encyclopedia of dietary supplements,2010

8/6/2019 Encyclopedia of Dietary Supplements,2010

1/918

Edited by

Paul M. Coates

Joseph M. Betz

Marc R. Blackman

Gordon M. Cragg

Mark Levine

Joel Moss

Jeffrey D. White

Encyclopedia of

Dietary SupplementsSecond Edition


2/918

Encyclopedia of Dietary Supplements


3/918

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 Womens 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.


4/918

Encyclopedia of Dietary Supplements

Second 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 Program

Division 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 Branch

National Institute of Diabetes and Digestive and Kidney Diseases


Joel MossTranslational Medicine Branch

National Heart, Lung, and Blood Institute


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

Division of Cancer Treatment and Diagnosis

National Cancer Institute, National Institutes of Health

Bethesda, Maryland, U.S.A.


5/918


6/918


7/918

vi Preface

Products Associations 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 Healthcares 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


8/918

Contents

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

S-Adenosylmethionine 1Jose 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

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

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

Cascara Sagrada 124

Kapil 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


9/918

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 Strmgaard, 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

-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


10/918

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 dArco 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 650Francois 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. Johns 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


11/918

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 ServiceWesternHuman 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

Francois 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 UniversityHadassah 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


12/918

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 Womens 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, CanadaKevin 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


13/918

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 Childrens 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 Hospital

and 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 Crohns 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.


14/918

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

Jose M. Mato CIC bioGUNE, Centro de InvestigacionBiomedica en Red de Enfermedades Hepaticas 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. Johns,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 dEtude des SubstancesVegetales a Activite Biologique, Faculte de Pharmacie,Institut des Sciences de la Vigne et du Vin de Bordeaux,Universite 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.


15/918

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, Westfalische Wilhelms-Universitat Munster,Munster, 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 School

of 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. Johns,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. Johns 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 Strmgaard 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 of

Agricultural and Life Sciences, University ofWisconsinMadison, 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, CanadaAnne 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,


16/918

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.


17/918

The Challenges of Dietary Supplement Research and

Considerations 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 supplement

use 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 THE

UNITED STATES

Findings from the 2007 National Health Interview Survey(NHIS), conducted by the Centers for Disease Control andPreventions 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 in

U.S. Adults2007a

Therapy Prevalence (%)

Dietary supplements 17.7

Deep breathing 12.7

Meditation 9.4

Chiropractic and osteopathic 8.6

Massage 8.3 Yoga 6.1

Diet-based therapies 3.6

Progressive relaxation 2.9

Guided imagery 2.2

Homeopathic treatment 1.8

aSource: Adapted from Ref. 1.

Table 2 The 10 Most Common Natural Products Used

in the United States2007a

Prevalence (%)

Adults

Fish oil/-3 37.4

Glucosamine 19.9

Echinacea 19.8Flaxseed oil/pills 15.9

Ginseng 14.1

Combination herb pills 13.0

Ginkgo biloba 11.3

Chondroitin 11.2

Garlic supplements 11.0

Coenzyme Q10 8.7

Children

Echinacea 37.2

Fish oil/-3 30.5

Combination herb pills 17.9

Flaxseed 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 reportedfor children in theUnitedStates 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


18/918

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 DIETARY

SUPPLEMENT 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 in batch-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

givenproduct 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, andproducts 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 andDrug Administration (FDA) releaseda 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 themethod 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 provided by the supplier. This early-stage testing must be con-ducted regardless of product complexity. Even purecompounds from widely known manufacturers have beennoted to be mislabeled, in that thecontent analysis demon-strated that the marketed product was not consistent


19/918

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 importantto determineearly in thecourse 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 selectsuppliersor vendors that have providedproductsfor other research studies and have a track record of sup-plying test materials with the requisite documentation.

CONSIDERATIONS FOR CLINICAL STUDIES

OF 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 becollectedon 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 trialdesign, adaptationsin 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). Theuse of such less commonly employeddesigns can provide a means for adequate data collection,markedly enhancing a products knowledge base, such


20/918


21/918


22/918

S-Adenosylmethionine

Jose 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 examinationof 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 FUNCTIONS

SAMe 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 addressed by Vincent du Vigneaud who, during the late 1930s,demonstrated that the sulfur atom of methionine was

converted to cysteine through the transsulfurationpathway 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 is

converted 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,Lasters 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 required

for 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 enzymeextremely well conserved through evo-lution with 59% sequence homology between the humanand Escherichia coli isoenzymes. In mammals, there are

1


23/918

2 Mato and Lu

NO

N

N

OO

S+

N

NN

O

CH3

S-AdenosylmethionineS-Adenosylmethionine

AdoMet, SAM, SAMeAdoMet, SAM, SAMe

Figure 1 Structure of SAMe. (S)-adenosylmethionine (SAMe) has been

shown to donate: (i) its methyl group to a large variety of acceptor molecules

including DNA, RNA, phospholipids, and proteins; (ii) its sulfur atom, via a

series 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 as

the methionine salvation pathway, to the resynthesis of this amino acid.

