyn S. Chung Food and Drug Administration,College Park, Maryland, U.S.A.

Matt Cleaver Aloha Medicinals Inc., Carson City,Nevada, U.S.A.

Daniel O. Clegg George E. Wahlen Department ofVeterans Affairs Medical Center and University of UtahSchool of Medicine, Salt Lake City, Utah, U.S.A.

Dallas L. Clouatre Glykon Technologies Group, L.L.C.,Las Vegas, Nevada, U.S.A.

Kevin M. Connolly Glykon Technologies Group,L.L.C., Las Vegas, Nevada, U.S.A.

Pedro Del Corral Grand Forks Human NutritionResearch Center, ARS/USDA, Grand Forks, NorthDakota, U.S.A.

Jerry M. Cott Fulton, Maryland, U.S.A.

Edward M. Croom School of Pharmacy, University ofMississippi, Oxford, Mississippi, U.S.A.

Gustav Dallner Department of Biochemistry andBiophysics, Stockholm University, and Rolf LuftResearch Centre for Diabetes, Karolinska Institutet,Stockholm, Sweden

Ye Deng Division of Medicinal Chemistry andPharmacognosy, College of Pharmacy, The Ohio StateUniversity, Columbus, Ohio, U.S.A.

Steven Dentali American Herbal Products Association,Silver Spring, Maryland, U.S.A.

Linda C. Duffy Natural Products Branch, NationalCenter for Complementary and Alternative Medicine,National Institutes of Health, Department of Health andHuman Services, Bethesda, Maryland, U.S.A.

Alan Edgar Fournier Pharma, Garches, France

Memory P. F. Elvin-Lewis Department ofBiology,Washington University, St. Louis, MO, U.S.A

Michael Graham Espey Molecular and ClinicalNutrition Section, Digestive Diseases Branch, NationalInstitute of Diabetes and Digestive and Kidney Diseases,National Institutes of Health, Bethesda, Maryland, U.S.A

Daniel S. Fabricant Natural Products Association,Washington, D.C., and UIC/NIH Center for BotanicalDietary Supplements Research for Women’s Health,Program for Collaborative Research in thePharmaceutical Sciences, College of Pharmacy,University of Illinois at Chicago, Chicago, Illinois,U.S.A.

Norman R. Farnsworth UIC/NIH Center for BotanicalDietary Supplements Research, Program forCollaborative Research in the Pharmaceutical Sciences,Department of Medicinal Chemistry and

Pharmacognosy, College of Pharmacy, University ofIllinois at Chicago, Chicago, Illinois, U.S.A.

Mina Ferne The Israeli Association of Medicinal Plants(EILAM), Israel

Cristina Fiore Department of Medical and SurgicalSciences, University of Padua, Padua, Italy

Julia A. Fogg Natural Health Products Directorate,Health Canada, Ottawa, Ontario, Canada

Kevin R. Fontaine Division of Rheumatology, JohnsHopkins University School of Medicine, Baltimore,Maryland, U.S.A.

Janet L. Funk Department of Medicine, College ofMedicine, Arizona Health Sciences Center, University ofArizona, Tucson, Arizona, U.S.A.

Sanford C. Garner SRA International, Durham, NorthCarolina, U.S.A.

Valentina Gasco Division of Endocrinology, Diabetesand Metabolism, Department of Internal Medicine,University of Turin, Turin, Italy

Ezio Ghigo Division of Endocrinology, Diabetes andMetabolism, Department of Internal Medicine,University of Turin, Turin, Italy

Frank Greenway Division of Clinical Trials,Pennington Biomedical Research Center, Louisiana StateUniversity System, Baton Rouge, Louisiana, U.S.A.

Steffany Haaz Division of Rheumatology, JohnsHopkins University School of Medicine, Baltimore,Maryland, U.S.A.

Craig Hadley Mead Johnson Nutritionals RegulatoryScience, Evansville, Indiana, U.S.A.

William S. Harris Sanford School of Medicine,University of South Dakota and Sanford Research/USD,Sioux Falls, South Dakota, U.S.A.

Robert P. Heaney Creighton University, Omaha,Nebraska, U.S.A.

Katherine Herrera Institute of Economic Botany, TheNew York Botanical Garden, Bronx, New York, U.S.A.

Patricia Hibberd Center for Global Health Research,Departments of Medicine, Pediatrics, and Public Health,Tufts University School of Medicine, Boston, MA, U.S.A.

Chi-Tang Ho Department of Food Science, CookCollege, Rutgers, The State University of New Jersey,New Brunwick, New Jersey, U.S.A.

John Holliday Aloha Medicinals Inc., Carson City,Nevada, U.S.A.

D. Craig Hopp National Institutes of Health, NationalCenter for Complementary and Alternative Medicine,Bethesda, Maryland, U.S.A.

Curtiss Hunt Vienna, Austria

C. Jakobs VU University Medical Center, Departmentof Clinical Chemistry, Metabolic Unit, Amsterdam, TheNetherlands

xii Contributors

Elizabeth H. Jeffery Department of Food Science andHuman Nutrition, University of Illinois atUrbana-Champaign, Urbana, Illinois, U.S.A.

Lee Jia Developmental Therapeutics Program, Divisionof Cancer Treatment and Diagnosis, National CancerInstitute, National Institutes of Health, Rockville,Maryland, U.S.A.

Elizabeth J. Johnson Jean Mayer USDA HumanNutrition Research Center on Aging at Tufts University,Boston, Massachusetts, U.S.A.

Wiltrud Juretzek Dr. Willmar Schwabe GmbH & Co.KG, Karlsruhe, Germany

Milosz Kaczmarek Natural Health ProductsDirectorate, Health Canada, Ottawa, Ontario, Canada

Chithan Kandaswami State University of New York atBuffalo, Buffalo, New York, U.S.A.

Anna-Sigrid Keck Department of Food Science andHuman Nutrition, University of Illinois at Urbana-Champaign, Urbana, Illinois, and Research Institute,Carle Foundation Hospital, Urbana, Illinois, U.S.A.

Kara M. Kelly Division of Pediatric Oncology,Integrative Therapies Program for Children with Cancer,College of Physicians and Surgeons, ColumbiaUniversity Medical Center, New York, U.S.A.

Arion J. Kennedy Department of Nutrition, Universityof North Carolina at Greensboro, Greensboro, NorthCarolina, U.S.A.

Ikhlas A. Khan National Center for Natural ProductsResearch, Research Institute of Pharmaceutical Sciences,School of Pharmacy, University of Mississippi,Mississippi, U.S.A.

Janet C. King Children’s Hospital Oakland ResearchInstitute, Oakland, California, U.S.A.

Kathryn S. King Program in Adult Endocrinology andMetabolism, Eunice Kennedy Shriver National Instituteof Child Health and Human Development, NationalInstitutes of Health, Bethesda, Maryland, U.S.A.

A. Douglas Kinghorn Division of Medicinal Chemistryand Pharmacognosy, College of Pharmacy, The OhioState University, Columbus, Ohio, U.S.A.

Marguerite A. Klein Office of Dietary Supplements,Office of the Director, National Institutes of Health,Bethesda, Maryland, U.S.A.

Leslie M. Klevay University of North Dakota School ofMedicine and Health Sciences, Grand Forks, NorthDakota, U.S.A.

Egon Koch Dr. Willmar Schwabe GmbH & Co. KG,Karlsruhe, Germany

Rachel Kopec The Ohio State University, Columbus,Ohio, U.S.A.

Elizabeth C. Krause UIC/NIH Center for BotanicalDietary Supplements Research, Program forCollaborative Research in the Pharmaceutical Sciences,

Department of Medicinal Chemistry andPharmacognosy, College of Pharmacy, University ofIllinois at Chicago, Chicago, Illinois, U.S.A.

David J. Kroll Natural Products Laboratory, ResearchTriangle Institute (RTI International), Research TrianglePark, North Carolina, U.S.A.

