Marilyn Barrett, PhDEditor

The Handbookof Clinically TestedHerbal Remedies

Volume 1

Pre-publicationREVIEWS,COMMENTARIES,EVALUATIONS . . .

T he Handbook of Clinically TestedHerbal Remedies is an importantaddition to the modern clinical litera-ture on herbs.

Adriane Fugh-Berman, MDAssociate Professor,Department of Physiologyand Biophysics,Georgetown University Schoolof Medicine

This book is well written by expertsin their respective fields and forthe first time provides information onspecific botanical products that relateto their therapeutic value. It should beof great interest to students and practi-tioners in any of the health sciences, tomanufacturers of botanical products, tothe lay public, to those in the mediawho can rely on information in thisbook to be authoritative, and to librar-ies.

Norman R. Farnsworth, PhDUIC Distinguished Professorand Research Professorof Pharmacognosy, College of Pharmacy,University of Illinois at Chicago

More pre-publicationREVIEWS, COMMENTARIES, EVALUATIONS . . .

This book includes profiles on thirty-two individual herbal medi-cines and ten combination formulas.These profiles include descriptions ofmost of the major published clinicalstudies, which have been analyzed by apanel of authoritative reviewers. It isobvious that great care was taken to en-sure completeness and accuracy of in-formation, and the reviewers com-ments regarding study quality areespecially informative and helpful.

Clinicians searching for detailedand accurate information on herbalclinical trials will find much in this textthat is useful. It is a significant achieve-ment in the field of evidence-basedanalyses of herbal medicine. It shouldbe of most help to clinicians or re-searchers who want specific details onherbal clinical studies that are notreadily available, or who are interestedin clinical-trial-quality assessments byauthoritative reviewers.

Michael Rotblatt, MD, PharmDAssociate Clinical Professor of Medicine,UCLA; Co-author,Evidence-Based Herbal Medicine

The purpose of this book is to pro-vide both consumers and healthcare providers with concise, evidence-based information on the most widelyused herbs and herbal formulas testedin clinical trials. The focus is on whatpreparations have been studied in clin-

ical trials and how good the evidence isas assessed by preset criteria appliedby botanical experts.

The book is broken down into threeparts. The first section is very informa-tive and sets the stage nicely for a dis-cussion of individual herbs. The secondpart describes the process of evidencegathering, sorting, grading, and peerreview. Those readers familiar with theNatural Standard database of naturalproducts will recognize the editors useof levels of evidence criteria as a use-ful tool to distill the information avail-able from clinical trials. In the thirdpart, the authors provide monographson the various herbals listed alphabeti-cally. These are concise and cover basicquestions of whether the trial was ran-domized and whether the methods wereclearly described. One unique feature isa detailed description of specific prod-ucts used in clinical trials. These arevery helpful to both clinicians inter-ested in recommending specific prod-ucts and to patients interested in find-ing these same products at their localhealth food stores.

This book provides valuable infor-mation to providers and patients look-ing to sort out which commonly usedherbs are evidence-based and particu-larly which specific products theyshould be looking for.

Philippe O. Szapary, MDAssistant Professor of Medicine,Division of General Internal Medicine,University of Pennsylvania Schoolof Medicine

NOTES FOR PROFESSIONAL LIBRARIANSAND LIBRARY USERS

This is an original book title published by The Haworth HerbalPress, Pharmaceutical Products Press, and The Haworth MedicalPress, imprints of The Haworth Press, Inc. Unless otherwise notedin specific chapters with attribution, materials in this book have notbeen previously published elsewhere in any format or language.

CONSERVATION AND PRESERVATION NOTESAll books published by The Haworth Press, Inc. and its imprints areprinted on certified pH neutral, acid-free book grade paper. This pa-per meets the minimum requirements of American National Standardfor Information Sciences-Permanence of Paper for Printed Material,ANSI Z39.48-1984.