MS

MTA

Putrescine Spermidine

Spermine

MTA

MetSAMe

SAH

Hcy

Cys

CBS

BHMT GNMT

MAT

MTs

Cystathionine

THF

5,10-MTHF

5-MTHF

X-

X-CH3

Ser

-Ketobutyrate

Betaine

N,N-Dimethyl-Gly

SerineGlycine

GSH

Figure 2 Hepatic metabolism of SAMe. Methionine (Met) is converted

into homocysteine (Hcy) via (S)-adenosylmethionine (SAMe) and (S)-

adenosylhomocysteine (SAH). The conversion of Met into SAMe is catalyzed

by methionine adenosyltransferase (MAT). After decarboxylation, SAMe can

donate the remaining propylamino moiety attached to its sulfonium ion to

putrescine to form spermidine and methylthioadenosine (MTA) and to sper-

midine to form spermine and a second molecule of MTA. SAMe donates

its methyl group in a large variety of reactions catalyzed by dozens of

methyltransferases (MTs), the most abundant in the liver being glycine- N-

methyltransferase (GNMT). The SAH thus generated is hydrolyzed to form

Hcy and adenosine through a reversible reaction catalyzed by SAH hydrolase.

Hcy can be remethylated to form methionine by two enzymes: methionine

synthase (MS) and betaine homocysteine methyltransferase (BHMT). In the

liver, Hcy can also undergo the transsulfuration pathway to form cysteine viaa two-step enzymatic process. In the presence of serine, Hcy is converted

to 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 due

to the lack of expression of one or more enzymes of the transsulfuration

pathway. The expression of BHMT is also limited to the liver. All mammalian

tissues convert Met into Hcy, via SAMe and SAH, and remethylate Hcy into

Met 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 MATIIIare tetramericand 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, MAT2 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 liverexpressesMAT1A, 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 thebasis of thedifferential 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 DISEASE

Altered 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 GNMTmutations have been identified and they also


24/918

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 MAT2, 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 thetranssulfurationpathway by regeneratingmethionine andtetrahydrofolate (THF) (aerobic methionine metabolism).MAT2A/MAT2-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 GNMTmutations 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 mayinvolve 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 plasmafolateandvitamin 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 phosphoproteinphosphatase methylesterase(PME1).PP2AC methylation has no effect on PP2A activity but hasa crucial role in the recruitment of specific PP2AB subunits


25/918

4 Mato and Lu

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 USAGE

SAMe 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-reperfusioninduced liver injury (18). SAMe treatmentalso diminished liver fibrosis in rats treated with carbon

tetrachloride (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 DiseasesSAMehasbeenused inhumansforthe past20 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 thebloodbrain 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 withplacebo, 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 DepressionOutof the39 studies in depression analyzed by theAHRQ,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, theseclinical studies arestilllacking.

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


26/918

S-Adenosylmethionine 5

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, UnitedKingdom, and Canada,andover thecounter as a dietary supplement in theUnitedStates, 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 mightincrease the effects and adverseeffects of products that increase serotonin levels, whichinclude herbs and supplements such as Hawaiian BabyWoodrose, St. Johns wort, and L-tryptophan, as well asdrugs that have serotonergic effects. These drugs includetramadol (Ultram), pentazocine (Talwin), clomipramine(Anafranil), fluoxetine (Prozac), paroxetine (Paxil), sertra-line (Zoloft), amitriptyline (Elavil), and many others. It isalso recommended that SAMe should be avoided in pa-tients taking monoamine oxidase inhibitors or within twoweeks of discontinuing such a medication.

CONCLUSIONS

Although evidence linking abnormal SAMe content withthe development of experimental and human liver dis-ease is very convincing, the results of clinical trials of

SAMe treatment of liver disease are not conclusive. Con-sequently, SAMe should not be used outside clinical trialsfor thetreatment of liver conditions other than cholestasis.A new clinical study enrolling a larger number of patientsshould be carried out to confirm that SAMe decreasesmortality in alcoholic liver cirrhosis. This is important be-cause if SAMe improves survival, SAMe will become theonly available treatment for patients with alcoholic livercirrhosis.