Catherine Kwik-Uribe Mars Chocolate NA,Hackettstown, New Jersey, U.S.A.

Elena Ladas Division of Pediatric Oncology, IntegrativeTherapies Program for Children with Cancer, College ofPhysicians and Surgeons, New York, U.S.A.

Joshua D. Lambert Department of Food Science, ThePennsylvania State University, University Park,Pennsylvania, U.S.A.

Bill Lands College Park, Maryland, U.S.A.

Fabio Lanfranco Division of Endocrinology, Diabetesand Metabolism, Department of Internal Medicine,University of Turin, Turin, Italy

Benjamin Z. Leder Massachusetts General Hospitaland Department of Medicine, Harvard Medical School,Boston, Massachusetts, U.S.A.

James E. Leklem Oregon State University, Corvallis,Oregon, U.S.A.

Mark Levine Molecular and Clinical Nutrition Section,Digestive Diseases Branch, National Institute of Diabetesand Digestive and Kidney Diseases, National Institutesof Health, Bethesda, Maryland, U.S.A

Walter H. Lewis Department of Biology, WashingtonUniversity, St. Louis, MO, U.S.A

Harris R. Lieberman Military Nutrition Division, U.S.Army Research Institute of Environmental Medicine,Natick, Massachusetts, U.S.A.

Tieraona Low Dog University of Arizona HealthSciences Center, Tucson, Arizona, U.S.A.

Shelly C. Lu Division of Gastroenterology and LiverDiseases, USC Research Center for Liver Diseases,Southern California Research Center for ALPD andCirrhosis, Keck School of Medicine, University ofSouthern California, Los Angeles, California, U.S.A.

Susan V. Lynch UCSF Crohn’s and Colitis MicrobiomeResearch Core, Division of Gastroenterology,Department of Medicine, University of California, SanFrancisco, CA, U.S.A.

Mauro Maccario Division of Endocrinology, Diabetesand Metabolism, Department of Internal Medicine,University of Turin, Turin, Italy

Gail B. Mahady Department of Pharmacy Practice,College of Pharmacy, PAHO/WHO Collaborating Centerfor Traditional Medicine, University of Illinois atChicago, Chicago, Illinois, U.S.A.

Irini Manoli Genetics and Molecular Biology Branch,National Human Genome Research Institute, NationalInstitutes of Health, Bethesda, Maryland, U.S.A.

Contributors xiii

Robin J. Marles Natural Health Products Directorate,Health Canada, Ottawa, Ontario, Canada

Kristina B. Martinez Department of Nutrition,University of North Carolina at Greensboro, Greensboro,North Carolina, U.S.A.

Julie K. Mason Department of Nutritional Sciences,Faculty of Medicine, University of Toronto, Toronto,Ontario, Canada

José M. Mato CIC bioGUNE, Centro de InvestigaciónBiomédica en Red de Enfermedades Hepáticas yDigestivas (CIBERehd), Bizkaia, Spain

Donald B. McCormick Department of Biochemistry,School of Medicine, Emory University, Atlanta, Georgia,U.S.A.

Crystal McDade-Ngutter Division of NutritionResearch Coordination, National Institutes of Health,Department of Health and Human Services, Bethesda,Maryland, U.S.A.

Michelle K. McGuire School of Molecular Biosciences,Washington State University, Pullman, Washington,U.S.A.

Michael K. McIntosh Department of Nutrition,University of North Carolina at Greensboro, Greensboro,North Carolina, U.S.A.

Dennis J. McKenna Center for Spirituality andHealing, Academic Health Center, University ofMinnesota, Minneapolis, Minnesota, U.S.A.

Mark Messina Department of Nutrition, School ofPublic Health, Loma Linda University, Loma Linda,California, and Nutrition Matters, Inc., Port Townsend,Washington, U.S.A.

Catherine M. Meyers National Institutes of Health,National Center for Complementary and AlternativeMedicine, Bethesda, Maryland, U.S.A.

Joanna L. Michel Department of Pharmacy Practice,College of Pharmacy, University of Illinois at Chicago,Chicago, Illinois, U.S.A.

Karla L. Miller University of Utah School of Medicine,Salt Lake City, Utah, U.S.A.

J. A. Milner Nutritional Science Research Group,Division of Cancer Prevention, National Cancer Institute,Rockville, Maryland, U.S.A.

Homan Miraliakbari Department of Biochemistry,Memorial University of Newfoundland, St. John’s,Newfoundland, Canada

Donald M. Mock Department of Biochemistry andMolecular Biology, University of Arkansas for MedicalSciences, Little Rock, Arkansas, U.S.A.

Joel Moss Translational Medicine Branch, NationalHeart, Lung, and Blood Institute, National Institutes ofHealth, Bethesda, Maryland, U.S.A.

Ilias Muhammad National Center for NaturalProducts Research, Research Institute of Pharmaceutical

Sciences, School of Pharmacy, University of Mississippi,Mississippi, U.S.A.

Madeleine Mumcuoglu Razei Bar Industries,Jerusalem, Israel

Laura E. Murray-Kolb Department of NutritionalSciences, The Pennsylvania State University, UniversityPark, Pennsylvania, U.S.A.

Steven M. Musser Office of Scientific Analysis andSupport, Center for Food Safety and Applied Nutrition,United States Food and Drug Administration, CollegePark, Maryland, U.S.A.

Koji Nakanishi Department of Chemistry, ColumbiaUniversity, New York, U.S.A.

Unwanaobong Nseyo Translational Medicine Branch,National Heart, Lung, and Blood Institute, NationalInstitutes of Health, Bethesda, Maryland, U.S.A.

Karel Pacak Program in Adult Endocrinology andMetabolism, Eunice Kennedy Shriver National Instituteof Child Health and Human Development, NationalInstitutes of Health, Bethesda, Maryland, U.S.A.

Sebastian Padayatty Molecular and Clinical NutritionSection, Digestive Diseases Branch, National Institute ofDiabetes and Digestive and Kidney Diseases, NationalInstitutes of Health, Bethesda, Maryland, U.S.A

Jae B. Park Phytonutrients, Genomics, andImmunology Laboratory, BHNRC, ARS, United StatesDepartment of Agriculture, Beltsville, Maryland, U.S.A.

Alison D. Pawlus Groupe d’Etude des SubstancesVégétales à Activité Biologique, Faculté de Pharmacie,Institut des Sciences de la Vigne et du Vin de Bordeaux,Université Bordeaux 2, Bordeaux, France

Mary Frances Picciano Office of Dietary Supplements,National Institutes of Health, Bethesda, Maryland, U.S.A.

Colleen E. Piersen UIC/NIH Center for BotanicalDietary Supplements Research, Program forCollaborative Research in the Pharmaceutical Sciences,Department of Medicinal Chemistry andPharmacognosy, College of Pharmacy, University ofIllinois at Chicago, Chicago, Illinois, U.S.A.

Gregory A. Plotnikoff Penny George Institute forHealth and Healing, Abbott Northwestern Hospital,Minneapolis, Minnesota, U.S.A.

Carol Pontzer Natural Products Branch, NationalCenter for Complementary and Alternative Medicine,National Institutes of Health, Department of Health andHuman Services, Bethesda, Maryland, U.S.A.

Devon Powell International Aloe Science Council,Silver Spring, Maryland, U.S.A.

Eugenio Ragazzi Department of Pharmacology andAnaesthesiology, University of Padua, Padua, Italy

Charles J. Rebouche Carver College of Medicine,University of Iowa, Iowa City, Iowa, U.S.A.

Richard S. Rivlin Rogosin Institute, New York, U.S.A.

xiv Contributors

Rebecca Robbins Mars Chocolate NA, Hackettstown,New Jersey, U.S.A.

Santiago Rodriguez Lorand Laboratories LLC,Houston, Texas, U.S.A.

Peter J. Rohdewald Institute of PharmaceuticalChemistry, Westfälische Wilhelms-Universität Münster,Münster, Germany

A. Catharine Ross Department of Nutritional Sciences,The Pennsylvania State University, University Park,Pennsylvania, U.S.A.