The Handbookof Clinically TestedHerbal Remedies

Volume 1

Haworth Series in Evidence-Based PhytotherapyMarilyn Barrett, PhD

Editor

The Handbook of Clinically Tested Herbal Remedies edited by MarilynBarrett

Other titles of related interest:

Herbal Medicine: Chaos in the Marketplace by Rowena K. Richter

Botanical Medicines: The Desk Reference for Major Herbal Supplements,Second Edition by Dennis J. McKenna, Kenneth Jones, and KerryHughes

Tylers Tips: The Shoppers Guide for Herbal Remedies by George H.Constantine

Handbook of Psychotropic Herbs: A Scientific Analysis of HerbalRemedies for Psychiatric Conditions by Ethan B. Russo

Tylers Honest Herbal: A Sensible Guide to the Use of Herbs and RelatedRemedies, Fourth Edition by Steven Foster and Varro E. Tyler

Tylers Herbs of Choice: The Therapeutic Use of Phytomedicinals,Second Edition by James E. Robbers and Varro E. Tyler

The Handbookof Clinically TestedHerbal Remedies

Volume 1

Part I: Fundamentals of Herbal MedicinePart II: Methods

Part III: Botanical ProfilesProduct and Clinical Trial Information

(ArtichokeGinseng)

Marilyn Barrett, PhDEditor

The Haworth Herbal PressPharmaceutical Products Press

The Haworth Medical PressImprints of The Haworth Press, Inc.

New York London Oxford

Published by

The Haworth Herbal Press, Pharmaceutical Products Press, and The Haworth Medical Press,imprints of The Haworth Press, Inc., 10 Alice Street, Binghamton, NY 13904-1580.

2004 by The Haworth Press, Inc. All rights reserved. No part of this work may be reproduced orutilized in any form or by any means, electronic or mechanical, including photocopying, microfilm,and recording, or by any information storage and retrieval system, without permission in writingfrom the publisher. Printed in the United States of America.

TR: 8.9.04.

PUBLISHERS NOTEThis book has been published solely for educational purposes and is not intended to substitutefor the medical advice of a treating physician. Medicine is an ever-changing science. As newresearch and clinical experience broaden our knowledge, changes in treatment may be required.While many potential treatment options are made herein, some or all of the options may not beapplicable to a particular individual. Therefore, the author, editor and publisher do not acceptresponsibility in the event of negative consequences incurred as a result of the informationpresented in this book. We do not claim that this information is necessarily accurate by the rigidscientific and regulatory standards applied for medical treatment. No Warranty, Expressed orImplied, is furnished with respect to the material contained in this book. The reader is urgedto consult with his/her personal physician with respect to the treatment of any medicalcondition.

Cover design by Marylouise E. Doyle.

Photography by Linda Nikaya.

Library of Congress Cataloging-in-Publication Data

The handbook of clinically tested herbal remedies, volumes 1 and 2 / Marilyn Barrett, editor.p. ; cm.

Includes bibliographical references and index.ISBN 0-7890-1068-2 Volumes 1 and 2 (hard : alk. paper)ISBN 0-7890-2723-2 Volume 1 (hard : alk. paper)ISBN 0-7890-2724-0 Volume 2 (hard : alk. paper)1. HerbsTherapeutic useHandbooks, manuals, etc. [DNLM: 1. Plant Preparations

Handbooks. QV 39 H2362 2004] I. Barrett, Marilyn.RM666.H33H363 2004615'.321dc22

2003025270

To Dr. Varro (Tip) Tyler, who believed in my abilities and soldthe idea of this book to the publisher of The Haworth Press

To my parents, Geoffrey and Elizabeth Barrett, whose faithand confidence in me has enabled me to embark on this book,

and many other adventures

CONTENTS

VOLUME 1

About the Editor xxi

Contributors xxiii

Preface xxxi

Acknowledgments xxxv

Editors Note xxxvii

PART I: FUNDAMENTALS OF HERBAL MEDICINE

Chapter 1. History and Regulation of Botanicalsin the United States 3

Loren D. IsraelsenMarilyn Barrett

Introduction 3History 3DSHEA Explained 5Drugs: OTC and Rx 10Prospectus 11

Chapter 2. Product Definition Deficiencies in ClinicalStudies of Herbal Medicines 13

Varro E. Tyler

Chapter 3. Identifying and Characterizing BotanicalProducts 23

Marilyn BarrettIdentifying Plants by Name 24Means of Assuring Plant Identity 26Preparations and Formulations 30Dose 30Bioavailability 30Guidelines 31Appendix: Preparations and Formulations 32

Chapter 4. Standardization of Botanical Preparations:What It Does and Does Not Tell Us 37

Uwe KoetterMarilyn Barrett

Introduction 37Standardization of Therapeutic Activity 38Standardization to Meet a Chemical Norm 39Standardization As a Reflection of Quality

Assurance Programs 41Guidance 43Situation in the Marketplace 44Perspective 45

Chapter 5. The Importance and Difficulty in Determiningthe Bioavailability of Herbal Preparations 49