Although depression has been associated with a de-ficiency in SAMe, it is not yet clear whether this is a con-sequence or the cause of depression. To clarify this point,more basic research and the development of new exper-

imental models are needed. Clinical trials indicate thatSAMe treatment is associated with an improvement ofdepression. Dose studies using oral SAMe should be per-formed to determine the best dose to be used in depres-sion. New studies should also be carried out where theefficacy of SAMe is compared with that of conventionalantidepressants.

With respect to osteoarthritis, at present there is noevidence associating a deficiency in SAMe with the ap-pearance of the disease. Moreover, the efficacy of SAMein the treatment of osteoarthritis is also not convincing atpresent.

ACKNOWLEDGMENTS

This work was supported by grants from NIH DK51719(to S. C. L.) and AT-1576 (to S. C. L. and J. M. M.) andSAF 2008-04800 (to J. M. M.). CIBERehd is funded by theInstituto de Salud Carlos III.

REFERENCES

1. Finkelstein JD. Homocysteine: A history in progress. NutrRev 2000; 58(7):193204.

2. MatoJM,LuSC.Roleof S-adenosylmethionine in liverhealthand injury. Hepatology 2007; 45:13061312.

3. Mato JM, Martnez-Chantar ML, Lu SC. Methioninemetabolism and liver disease. Annu Rev Nutr 2008; 28;273293.

4. Duce AM,Ortiz P, Cabrero C,et al.S-Adenosyl-L-methioninesynthetase and phospholipid methyltransferase are inhib-ited in human cirrhosis. Hepatology 1988; 8(1):6568.

5. Avila MA, Berasain C, Torres L, et al. Reduced mRNAabundance of the main enzymes involved in methioninemetabolism in human liver cirrhosis and hepatocellular car-cinoma. J Hepatol 2000; 33(6):907914.

6. Mudd SH, Cerone R, Schiaffimo MC, et al. Glycine N-methyltransferase deficiency: A novel inborn error causingpersistent isolated hypermethioninemia. J Inherit Metab Dis2001; 24;448464.

7. Martnez-Chantar ML, Vazquez-Chantada M, Ariz U, et al.Loss of the gycine N-methyltransferase gene leads to steato-sis and hepatocellular carcinoma in mice. Hepatology 2008;47(4):11911199.

8. Yuan J-M, Lu SC, Van den Berg D, et al. Genetic poly-morphisms in the methylenetetrahydrofolate reductase andthymidylate synthase genes and risk of hepatocellular carci-noma. Hepatology 2007; 46(3):749758.

9. Martnez-Chantar ML, Vazquez-Chantada M, Garnacho M,et al. S-Adenosylmethionine regulates cytoplasmic HuRvia AMP-activated kinase. Gastroenterology 2006; 131;

223232.10. Vazquez-Chantada M, Ariz U, Varela-Rey M, et al. Evidencefor LKB1/AMP-activated protein kinase/endothelial nitricoxide synthase cascade regulated by hepatocyte growth fac-tor, S-adenosylmethionine, and nitric oxide in hepatocyteproliferation. Hepatology 2009; 49:608617.

11. Santamara E, Avila MA, Latasa MU, et al. Functional pro-teomics of non-alcoholic steatohepatitis: Mitochondrial pro-teins as targets of S-adenosylmethionine. Proc Nat Acad SciU S A 2003; 100(6):30653070.

12. Tomasi ML, Iglesias-Ara A, Yang H, et al. S-adenosylmethionine regulates apurinic/apyrimidinicendonuclease 1 stability: Implication in hepatocarcinogene-sis. Gastroenterology 2009; 136(3):10251036.


27/918

6 Mato and Lu

13. Tomasi ML, Ramani K, Lopitz-Osada F, et al. S-Adenosylmethionine regulates dual-specificity mitogen-activated protein kinase phosphatase expression in mouseand human hepatocytes. Hepatology 2010, in press.

14. Bottiglieri T. S-Adenosyl-L-methionine (SAMe): From the bench to the bedsideMolecular basis of a pleiotrophicmolecule. Am J Clin Nutr 2002; 76(5):1151S1157S.

15. Miller AL. The methylation, neurotransmitter, and antioxi-dantconnections between folate and depression. Altern MedRev 2008; 13;216226.

16. Sontag J-M, Nunbhakdi-Craig V, Montgomery L, et al. Folatedeficiency induces in vitro and mouse brain region-specificdownregulation of leucine carboxyl methyltransferase-1 andprotein phosphatase 2A B subunit expression that corre-late with enhanced Tau phosphorylation. J Neurosci 2008;28(45):1147711487.