Robert K. Rude Keck School of Medicine, University ofSouthern California, Los Angeles, California, U.S.A.

Robert M. Russell Office of Dietary Supplements,National Institutes of Health, Bethesda, Maryland, andJean Mayer USDA Human Nutrition Research Center onAging, Tufts University, Boston, Massachusetts, U.S.A.

Daniel Safirman Razei Bar Industries, Jerusalem, Israel

Hamid M. Said Department of Medicine andPhysiology/Biophysics, University of California Schoolof Medicine, Irvine, California, U.S.A., and Departmentof Medical Research, VA Medical Center, Long Beach,California, U.S.A.

G. S. Salomons VU University Medical Center,Department of Clinical Chemistry, Metabolic Unit,Amsterdam, The Netherlands

Shengmin Sang Center for Excellence in Post-HarvestTechnologies, North Carolina Agricultural and TechnicalState University, North Carolina Research Campus,Kannapolis, North Carolina, U.S.A.

John Paul SanGiovanni Division of Epidemiologyand Clinical Applications, National Eye Institute,National Institutes of Health, Bethesda, Maryland,U.S.A.

Steven J. Schwartz The Ohio State University,Columbus, Ohio, U.S.A.

Mariangela Seardo Division of Endocrinology,Diabetes and Metabolism, Department of InternalMedicine, University of Turin, Turin, Italy

Navindra P. Seeram Bioactive Botanical ResearchLaboratory, Department of Biomedical andPharmaceutical Sciences, College of Pharmacy,University of Rhode Island, Kingston, Rhode Island,U.S.A.

Michael C. W. Sek Natural Health ProductsDirectorate, Health Canada, Ottawa, Ontario, Canada

Fereidoon Shahidi Department of Biochemistry,Memorial University of Newfoundland, St. John’s,Newfoundland, Canada

Barry Shane Nutritional Sciences and Toxicology,University of California, Berkeley, California, U.S.A.

William L. Smith University of Michigan MedicalSchool, Ann Arbor, Michigan, U.S.A.

Gloria Solano-Aguilar Diet, Genomics, andImmunology Laboratory, Beltsville Human Nutrition

Research Center, Agricultural Research Service, UnitedStates Department of Agriculture, Beltsville, Maryland,U.S.A.

Fabio Soldati Pharmaton SA, Scientific Coordination,Bioggio, Switzerland

Kapil K. Soni Department of Pharmacy Practice,College of Pharmacy, PAHO/WHO Collaborating Centerfor Traditional Medicine, University of Illinois atChicago, Chicago, Illinois, U.S.A.

Stephen Sporn St. John’s Integrative Medicine Clinic,Springfield, MO, U.S.A.

Joseph Steet Department of Biology, ColumbiaUniversity, New York, U.S.A.

Roland Stocker Centre for Vascular Research, School ofMedical Sciences (Pathology) and Bosch Institute,Sydney Medical School, University of Sydney, Sydney,New South Wales, Australia

Kristian Strømgaard Department of MedicinalChemistry, The Faculty of Pharmaceutical Sciences,University of Copenhagen, Copenhagen, Denmark

Mary Stukenberg Department of Biological Sciences,Wright State University, Dayton, Ohio, U.S.A.

Bao-Ning Su Analytical Research and Development,Bristol-Myers Squibb, New Brunswick, New Jersey,U.S.A.

Naresh Sundaresan Translational Medicine Branch,National Heart, Lung, and Blood Institute, NationalInstitutes of Health, Bethesda, Maryland, U.S.A.

Roger A. Sunde Department of Nutritional Sciences,University of Wisconsin, Madison, Wisconsin, U.S.A.

J. W. Suttie Department of Biochemistry, College ofAgricultural and Life Sciences, University ofWisconsin–Madison, Madison, Wisconsin, U.S.A.

Lawrence Sweetman Mass Spectrometry Laboratory,Institute of Metabolic Disease, Baylor Research Institute,Dallas, Texas, U.S.A.

Mojca Tajnik Institute of Pathology, Faculty ofMedicine, University of Ljubljana, Slovenia

Lauren A. Thompson Military Nutrition Division, U.S.Army Research Institute of Environmental Medicine,Natick, Massachusetts, U.S.A.

Lilian U. Thompson Department of NutritionalSciences, Faculty of Medicine, University of Toronto,Toronto, Ontario, Canada

Anne L. Thurn Office of Dietary Supplements,National Institutes of Health, Bethesda, Maryland, U.S.A.

Maret G. Traber Department of Nutrition and ExerciseSciences, Linus Pauling Institute, Oregon StateUniversity, Corvallis, Oregon, U.S.A.

Roy Upton American Herbal Pharmacopoeia R©, ScottsValley, California, U.S.A.

Stine B. Vogensen Department of MedicinalChemistry, The Faculty of Pharmaceutical Sciences,

Contributors xv

University of Copenhagen, Universitetsparken 2,DK-2100 Copenhagen, Denmark

Chong-Zhi Wang Tang Center for Herbal MedicineResearch, University of Chicago, Chicago, Illinois, U.S.A.

Solomon P. Wasser Department of Evolutionary andEnvironmental Biology, Faculty of Science and ScienceEducation and Institute of Evolution, University ofHaifa, Haifa, Israel, and N. G. Kholodny Institute ofBotany National Academy of Sciences of Ukraine, Kiev,Ukraine

K. Y. Williams Department of Biostatistics/NutritionObesity Research Center, The University of Alabama atBirmingham, Birmingham, Alabama, U.S.A.

Karin Woelkart Institute of Pharmaceutical Sciences,Department of Pharmacognosy, Karl-Franzens-University Graz, Graz, Austria

Richard J. Wurtman Cecil H. Green DistinguishedProfessor, M.I.T. Department of Brain & Cognitive

Sciences, Massachusetts Institute of Technology,Cambridge, Massachusetts, U.S.A.

M. Wyss DSM Nutritional Products Ltd., Research andDevelopment Base Products, Basel, Switzerland

Chung S. Yang Department of Chemical Biology, SusanLehman Cullman Laboratory for Cancer Research, ErnestMario School of Pharmacy, Rutgers, The State Universityof New Jersey, Piscataway, New Jersey, U.S.A.

Chun-Su Yuan Tang Center for Herbal MedicineResearch, University of Chicago, Chicago, Illinois, U.S.A.

Steven H. Zeisel Department of Nutrition, UNCNutrition Research Institute, University of NorthCarolina at Chapel Hill, Chapel Hill, North Carolina,U.S.A.

Jianping Zhao National Center for Natural ProductsResearch, Research Institute of Pharmaceutical Sciences,School of Pharmacy, University of Mississippi,Mississippi, U.S.A.

The Challenges of Dietary Supplement Research andConsiderations for Future Studies

D. Craig Hopp and Catherine M. Meyers

INTRODUCTION

The American public and the popular press have con-siderable interest in the use of dietary supplements (1,2).In view of observed widespread use, there is a need forfurther information regarding dietary supplement prod-ucts and their potential clinical applications. This reportpresents recently compiled data on dietary supplementuse in the United States and discusses primary consider-ations for further research in this area. These considera-tions focus largely on the need for a standard approach toproduct characterization and the need to develop an ap-propriate knowledge base for individual products, priorto embarking on large multicenter trials assessing productefficacy.

BACKGROUND ON DIETARY SUPPLEMENT USE IN THEUNITED STATES

Findings from the 2007 National Health Interview Survey(NHIS), conducted by the Centers for Disease Control andPrevention’s National Center for Health Statistics, haveprovided extensive information on dietary supplementuse by the American public (1). The NHIS is an annualin-person survey of Americans regarding their health-and illness-related experiences. The 2007 NHIS included acomplementary and alternative medicine (CAM) sectionand collected information from nearly 24,000 adults, aswell as nearly 9500 children under the age of 18 years.