Anton BiberFriedrich Lang

Chapter 6. Borrowed Science and Phytoequivalence:Can Two Herbal Products Be Judged Equivalent? 59

Marilyn BarrettChemical or Pharmaceutical Equivalency 61

62Application of the Concepts, Ginkgo As an Example 63Meta-Analyses 65Perspective 66

Chapter 7. Determining Efficacy of Herbal Preparations 69Tieraona Low Dog

Observational Medicine 70Evidence-Based Medicine 71Summary 74

Chapter 8. Evaluating Safety of Herbal Preparations 77Ezra BjarJoseph M. BetzMarilyn Barrett

Evaluation of Safety 78Adverse Reactions 80Adverse-Event Reporting Systems 81Categorization According to the Degree of Safety 82

Product Quality As an Aspect of Safety 84Contraindications 85Drug-Herb Interactions 85Improving Our Knowledge of Safety 87

Chapter 9. Conducting Clinical Trials on Herbal DietarySupplements in North America: Commercialization,Confidence, and Conflicts 91

Anthony L. AlmadaThe Spirit to Sponsor: Is There an Adequate Economic

Incentive to Fund Research? 92Extracting Value from Science 95Competitor Kevlar: Preventing Piracy of Product-Specific

Data 96How Much Data Is Enough? 100We Have DataNow What? 103Who Has Science and How Did They Acquire It? 105Conclusion 105

Chapter 10. Motives for Conducting Clinical Trialson Botanicals in Europe: A Focus on Germany 107

Joerg GruenwaldStefan Spiess

Chapter 11. Pharmacopoeias and Botanical Monographs 115Marilyn BarrettRoy UptonV. Srini Srinivasan

United States Pharmacopeia and National Formulary(USP-NF) 116

American Herbal Pharmacopoeia (AHP) and TherapeuticCompendium 118

European Pharmacopoeia (EP) 119British Herbal Pharmacopoeia (BHP) and British Herbal

Compendium (BHC) 119German Commission E 120European Scientific Cooperative on Phytotherapy (ESCOP) 121Chinese Pharmacopoeia 121African Pharmacopoeia 122The Pharmacopoeia of Japan 122The Pharmacopoeias of India 123

World Health Organization (WHO) 123Other Pharmacopoeias 124Summary and Perspective 124Sources of Pharmacopoeias 125

PART II: METHODS

Chapter 12. Methods of Product and Trial Inclusionand Evaluation 129

Marilyn BarrettGathering Information on Products and Trials 129Data on Products and Trials 134Evaluation of Clinical Trial Quality 137

Chapter 13. Clinical Trial Reviewers Guidanceand Checklist 141

Tieraona Low DogLevels of Evidence 141Guidelines for Reviewer Checklist: Part I 142Guidelines for Reviewer Checklist: Part II 144Scoring 146

PART III: BOTANICAL PROFILESPRODUCT AND CLINICAL TRIAL INFORMATION

(ArtichokeGinseng)Single Herbs 151

Artichoke 151

Preparations Used in Reviewed Clinical Studies 151Artichoke Summary Table 152Summary of Reviewed Clinical Studies 153Postmarketing Surveillance Studies 154Adverse Reactions or Side Effects 154Information from Pharmacopoeial Monographs 155Details on Artichoke Products and Clinical Studies 157

Bilberry 163

Preparations Used in Reviewed Clinical Studies 163Bilberry Summary Table 164

Summary of Reviewed Clinical Studies 165Adverse Reactions or Side Effects 167Information from Pharmacopoeial Monographs 168Details on Bilberry Products and Clinical Studies 171

Black Cohosh 185

Preparations Used in Reviewed Clinical Studies 185Black Cohosh Summary Table 186Summary of Reviewed Clinical Studies 187Postmarketing Surveillance Studies 189Adverse Reactions or Side Effects 189Information from Pharmacopoeial Monographs 190Details on Black Cohosh Products and Clinical Studies 194

Boxwood 207

Preparations Used in Reviewed Clinical Studies 207Summary of Reviewed Clinical Studies 207Boxwood Summary Table 208Adverse Reactions or Side Effects 209Details on Boxwood Products and Clinical Studies 210

Butterbur, Purple 213

Preparations Used in Reviewed Clinical Studies 213Butterbur Summary Table 214Summary of Reviewed Clinical Studies 215Adverse Reactions or Side Effects 216Information from Pharmacopoeial Monographs 216Details on Butterbur Products and Clinical Studies 218