17. Vishrup DM, Shenolikar S. From promiscuity to preci-sion: Protein phosphatases get a makeover. Mol Cell 2009;33(5):537545.

18. Mato JM, Alvarez L, Ortiz P, et al. S-Adenosylmethioninesynthesis: Molecular mechanisms and clinical implications.Pharmacol Ther 1997; 73(3):265280.

19. Pascale RM, Simile MM, De Miglio MR, et al. Chemopre-vention of hepatocarcinogenesis: S-adenosyl-L-methionine.Alcohol 2002; 27(3):193198.

20. Lu SC, Ramani K, Ou X, et al. S-Adenosylmethionine in thechemoprevention and treatment of hepatocellularcarcinomain a rat model. Hepatology 2009; 50(2):462471.

21. Chen H, Xia M, Lin M, et al. Role of methionine adeno-syltransferase 2A and S-adenosylmethionine in mitogen-induced growth of human colon cancer cells. Gastroenterol-ogy 2007; 133(5):207218.

22. Li TW, Zhang Q, Oh P, et al. S-Adenosylmethionine andmethylthioadenosine inhibit cellular FLICE inhibitory pro-tein expression and induce apoptosis in colon cancer cells.Mol Pharmacol 2009; 76(1):192200.

23. Agency for Healthcare Research and Quality. S-Adenosyl-L-Methionine for Treatments of Depression, Osteoarthritis,andLiver Disease. Rockville, MD: Agency for Healthcare Re-search and Quality; 2002. Evidence Report/Technology As-sessment 64. http://www.ahrq.gov/clinic/tp/sametp.htm.Accessed August 2002.

24. Rambaldi A, Gluud C. S-Adenosyl-L-methionine for al-coholic liver disease. Cochrane Database Syst Rev 2001;4:CD002235.

25. Mato JM, Camara J, Fernandez de Paz J, et al. S-Adenosylmethionine in alcoholic liver cirrhosis: a ran-domized placebo-controlled, double-blind, multicentre trial.

J Hepatol 1999; 30(6):10811089.26. Rutjes AW, Nuesch E, Reichenbach S, et al. S-

Adenosylmethionine for osteoarthritis of the knee or hip.Cochrane Database Syst Rev 2009; 4:CD007321.

27. Ochoa B, Bobadilla N, Arrellin G, et al. S-

Adenosylmethionine-L-methionine increases serum BUNand creatinine in cisplatin-treated mice. Arch Med Res 2009;40(1):5458.


28/918

Aloe Vera

Santiago Rodriguez, Steven Dentali, and Devon Powell

INTRODUCTION

Aloe vera is one of the oldest known medicinal herbs witha history of use that spans thousands of years. Today, aloevera is cultivated andused in a large variety of commercialpreparations. It is an economic driver in the food, dietarysupplement, and personal care industries worldwide. Thetwo main commercial materials derived from aloe vera arealoe vera juice and aloe latex. Aloe vera juice is used forvarious dietary, cosmetic, and medical purposes such asburn treatment, wound healing, and skincare. It is avail-

able in several forms including liquid juice, juice powder,and concentrates. Aloe latex was formerly recognized asan over-the-counter (OTC) laxative drug in the UnitedStates. It has seen limited use in dietary supplements asa laxative and in the personal care industry as a skinlightener.

Confusion among consumers, researchers, and reg-ulatory bodies has arisen from the fact that products fromaloe latex are often referred to as simply aloe or aloe juice (including in pharmacopoeias and other officialdocuments around the world), which is physically, chem-ically, and biologically distinct from products made fromthecharcoal filtered whole leaf or inner leaf aloe vera juice.These latex-free juice products represent the vast majority

of aloe products on the market. Regardless, the promi-nence of, interest in, and use of aloe vera products forcenturies attests to the plants myriad value and benefits.

BACKGROUND

Aloe vera (L.) Burm. f. is one of more than 400 known Aloespecies in the Asphodelaceae family, though it is some-times classified in Aloaceae. Because most aloe speciesare indigenous to Africa, it is most likely that aloe veraalso originated from that continent. However, because ofits now worldwide cultivation, its origin is difficult to es-tablish. Linnaeus classified aloe vera as the true aloehence the name vera, meaning true in Latin. Althoughit has also been known as Aloe barbadensis, Aloe chinensis,Aloe indica, Aloe vulgaris, and others, A. vera (L.) Burm.f. has precedence (1). Its standardized common name isaloe vera though it has also been called Barba

encyclopedia of dietary supplements,2010

Documents