The 2007 NHIS data (Table 1) reveal that approxi-mately 38% of adults, nearly 39 million Americans, usesome form of CAM therapy and further that nearly 18%of adults use at least one nonvitamin, nonmineral dietarysupplement (1). Similarly, approximately 12% of childrenless than 18 years of age use some form of CAM therapy,with nearly 4% using at least one dietary supplement (1).The most common reason provided for dietary supple-ment use is for enhancing wellness (40%). Another 35% ofrespondents indicate that dietary supplements are usedfor both wellness and for treatment of a specific condi-tion, whereas only 20% relate that dietary supplementsare used to treat a specific condition. The most commonhealth conditions related to CAM product use are thoseassociated with chronic pain, largely of musculoskeletalorigin (1).

The most commonly used dietary supplements re-ported in the 2007 NHIS are listed in Table 2 (1). The 10

Table 1 The 10 Most Common CAM Therapies Used inU.S. Adults–2007a

Therapy Prevalence (%)

Dietary supplements 17.7Deep breathing 12.7Meditation 9.4Chiropractic and osteopathic 8.6Massage 8.3Yoga 6.1Diet-based therapies 3.6Progressive relaxation 2.9Guided imagery 2.2Homeopathic treatment 1.8aSource: Adapted from Ref. 1.

Table 2 The 10 Most Common Natural Products Usedin the United States–2007a

Prevalence (%)

AdultsFish oil/�-3 37.4Glucosamine 19.9Echinacea 19.8Flaxseed oil/pills 15.9Ginseng 14.1Combination herb pills 13.0Ginkgo biloba 11.3Chondroitin 11.2Garlic supplements 11.0Coenzyme Q10 8.7

ChildrenEchinacea 37.2Fish oil/�-3 30.5Combination herb pills 17.9Flaxseed oil/pills 16.7

aSource: Adapted from Ref. 1.

most commonly used products in adult respondents arefish oil or �-3 fatty acids, including docosahexaenoic acid,glucosamine, echinacea, flaxseed oil or pills, ginseng com-bination herb pills, ginkgo biloba, chondroitin, garlic sup-plements, and coenzyme Q10. Most dietary supplementuse reported for children in the United States is focused onfour products: echinacea (37.2%), fish oil or �-3 fatty acids(30.5%), combination herb pills (17.9%), and flaxseed oilor pills (16.7%) (1).

Use of CAM therapies, including dietary supple-ments, is widespread across all demographic groups ofthe U.S. population (1,2) and is more prevalent in women

xvi

The Challenges of Dietary Supplement Research and Considerations for Future Studies xvii

than in men, with regional variability, in that the use ismore prevalent in the West than in the Midwest, North-east, or Southern regions of the United States. Greater useof CAM therapies is observed between the ages of 30 and69 years and is also associated with higher levels of ed-ucation, former smokers, and reported regular levels ofphysical activity. CAM therapy use is also higher in re-spondents who report more health conditions or doctorvisits, although 20% of CAM users did not report under-lying health conditions (1,2).

In view of this extensive use, there is a need forfurther study of dietary supplements. Rigorous testing ofindividual dietary supplements, however, is frequentlylimited because of lack of critical information on sev-eral product attributes. In particular, lack of informationon product characterization, purity, active ingredients,pharmacokinetics, potential mechanisms of action, orbiomarkers for activity limits early phase testing of prod-ucts. Lack of dosing information and definition of appro-priate clinical outcome measures also limit planning ofclinical trials. A more standardized approach to productcharacterization and development of a richer knowledgebase on individual supplements will be essential to ad-vancing investigative efforts in this field.

PRODUCT INTEGRITY ISSUES FOR DIETARYSUPPLEMENT RESEARCH

One of the unique challenges inherent to dietary supple-ment research is that the product complexity is highlyvariable. This issue poses a serious challenge to estab-lishing a “standard” list of quality control proceduresfor these products. Although single-component supple-ments such as resveratrol or melatonin can be accuratelycharacterized and exactly reproduced, plant extracts aremuch more complex. Furthermore, as has been widelydocumented, there can be considerable inconsistency inbatch-to-batch, bottle-to-bottle, and brand-to-brand con-tent of “off-the-shelf” dietary supplements (3). For botan-ical products, there is a high level of complexity and nat-ural variability, which prevent investigators from entirelycharacterizing or exactly reproducing a particular extract.It is estimated that individual plant species are capableof producing thousands of metabolites at varying concen-trations. Additional variables for these products includethe observation that the same species grown in differentplaces, or even different years in the same place, will notgenerate the same metabolic profile. It is therefore appar-ent that a certain amount of product variability, for somesupplements, is to be expected. Despite these obstacles,researchers must still strive to conduct a thorough anal-ysis of products used for research purposes. Extensivecharacterization of research materials is a necessary initialstep so that subsequent study results can be appropriatelyinterpreted and reliably reproduced.

It is also apparent that comprehensive characteri-zation, especially for botanical products, can require anenormous amount of effort and expense. Products typi-cally pass through several hands from the grower to theprocessor and the distributor, prior to arrival at the ven-dor, and possibly others before reaching consumers. Itcan be very difficult and sometimes impossible to trace a

given product back to its origins. Furthermore, the identityof every minor component in an extract is almost neverknown. However, with some important exceptions, thisdegree of detail in product characterization is neither nec-essary nor practical. A pragmatic approach is to establishquality control methods that are appropriate for the com-plexity of the product, the proposed research plan, andproduct’s intended use.

A clinical trial testing a herbal extract will requirea substantial dossier of information to document safety,stability, and reproducibility of that product. This dossierwill include detailed knowledge about every step in thechain of custody of that material from the time it wasgrown to the time it was administered to patients. The U.S.Food and Drug Administration (FDA) released a guidancedocument for botanical drugs in 2004, which is an appro-priate resource on quality control procedures to followfor randomized controlled trials (RCTs) of herbal prod-ucts (4). Investigators intending to conduct clinical stud-ies are strongly encouraged to contact FDA and determinewhether an IND (investigational new drug) application isneeded for the study of a product in the United States.If an IND is needed for a given study, FDA will providespecific guidance regarding type of information requiredand level of detail for product characterization.

The characterization requirements for complexproducts used for in vitro studies are perhaps less clear.Similarly, the requirements for early-stage clinical studieson refined products that are botanically derived, but farless complex than the parent extract from which they orig-inated, are less well defined. In these examples, it might beargued that the focus should be more on accurate prod-uct characterization. High-pressure liquid chromatogra-phy is the analytical technique most commonly employedfor generating a product “fingerprint,” but there are othermethods that could be appropriate depending on the sam-ple. This fingerprint, regardless of the method used to gen-erate it, establishes the identity of a given product withouthaving to know the identity of every product component.Furthermore, it sets a reference point that can be used todocument batch-to-batch reproducibility and assess prod-uct stability over time. Whichever analytical technique ischosen, the fingerprint must be unique enough to distin-guish it from related products and sensitive enough todetect significant changes over time. As the particular di-etary supplement research progresses into animals andultimately humans, progressively more information willbe needed regarding product origin and its manufactur-ing process. A realistic balance should be sought betweenthe need for further studies of dietary supplements andthe need for extensive product characterization prior tobeginning research studies. Such a balance will ensure thefeasibility of future research efforts on these products.

Investigators need to be cognizant of the need forproduct characterization even in early stages of dietarysupplement research. Part of this effort involves inde-pendent product analysis, either by the investigator orthird party laboratory, to confirm specifications providedby the supplier. This early-stage testing must be con-ducted regardless of product complexity. Even “pure”compounds from widely known manufacturers have beennoted to be mislabeled, in that the content analysis demon-strated that the marketed product was not consistent

xviii Hopp and Meyers

with label specifications. For products that have not beenextensively studied, it may not be feasible to have anindependent analysis performed as validated methodsmay not be available. Moreover, developing or imple-menting new methods for such products can representan appropriate independent research endeavor. In suchcases, the information provided requires close scrutiny todetermine whether additional product concerns remain.