Cats Claw 225

Preparations Used in Reviewed Clinical Studies 225Cats Claw Summary Table 226Summary of Reviewed Clinical Studies 227Adverse Reactions or Side Effects 227Details on Cats Claw Products and Clinical Studies 228

Chaste Tree 231

Preparations Used in Reviewed Clinical Studies 231Chaste Tree Summary Table 232Summary of Reviewed Clinical Studies 233Postmarketing Surveillance Studies 235Adverse Reactions or Side Effects 236Information from Pharmacopoeial Monographs 236Details on Chaste Tree Products and Clinical Studies 240

Cordyceps 255

Preparations Used in Reviewed Clinical Studies 255Summary of Reviewed Clinical Studies 255Cordyceps Summary Table 256Adverse Reactions or Side Effects 258Information from Pharmacopoeial Monographs 258Details on Cordyceps Products and Clinical Studies 260

Cranberry 265

Preparations Used in Reviewed Clinical Studies 265Summary of Reviewed Clinical Studies 265Cranberry Summary Table 266Adverse Reactions or Side Effects 267Information from Pharmacopoeial Monographs 268Details on Cranberry Products and Clinical Studies 270

Devils Claw 277

Preparations Used in Reviewed Clinical Studies 277Summary of Reviewed Clinical Studies 277Devils Claw Summary Table 278Adverse Reactions or Side Effects 280Information from Pharmacopoeial Monographs 280Details on Devils Claw Products and Clinical Studies 283

Dragons Blood Croton 291

Preparations Used in Reviewed Clinical Studies 291Dragons Blood Croton Summary Table 292Summary of Reviewed Clinical Studies 293

Adverse Reactions or Side Effects 293Details on Dragons Blood Products and Clinical Studies 295

Echinacea 303

Preparations Used in Reviewed Clinical Studies 303Echinacea Summary Table 304Summary of Reviewed Clinical Studies 307Reviews and Meta-Analyses of Clinical Studies 311Adverse Reactions or Side Effects 312Information from Pharmacopoeial Monographs 313Details on Echinacea Products and Clinical Studies 321

Elderberry 351

Preparations Used in Reviewed Clinical Studies 351Elderberry Summary Table 352Summary of Reviewed Clinical Studies 353Adverse Reactions or Side Effects 353Information from Pharmacopoeial Monographs 353Details on Elderberry Products and Clinical Studies 356

Evening Primrose 359

Preparations Used in Reviewed Clinical Studies 359Evening Primrose Summary Table 360Summary of Reviewed Clinical Studies 362Systematic Reviews and Meta-Analyses 367Adverse Reactions or Side Effects 368Details on Evening Primrose Products and Clinical Studies 370

Garlic 403

Preparations Used in Reviewed Clinical Studies 403Garlic Summary Table 404Summary of Reviewed Clinical Studies 408Meta-Analyses and Systematic Clinical Reviews 419Epidemiological Studies 421Adverse Reactions or Side Effects 421Information from Pharmacopoeial Monographs 422Details on Garlic Products and Clinical Studies 429

Ginger 493Preparations Used in Reviewed Clinical Studies 493Ginger Summary Table 494Summary of Reviewed Clinical Studies 495Systematic Reviews and Meta-Analyses 501Adverse Reactions or Side Effects 501Information from Pharmacopoeial Monographs 502Details on Ginger Products and Clinical Studies 508

Ginkgo 547Preparations Used in Reviewed Clinical Studies 547Ginkgo Summary Table 548Summary of Reviewed Clinical Studies 551Meta-Analyses and Systematic Reviews 562Adverse Reactions or Side Effects 565Information from Pharmacopoeial Monographs 566Details on Ginkgo Products and Clinical Studies 575

Ginseng 673Preparations Used in Reviewed Clinical Studies 673Ginseng Summary Table 674Summary of Reviewed Clinical Studies 676Systematic Reviews 683Epidemiological Studies 683Adverse Reactions or Side Effects 684Information from Pharmacopoeial Monographs 685Details on Ginseng Products and Clinical Studies 691

VOLUME 2PART III: BOTANICAL PROFILES

PRODUCT AND CLINICAL TRIAL INFORMATION(Grape SeedValerian and Herbal Formulas)

Grape Seed 745Preparations Used in Reviewed Clinical Studies 745Grape Seed Summary Table 746Summary of Reviewed Clinical Studies 747Adverse Reactions or Side Effects 750Details on Grape Seed Products and Clinical Studies 752