Finally, another important product consideration forinvestigating dietary supplements focuses on familiaritywith the product supplier. Whenever possible, investiga-tors should begin cultivating relationships with the prod-uct supplier at early stages of their research and start ac-quiring information that will be required for future stud-ies. It is important to determine early in the course of inves-tigations whether the supplier has stringent quality con-trol procedures in place and whether they will provide therequisite product documentation. This is especially true ifthe ultimate goal is to develop a knowledge base neces-sary for performing clinical studies. It is therefore prudentto select suppliers or vendors that have provided productsfor other research studies and have a track record of sup-plying test materials with the requisite documentation.

CONSIDERATIONS FOR CLINICAL STUDIESOF DIETARY SUPPLEMENTS

Clinical studies are an essential tool for assessing safetyand efficacy of therapeutic interventions, whether theyare conventional drugs, medical devices, or dietary sup-plements (5). Similar to standards for assessing efficacy ofpharmaceuticals, RCTs play a major role in determiningwhether a compound or product is safe and effective for aspecific indication (5). Prior to initiating (phase III) RCTs,however, there is substantial information that should becollected on a given product. In the pharmaceutical indus-try, extensive preliminary preclinical and clinical studies(i.e., pharmacokinetics, dosing strategies) are typically un-dertaken prior to performing large multicenter trials, dueto regulatory requirements enforced by FDA. There is asimilar need for extensive preliminary studies for dietarysupplement investigations, particularly when the researchquestion for the study includes treatment of a disease orcondition.

It is important to develop a knowledge base for indi-vidual dietary supplements, which will provide directionfor further clinical investigations. The optimum knowl-edge base for a product includes information on mecha-nism(s) of action, clinical chemistry, biomarkers for in vivoeffect, appropriate clinical outcome measures, and the tar-get patient population for the product. For many dietarysupplements, information is lacking on many aspects ofthis knowledge base, which has hampered progress inconducting definitive clinical studies.

As discussed in the previous section, it is essential tohave standardized data collection on product characteri-zation, as well as pharmacokinetics, prior to embarkingon clinical trials of dietary supplements. In addition, col-lecting adequate data regarding dosing, potential toxicity,and development of an appropriate placebo for a givenproduct are also requisite early tasks prior to designing

clinical trials. For some dietary supplements, product tasteor odor may significantly limit the ability to generate anacceptable placebo for clinical testing.

Understanding the putative mechanism of action ofa given product is also an important aspect of the knowl-edge base, as it strengthens the plausibility of the inter-vention, and, most importantly facilitates identificationof biomarkers to document in vivo effect of the dietarysupplement. Availability of a biomarker that can be usedto document activity of the agents is of great value. Abiomarker facilitates a rational approach to dosing, makesit possible to determine which patients are responding tothe intervention, and can assist in identification of out-come measures that are maximally sensitive. The absenceof this information can limit expansion of clinical studiesbeyond early phase testing, particularly for products suchas dietary supplements that are generally anticipated tohave mild to modest clinical effects.

In planning informative large RCTs, it is essential tohave standardized outcome measures that are maximallysensitive and can reliably be implemented in the contextof a clinical trial (5). It is also important to have adequatepreliminary data on the target patient population beforeembarking on a large clinical trial (5). Although the pri-mary standard for establishing safety and efficacy remainsthe RCT, early-phase investigations can exploit other de-sign strategies. For example, adaptive trial designs or n-of-1 designs could be used for expanding the knowledgebase on individual products prior to planning subsequentlarger studies.

Recent trends in clinical trial design have attemptedto facilitate methods for improving trial strategies formedical product development. In clinical studies of newpotential therapies, investigators and regulatory agencieshave considered adaptations in early-phase trials beforeplanning a large-scale confirmatory phase III RCT (6). Tofacilitate optimizing final trial design, adaptations in inter-ventional studies may include changes in sample size, en-rollment criteria (target subject population), product dose,study end points, and statistical methods for analysis ofclinical outcome data (6). As previously discussed, theknowledge base for many products is lacking in severalcritical aspects, including target subject population, dose,and appropriate end points. Although adaptive designmethods provide a mechanism for informed changes tostudy design after study initiation, appropriate analyticmethods must be implemented in the planning of studiessuch that the scientific validity and integrity of the studyare maintained (6).

As dietary supplements are frequently used forchronic conditions, individualized medication effective-ness tests (n-of-1 trials) have been considered a potentialstrategy for specific products (7,8). Unlike the RCT design,n-of-1 trials are individualized within-patient, are ran-domized and placebo-controlled, and include multiplecrossover comparisons of product versus placebo, orversus another active treatment (7,8). Also unlike theRCT, the n-of-1 trial provides a mechanism for assess-ing intervention effects in individual patients who mightnot otherwise be included in the targeted RCT subjectpopulation (7,8). The use of such less commonly employeddesigns can provide a means for adequate data collection,markedly enhancing a product’s knowledge base, such

The Challenges of Dietary Supplement Research and Considerations for Future Studies xix

that more definitive clinical trials can be optimally de-signed and implemented.

CONCLUSION

In developing productive research programs for dietarysupplements, it is important to build a hierarchy of evi-dence for individual supplements, including understand-ing essentials of individual product characterization, ba-sic product clinical chemistry, and subsequent rigoroustesting in the setting of clinical studies. Multiple lines ofinvestigation can then be coordinated for enhancing theknowledge base on a product, with the goal of inform-ing practitioners and the public on safety and efficacy ofdietary supplement use.

REFERENCES

1. Barnes PM, Bloom B, Nahin RL. Complementary and alterna-tive medicine use among adults and children: United States,

2007. National Health Statistics Reports 12. Hyattsville, MD:National Center for Health Statistics, 2008:1–23.

2. Barnes PM, Powell-Griner E, McFann K, et al. Complementaryand alternative medicine use among adults: United States,2002. Advance Data from Vital and Health Statistics: No. 343.Hyattsville, MD: National Center for Health Statistics, 2004.

3. Krochmal R, Hardy M, Bowerman S, et al. Phytochemical as-says of commercial botanical dietary supplements. Evid BasedComplement Altern Med 2004; 1(3):305–313.

4. U.S. Department of Health and Human Services; Food andDrug Administration; Center for Drug Evaluation and Re-search (CDER). Guidance for Industry: Botanical Drug Prod-ucts, 2004:1–52.

5. Friedman LM, Furberg DC, DeMets DL. Fundamentals ofClinical Trials. 3rd ed. New York: Springer-Verlag, 1998:1–125.

6. Chow S-C, Chang M. Adaptive Design Methods in ClinicalTrials (Chapman & Hall/CRC Biostatistic Series). Boca Raton,FL: Chapman & Hall/CRC, Taylor & Francis Group, 2007:1–46.

7. Guyatt GH, Keller JL, Jaeschke R, et al. The n-of-1 random-ized controlled trial: Clinical usefulness. Our three-year expe-rience. Ann Intern Med 1990; 112(4):293–299.

8. Nikles CJ, Clavarino AM, Del Mar CB. Using n-of-1 trials asa clinical tool to improve prescribing. Br J Gen Pract 2005;55(512):175–180.

S-Adenosylmethionine

José M. Mato and Shelly C. Lu

ABBREVIATIONS

CSF, cerebrospinal fluid; GNMT, glycine N-methyltrans-ferase; GSH, glutathione; HCC, hepatocellular carcinoma;Hcy, homocysteine; MAT, methionine adenosyltrans-ferase; MTA, 5′-deoxy-5′-methylthioadenosine; MTHFR,5,10-methylenetetrahydrofolate reductase; NASH, nonal-coholic steatohepatitis; SAH, (S)-adenosylhomocysteine;SAMe, (S)-adenosylmethionine.

INTRODUCTIONCommon and Scientific NameS-Adenosyl-L-methionine, also known as 5′-[(3-Amino-3-carboxypropyl) methylsulfonio]-5′-deoxyadenosine; (S)-(5′-desoxyadenosin-5-yl) methionine; [C15H23N6O5S]+, isabbreviated in the scientific literature as AdoMet, SAM,or SAMe. In the early literature, before the identificationof its structure, SAMe was known as “active methionine.”

General DescriptionSAMe was discovered in 1953 and since then has beenshown to regulate key cellular functions such as differen-tiation, growth, and apoptosis. Abnormal SAMe contenthas been linked to the development of experimental andhuman liver disease, and this led to the examination of theeffect of SAMe supplementation in various animal mod-els of liver disease and in patients with liver disease. Bothserum and cerebrospinal fluid (CSF) levels of SAMe havebeen reported to be low in depressed patients, which hasled to the examination of the effect of SAMe treatmentin this condition. The effect of SAMe in the treatment ofother diseases, such as osteoarthritis, has also been in-vestigated. This chapter reviews (i) the biochemistry andfunctions of SAMe; (ii) altered SAMe metabolism in liverdisease; (iii) SAMe deficiency in depression; and (iv) theeffect of SAMe treatment in liver disease, depression, andosteoarthritis.

BIOCHEMISTRY AND FUNCTIONSSAMe DiscoveryAlthough SAMe was discovered by Giulio Cantoni in1953, the story of this molecule begins in 1890 withWhilhelm His when he fed pyridine to dogs andisolated N-methylpyridine from the urine and empha-sized the need to demonstrate both the origin of themethyl group as well as the mechanism for its additionto the pyridine (1). Both questions were addressedby Vincent du Vigneaud who, during the late 1930s,demonstrated that the sulfur atom of methionine was

converted to cysteine through the “transsulfuration”pathway and discovered the “transmethylation” path-way, that is, the exchange of methyl groups betweenmethionine, choline, betaine, and creatine. In 1951, Can-toni demonstrated that a liver homogenate supplementedwith ATP and methionine converted nicotinamide to N-methylnicotinamide. Two years later, he established thatmethionine and ATP reacted to form a product, that heoriginally called “Active Methionine,” capable of trans-ferring its methyl group to nicotinamide, or guanidoaceticacid, to form N-methylmethionine, or creatine in theabsence of ATP, which, after determination of its struc-ture, he called “AdoMet” (Fig. 1). Subsequently, Cantoniand his colleagues discovered the enzyme that synthe-sizes SAMe, methionine adenosyltransferase (MAT);(S)-adenosylhomocysteine (SAH), the product of trans-methylation reactions; and SAH hydrolase, the enzymethat converts SAH into adenosine and homocysteine(Hcy). At about the same time, Bennett discovered thatfolate and vitamin B12 could replace choline as a source ofmethyl groups in rats maintained on diets containing Hcyin place of methionine, a finding that led to the discoveryof methionine synthase (MS). In 1961, Tabor demon-strated that the propylamino moiety of SAMe isconverted via a series of enzymatic steps to spermi-dine and spermine. In the biosynthesis of polyamines,5′-deoxy-5′-methylthioadenosine (MTA) was identifiedas an end product. Thus, by the beginning of the 1960s,Laster’s group could finally provide an integrated view,similar to that depicted in Figure 2, combining thetransmethylation and transsulfuration pathways withpolyamine synthesis.

Since then, SAMe has been shown to donate (i) itsmethyl group to a large variety of acceptor moleculesincluding DNA, RNA, phospholipids, and proteins;(ii) its sulfur atom, via a series of reactions, to cysteine andglutathione (GSH), a major cellular antioxidant; (iii) itspropylamino group to polyamines, which are requiredfor cell growth; and (iv) its MTA moiety, via a complexset of enzymatic reactions known as the “methionine sal-vage pathway,” to the resynthesis of this amino acid. Allthese reactions can affect a wide spectrum of biologi-cal processes ranging from metal detoxication and cat-echolamine metabolism to membrane fluidity, gene ex-pression, cell growth, differentiation, and apoptosis (2), toestablish what Cantoni called the “AdoMet Empire.”

SAMe Synthesis and MetabolismMAT is an enzyme extremely well conserved through evo-lution with 59% sequence homology between the humanand Escherichia coli isoenzymes. In mammals, there are

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N O

N

N

OO

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N

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S-AdenosylmethionineS-Adenosylmethionine

AdoMet, SAM, SAMeAdoMet, SAM, SAMe

Figure 1 Structure of SAMe. (S)-adenosylmethionine (SAMe) has beenshown to donate: (i) its methyl group to a large variety of acceptor moleculesincluding DNA, RNA, phospholipids, and proteins; (ii) its sulfur atom, via aseries of reactions, to cysteine and glutathione, a major cellular antioxidant;(iii) its propylamino group to polyamines, which are required for cell growth;and (iv) its MTA moiety, via a complex set of enzymatic reactions known asthe “methionine salvation pathway,” to the resynthesis of this amino acid.

MS

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SerineGlycine

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Figure 2 Hepatic metabolism of SAMe. Methionine (Met) is convertedinto homocysteine (Hcy) via (S)-adenosylmethionine (SAMe) and (S)-adenosylhomocysteine (SAH). The conversion of Met into SAMe is catalyzedby methionine adenosyltransferase (MAT). After decarboxylation, SAMe candonate the remaining propylamino moiety attached to its sulfonium ion toputrescine to form spermidine and methylthioadenosine (MTA) and to sper-midine to form spermine and a second molecule of MTA. SAMe donatesits methyl group in a large variety of reactions catalyzed by dozens ofmethyltransferases (MTs), the most abundant in the liver being glycine-N-methyltransferase (GNMT). The SAH thus generated is hydrolyzed to formHcy and adenosine through a reversible reaction catalyzed by SAH hydrolase.Hcy can be remethylated to form methionine by two enzymes: methioninesynthase (MS) and betaine homocysteine methyltransferase (BHMT). In theliver, Hcy can also undergo the transsulfuration pathway to form cysteine viaa two-step enzymatic process. In the presence of serine, Hcy is convertedto cystathionine in a reaction catalyzed by cystathionine �-synthase (CBS).Cystathionine is then hydrolyzed by cystathionase to form cysteine, a pre-cursor of the synthesis of glutathione (GSH). In tissues other than the liver,kidney, and pancreas, cystathionine is not significantly converted to GSH dueto the lack of expression of one or more enzymes of the transsulfurationpathway. The expression of BHMT is also limited to the liver. All mammaliantissues convert Met into Hcy, via SAMe and SAH, and remethylate Hcy intoMet via the MS pathway. Abbreviations: THF, tetrahydrofolate; 5,10-MTHF,methylenetetrahydrofolate; 5-MTHF, methyltetrahydrofolate; Ser, serine; Gly,glycine; X, methyl acceptor molecule; X-CH3, methylated molecule.