Grass Pollen 773Preparation Used in Reviewed Clinical Studies 773Summary of Reviewed Clinical Studies 773Grass Pollen Summary Table 774Systematic Reviews 776Adverse Reactions or Side Effects 777Information from Pharmacopoeial Monographs 777Details on Grass Pollen Products and Clinical Studies 780

Green Tea 787Preparations Used in Reviewed Clinical Studies 787Green Tea Summary Table 788Summary of Reviewed Clinical Studies 789Epidemiological Studies 792Adverse Reactions or Side Effects 793Details on Green Tea Products and Clinical Studies 796

Hawthorn 809Preparations Used in Reviewed Clinical Studies 809Hawthorn Summary Table 810Summary of Reviewed Clinical Studies 811Postmarketing Surveillance Studies 813Adverse Reactions or Side Effects 814Information from Pharmacopoeial Monographs 814Details on Hawthorn Products and Clinical Studies 820

Horse Chestnut 843Preparations Used in Reviewed Clinical Studies 843Horse Chestnut Summary Table 844Summary of Reviewed Clinical Studies 845Systematic Reviews 849Adverse Reactions or Side Effects 850Information from Pharmacopoeial Monographs 851Details on Horse Chestnut Products and Clinical Studies 855

Kava 887

Preparations Used in Reviewed Clinical Studies 887Summary of Reviewed Clinical Studies 887Kava Summary Table 888Systematic Reviews 892Adverse Reactions or Side Effects 893Information from Pharmacopoeial Monographs 895Details on Kava Products and Clinical Studies 899

Lemon Balm 923

Preparations Used in Reviewed Clinical Studies 923Summary of Reviewed Clinical Studies 923Lemon Balm Summary Table 924Adverse Reactions or Side Effects 925Information from Pharmacopoeial Monographs 926Details on Lemon Balm Products and Clinical Studies 928

Milk Thistle 933

Preparations Used in Reviewed Clinical Studies 933Milk Thistle Summary Table 934Summary of Reviewed Clinical Studies 935Meta-Analyses and Systematic Reviews 941Adverse Reactions or Side Effects 942Information from Pharmacopoeial Monographs 943Details on Milk Thistle Products and Clinical Studies 947

Pygeum 981

Preparations Used in Reviewed Clinical Studies 981Pygeum Summary Table 982Summary of Reviewed Clinical Studies 983Systematic Reviews 987Adverse Reactions or Side Effects 987Details on Pygeum Products and Clinical Studies 990

Red Clover 1011

Preparations Used in Reviewed Clinical Studies 1011Summary of Reviewed Clinical Studies 1011Red Clover Summary Table 1012Adverse Reactions or Side Effects 1015Information from Pharmacopoeial Monographs 1015Details on Red Clover Products and Clinical Studies 1017

Red Yeast Rice 1027

Preparations Used in Reviewed Clinical Studies 1027Red Yeast Summary Table 1028Summary of Reviewed Clinical Studies 1029Adverse Reactions or Side Effects 1031Details on Red Yeast Products and Clinical Studies 1033

Saw Palmetto 1043

Preparations Used in Reviewed Clinical Studies 1043Saw Palmetto Summary Table 1044Summary of Reviewed Clinical Studies 1046Meta-Analyses and Systematic Reviews 1052Adverse Reactions or Side Effects 1053Information from Pharmacopoeial Monographs 1053Details on Saw Palmetto Products and Clinical Studies 1059

St. Johns Wort 1101

Preparations Used in Reviewed Clinical Studies 1101St. Johns Wort Summary Table 1102Summary of Reviewed Clinical Studies 1105Systematic Reviews and Meta-Analyses 1114Postmarketing Surveillance Studies 1115Adverse Reactions or Side Effects 1116Drug Interactions 1117Information from Pharmacopoeial Monographs 1121Details on St. Johns Wort Products and Clinical Studies 1131

Valerian 1197

Preparations Used in Reviewed Clinical Studies 1197Valerian Summary Table 1198Summary of Reviewed Clinical Studies 1200Adverse Reactions or Side Effects 1207Information from Pharmacopoeial Monographs 1208Details on Valerian Products and Clinical Studies 1214

Herbal Formulas 1249

2nd Wind 1249

Preparations Used in Reviewed Clinical Studies 1249Summary of Reviewed Clinical Studies 12492nd Wind Summary Table 1250Adverse Reactions or Side Effects 1251Details on 2nd Wind Product and Clinical Studies 1252