three isoforms of MAT (MATI, MATII, and MATIII) thatare encoded by two genes (MAT1A and MAT2A). MATIand MATIII are tetrameric and dimeric forms, respectively,of the same subunit (�1) encoded by MAT1A, whereas theMATII isoform is a tetramer of a different subunit (�2) en-coded by MAT2A. A third gene, MAT2β encodes for a �subunit that regulates the activity of MATII (lowering theKm and Ki for methionine and SAMe, respectively) but notof MATI or MATIII (2). Adult differentiated liver expressesMAT1A, whereas extrahepatic tissues and fetal liver ex-press MAT2A. MAT1A expression is silenced in HCC. Itis an intriguing question why there are three differentMAT isoforms in the liver. The predominant liver form,MATIII, has lower affinity for its substrates, a hystereticresponse to methionine (a hysteretic behavior, defined asa slow response to changes in substrate binding, has beendescribed for many important enzymes in metabolic reg-ulation), and higher Vmax, contrasting with the other twoenzymes. On the basis of the differential properties of hep-atic MAT isoforms, it has been postulated that MATIII isthe truly liver-specific isoform. Under normal conditions,MATI would, as MATII outside the liver, synthesize mostof the SAMe required by the hepatic cells. However, af-ter an increase in methionine concentration, that is, af-ter a protein-rich meal, conversion to the high-activityMATIII would occur and methionine excess will be elim-inated (Fig. 2). This will lead to accumulation of SAMeand activation of glycine N-methyltransferase (GNMT),the main enzyme involved in hepatic SAMe catabolism.Consequently, the excess of SAMe will be eliminated andconverted to homocysteine via SAH. Once formed, theexcess of homocysteine will be used for the synthesis ofcysteine and �-ketobutyrate as a result of its transsulfu-ration. This pathway involves two enzymes: cystathio-nine �-synthase (CBS), that is activated by SAMe, andcystathionase. Cysteine is then utilized for the synthe-sis of GSH as well as other sulfur-containing moleculessuch as taurine, while �-ketobutyrate penetrates the mi-tochondria where it is decarboxylated to carbon dioxideand propionyl CoA. Because SAMe is an inhibitor of 5,10-methylene-tetrahydrofolate-reductase (MTHFR), this willprevent the regeneration of methionine after a load of thisamino acid. At the mRNA level, SAMe maintains MAT1Aand GNMT expression while inhibiting MAT2A expres-sion. This modulation by SAMe of both the flux of methio-nine into the transsulfuration pathway and the regenera-tion of methionine maximizes the production of cysteineand �-ketobutyrate, and consequently of ATP, after a me-thionine load minimizing the regeneration of this aminoacid (oxidative methionine metabolism).

ALTERED SAMe METABOLISM AND DISEASEAltered SAMe Metabolism in Liver DiseaseAccumulating evidence supports the importance of main-taining normal SAMe level in mammalian liver, as bothchronic deficiency and excess lead to liver injury, steato-sis, and development of hepatocellular carcinoma (HCC)(2,3). Majority of the patients with cirrhosis have impairedSAMe biosynthesis because of lower MAT1A mRNA lev-els and inactivation of MATI/III (4,5). However, patientswith GNMT mutations have been identified and they also

S-Adenosylmethionine 3

have evidence of liver injury (6). In mice, loss of GNMTresults in supraphysiological levels of hepatic SAMe andaberrant methylation (7). The molecular mechanisms re-sponsible for injury and HCC formation are different inMAT1A and GNMT knockout mice but these findings il-lustrate the importance of keeping SAMe level within acertain range within the cell.

In contrast to normal nonproliferating (differenti-ated) hepatocytes, which rely primarily on MATI/III togenerate SAMe and maintain methionine homeostasis,embryonic and proliferating adult hepatocytes as wellas liver cancer cells instead rely on MATII to synthe-size SAMe (2). Liver cancer cells often have very lowlevels of GNMT and CBS expression and increased ex-pression of MAT2β, which, as mentioned earlier, lowersthe Km for methionine and the Ki for SAMe of MATII.Consequently, proliferating hepatocytes and hepatomacells tend to utilize methionine into protein synthesis re-gardless of whether methionine is present in high or lowamounts and to divert most homocysteine away from thetranssulfuration pathway by regenerating methionine andtetrahydrofolate (THF) (aerobic methionine metabolism).MAT2A/MAT2β-expressing hepatoma cells have lowerSAMe levels than cells expressing MAT1A, which also fa-vors the regeneration of methionine and THF. From theseresults, it becomes evident that proliferating hepatocytesand hepatoma cells do not tolerate well high SAMe levelsfor converting methionine via the transsulfuration path-way to cysteine and �-ketobutyrate.

The finding that MAT1A, GNMT, MTHFR, and CBSknockout mice spontaneously develop fatty liver (steato-sis) and, in the case of MAT1A- and GNMT-deficient an-imals, HCC also (3) demonstrates the synchronization ofmethionine metabolism with lipid metabolism and hepa-tocyte growth.

The medical implications of these observations areobvious, since the majority of cirrhotic patients, inde-pendent of the etiology of their disease, have impairedmetabolism of methionine and reduced hepatic SAMesynthesis and are predisposed to develop HCC (4,5); andindividuals with GNMT mutations that lead to abnormalSAMe catabolism develop liver injury (6). Moreover, theobservation that genetic polymorphisms that associatewith reduced MTHFR activity and increased thymidy-late synthase activity, both of which are essential in min-imizing uracyl misincorporation into DNA, may protectagainst the development of HCC in humans (8) furthersupports that this synchronization may be an adaptivemechanism that is programmed to fit the specific needs ofhepatocytes, and that alterations in the appropriate bal-ance between methionine metabolism and proliferationmay be at the origin of the association of cancer with fattyliver disease.

An explanation for these observations connectingmethionine metabolism with the development of fattyliver and HCC has remained elusive because the as-sociation of SAMe with lipid metabolism and hepato-cyte proliferation is, at first glance, not intuitive. Duringthe past years, a signaling pathway that senses cellularSAMe content and that involves AMP-activated proteinkinase (AMPK) has been identified to operate in hepato-cytes (9,10). AMPK is a serine/threonine protein kinasethat plays a crucial role in the regulation of energy home-

ostasis and cell proliferation. AMPK is activated by stressconditions leading to an increase in the AMP/ATP ratio,such as during liver regeneration. Once activated, AMPKshuts down anabolic pathways that mediate the synthesisof proteins, fatty acids, lipids, cholesterol, and glycogenand stimulates catabolic pathways such as lipid oxida-tion and glucose uptake restoring ATP levels and keep-ing the cellular energy balance. The finding that in theliver AMPK activity is tightly regulated by SAMe (9,10)has provided a first link between methionine metabolism,lipid metabolism, and cell proliferation. Moreover, ex-cess SAMe can induce aberrant methylation of DNA andhistones, resulting in epigenetic modulation of criticalcarcinogenic pathways (7). Finally, there is evidence in-dicating that SAMe regulates proteolysis, widening itsspectrum of action. In hepatocytes, the protein levels ofprohibitin 1 (PHB1) (11), the apurinic/apyrimidininc en-donuclease (APEX1) (12), and the dual specificity MAPKphosphatase (DUSP1) (13) are stabilized by SAMe througha process that may involve proteasome inactivation. PHB1is a chaperone-like protein involved in mitochondrialfunction, APEX1 is a key protein involved in DNA repairand genome stability, and DUSP1 is a member of a fam-ily of mitogen-activated protein kinases (MAPKs) phos-phatases, which simultaneously dephosphorylates bothserine/threonine and tyrosine residues.

SAMe Deficiency in DepressionMajor depression has been associated with a deficiencyin methyl groups (folate, vitamin B12, and SAMe) (14,15).Thus, depressed patients often have low plasma folate andvitamin B12 and reduced SAMe content in the CSF. More-over, patients with low plasma folate appear to respondless well to antidepressants. The mechanism by which lowSAMe concentrations may contribute to the appearanceand evolution of depression is, however, not well known.SAMe-dependent methylation reactions are involved inthe synthesis and inactivation of neurotransmitters, suchas noradrenaline, adrenaline, dopamine, serotonin, andhistamine; and the administration of drugs that stimulatedopamine synthesis, such as L-dihydroxyphenylalanine,cause a marked decrease in SAMe concentration in ratbrain and in plasma and CSF in humans. Moreover, vari-ous drugs that interfere with monoaminergic neurotrans-mission, such as imipramine and desipramine, reducebrain SAMe content in mice (14,15). As in the liver, abnor-mal SAMe levels may contribute to depression throughperturbation of multiple metabolic pathways in the brain.Interestingly, alterations in methionine metabolism thatlead to a decrease in the brain SAMe/SAH ratio asso-ciate with reduced leucine carboxyl methyltransferase-1(LCMT-1) and phosphoprotein phosphatase 2AB (PP2AB)subunit expression, and accumulation of unmethylatedPP2A (16). PP2A enzymes exist as heterotrimeric com-plexes consisting of catalytic (PP2AC), structural (PP2AA),and regulatory (PP2AB) subunits (17). Different PP2ABsubunits have been described that determine the substratespecificity of the enzyme. PP2AC subunit is methylatedby SAMe-dependent LCMT-1 and demethylated by a spe-cific phosphoprotein phosphatase methylesterase (PME1).PP2AC methylation has no effect on PP2A activity but hasa crucial role in the recruitment of specific PP2AB subunits

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to the PP2AA,B complex and therefore PP2A substratespecificity. Downregulation of LCMT-1 and PP2AB andaccumulation of unmethylated PP2A are associated withenhanced Tau phosphorylation and neuronal cell death(16).

INDICATIONS AND USAGESAMe Treatment in Animal Models of Liver DiseaseThe importance of the metabolism of methyl groups ingeneral, and SAMe in particular, to normal hepatic phys-iology, coupled with the convincing body of evidencelinking abnormal SAMe content with the developmen-tal of experimental and human liver disease, led to theexamination of the effect of SAMe supplementation invarious animal models of liver disease. SAMe adminis-tration to alcohol-fed rats and baboons reduced GSH de-pletion and liver damage (2,18). SAMe improved survivalin animal models of galactosamine-, acetaminophen- andthioacetamide-induced hepatotoxicity, and in ischemia-reperfusion–induced liver injury (18). SAMe treatmentalso diminished liver fibrosis in rats treated with carbontetrachloride (18) and reduced neoplastic hepatic nodulesin animal models of HCC (19,20). Similar to the liver,SAMe can block mitogen-induced growth and induceapoptosis in human colon cancer cells (21,22).

SAMe Treatment in Human DiseasesSAMe has been used in humans for the past 20 years for thetreatment of osteoarthritis, depression, and liver disease.In 2002, the Agency for Healthcare Research and Quality(AHRQ) reviewed 102 individual clinical trials of SAMe(23). Of these 102 studies, 47 focused on depression, 14focused on osteoarthritis, and 41 focused on liver disease.Of the 41 studies in liver disease, 9 were for cholestasis ofpregnancy, 12 were for other causes of cholestasis, 7 werefor cirrhosis, 8 were for chronic hepatitis, and 4 were forvarious other chronic liver diseases.

Pharmacokinetics of SAMeOrally administered SAMe has low bioavailability, pre-sumably because of a significant first-pass effect (degra-dation in the gastrointestinal tract) and rapid hepaticmetabolism. Peak plasma concentrations obtained withan enteric-coated tablet formulation are dose related, withpeak plasma concentrations of 0.5 to 1 mg/L achievedthree to five hours after single doses ranging from 400 to1000 mg (23). Peak levels decline to baseline within 24hours. One study showed a significant gender differencein bioavailability, with women showing three- to sixfoldgreater peak plasma values than men (23). Plasma-proteinbinding of SAMe is no more than 5%. SAMe crosses theblood–brain barrier, with slow accumulation in the CSF.Unmetabolized SAMe is excreted in urine and feces.

Parenterally administered SAMe has much higherbioavailability. However, this form is currently not ap-proved for use in the United States.

SAMe Treatment in Liver DiseasesOut of the 41 studies in liver disease analyzed by AHRQ,8 studies were included in a meta-analysis of the effi-cacy of SAMe to relieve pruritus and decrease elevated

serum bilirubin levels associated with cholestasis of preg-nancy (23). Compared with placebo, treatment with SAMewas associated with a significant decrease in pruritus andserum bilirubin levels. Similar results were obtained whensix studies were included in a meta-analysis of the efficacyof SAMe to relieve pruritus and decrease bilirubin levelsassociated with cholestasis caused by various liver dis-eases other than pregnancy.

In 2001, the Cochrane Hepato-Biliary Group an-alyzed eight clinical trials of SAMe treatment of alco-holic liver disease including 330 patients (24). This meta-analysis found SAMe decreased total mortality [oddsratio (OR) 0.53, 95% confidence interval (CI): 0.22 to 1.29]and liver-related mortality (OR 0.63, 95% CI: 0.25 to 1.58).However, because many of the studies were small andthe quality of the studies varied greatly, the CochraneGroup concluded, “SAMe should not be used for alcoholicliver disease outside randomized clinical trials” (24). TheAHRQ reached a similar conclusion, “For liver conditionsother than cholestasis additional smaller trials should beconducted to ascertain which patient populations wouldbenefit more from SAMe, and what interventions (doseand route of administration) are most effective” (23). TheCochrane Hepato-Biliary Group also concluded that onlyone trial including 123 patients with alcoholic cirrhosisused adequate methodology and reported clearly on mor-tality and liver transplantation. In this study (25), mortal-ity decreased from 30% in the placebo group to 16% inthe SAMe group (P = 0.077). When patients with moreadvanced cirrhosis (Child score C) were excluded fromthe analysis (eight patients), the mortality was signifi-cantly less in the SAMe group (12%) as compared with theplacebo group (25%, P = 0.025). In this study, 1200 mg/daywas administered orally. Unfortunately, new controlledprospective double-blind multicenter studies on the ben-efits of SAMe for liver diseases are lacking.

SAMe Treatment in DepressionOut of the 39 studies in depression analyzed by the AHRQ,28 studies were included in a meta-analysis of the efficacyof SAMe to decrease symptoms of depression (23). Com-pared with placebo, treatment with SAMe was associatedwith an improvement of approximately six points in thescore of the Hamilton Rating Scale for Depression mea-sured at three weeks (95% CI: 2.2 to 9.0). This degree ofimprovement was statistically as well as clinically signif-icant. However, compared with the treatment with con-ventional antidepressant pharmacology, treatment withSAMe was not associated with a statistically significantdifference in outcomes. With respect to depression, theAHRQ report concluded, “Good dose-escalation studieshave not been performed using the oral formulation ofSAMe for depression” (23). The AHRQ report also con-cluded, that “Additional smaller clinical trials of an ex-ploratory nature should be conducted to investigate usesof SAMe to decrease the latency of effectiveness of con-ventional antidepressants and to treat of postpartum de-pression” (23). Unfortunately, these clinical studies are stilllacking.

SAMe Treatment in OsteoarthritisOut of the 13 studies in osteoarthritis analyzed by theAHRQ, 10 studies were included in a meta-analysis of

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the efficacy of SAMe to decrease pain of osteoarthritis(23). Compared with placebo, one large randomized clin-ical trial showed a decrease in the pain of osteoarthri-tis with SAMe treatment. Compared with the treatmentwith nonsteroidal anti-inflammatory medications, treat-ment with oral SAMe was associated with fewer adverseeffects while comparable in reducing pain and improvingfunctional limitation. In 2009, the Cochrane OsteoarthritisGroup analyzed 4 clinical trials including 656 patients, allcomparing SAMe with placebo (26). The Cochrane Groupconcluded, “The effects of SAMe on both pain and func-tion may be potentially clinically relevant and, althougheffects are expected to be small, deserve further clini-cal evaluation in adequately sized randomized, parallel-group trials in patients with knee or hip osteoarthri-tis. Meanwhile, routine use of SAMe should not beadvised” (26).

Adverse EffectsThe risks of SAMe are minimal. SAMe has been used inEurope for more than 20 years and is available under pre-scription in Italy, Germany, United Kingdom, and Canada,and over the counter as a dietary supplement in the UnitedStates, China, Russia, and India. The most common sideeffects of SAMe are nausea and gastrointestinal distur-bance, which occurs in less than 15% of treated subjects.Recently, SAMe administration to mice treated with cis-platin has been found to increase renal dysfunction (27).Whether SAMe increases cisplatin renal toxicity in hu-mans is not known.

Interactions with Herbs, Supplements, and DrugsTheoretically, SAMe might increase the effects and adverseeffects of products that increase serotonin levels, whichinclude herbs and supplements such as Hawaiian BabyWoodrose, St. J

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