Cystone 1257

Preparations Used in Reviewed Clinical Studies 1257Cystone Summary Table 1258Summary of Reviewed Clinical Studies 1259Adverse Reactions or Side Effects 1260Details on Cystone Product and Clinical Studies 1261

Gastrim 1265

Preparations Used in Reviewed Clinical Studies 1265Gastrim Summary Table 1266Summary of Reviewed Clinical Studies 1267Adverse Reactions or Side Effects 1268Details on Gastrim Product and Clinical Studies 1269

Geriforte 1275

Preparations Used in Reviewed Clinical Studies 1275Geriforte Summary Table 1276Summary of Reviewed Clinical Studies 1277Adverse Reactions or Side Effects 1277Details on Geriforte Product and Clinical Studies 1279

Iberogast 1283

Preparations Used in Reviewed Clinical Studies 1283Summary of Reviewed Clinical Studies 1283Iberogast Summary Table 1284Adverse Reactions or Side Effects 1286Details on Iberogast Product and Clinical Studies 1288

Padma 1295

Padma Summary Table 1296Preparations Used in Reviewed Clinical Studies 1297Summary of Reviewed Clinical Studies 1298Adverse Reactions or Side Effects 1301Details on Padma Product and Clinical Studies 1303

Phytodolor 1321

Preparations Used in Reviewed Clinical Studies 1321Phytodolor Summary Table 1322Summary of Reviewed Clinical Studies 1323Systematic Reviews 1324Adverse Reactions or Side Effects in Clinical Studies 1325Details on Phytodolor Product and Clinical Studies 1326

Prostane 1333

Preparations Used in Reviewed Clinical Studies 1333Summary of Reviewed Clinical Studies 1333Prostane Summary Table 1334Adverse Reactions or Side Effects 1335Details on Prostane Product and Clinical Studies 1336

Resistex 1339

Preparations Used in Reviewed Clinical Studies 1339Summary of Reviewed Clinical Studies 1339Resistex Summary Table 1340Adverse Reactions or Side Effects 1341Details on Resistex Product and Clinical Studies 1343

Sinupret 1347

Preparations Used in Reviewed Clinical Studies 1347Summary of Reviewed Clinical Studies 1347Sinupret Summary Table 1348Postmarketing Surveillance Study 1350Adverse Reactions or Side Effects 1350Details on Sinupret Product and Clinical Studies 1353

Appendix A. Products Listed by Manufacturer/Distributor 1359

Appendix B. Manufacturer/Distributor ContactInformation 1367

Index 1377

About the EditorABOUT THE EDITOR

Marilyn Barrett, PhD, is founder and principal of PharmacognosyConsulting, whose mission is to provide a scientific foundation forbotanical medicine. She was awarded a PhD in pharmacognosy fromthe School of Pharmacy, University of London, UK, in 1985 and a BAin botany from the University of California, Berkeley, CA, in 1977.

Since 1994, Dr. Barrett has provided scientific information andtechnical expertise to manufacturers, associations, and governmentconcerning medicinal plant products through her consulting busi-ness. She is a member of the United States Pharmacopeia Committeeof Experts for Dietary Supplements Information, an external advi-sory board member for the University of California at Los AngelesCenter for Dietary Supplements (an NIH-funded center) and a con-sultant to the Office of Dietary Supplements in preparation of theirbotanical fact sheets. Dr. Barrett served on a working group for theInstitute of Medicine of the National Academy of Sciences Commit-tee developing a Framework for Evaluating the Safety of DietarySupplements. She is a member of the American Botanical CouncilAdvisory Board, the American Herbal Pharmacopoeia and Thera-peutic Compendium Technical Advisory Board, and the AmericanHerbal Products Associations Scientific Advisory Board.

Dr. Barrett has published over 30 publications in peer-reviewedjournals and a booklet titled Reference on Evaluating Botanicals forthe Council for Responsible Nutrition, in 1998. More information isavailable on her Web site at .

ContributorsCONTRIBUTORS

Authors of Chapters in Part IAnthony L. Almada, MSc, has worked within the dietary supplementindustry since 1975. He has a BSc in physiology with a nutritional bio-chemistry minor from California State University, Long Beach, and anMSc from Berkeley (with a research thesis in antioxidant-exercise bio-chemistry). He is the cofounder/past president of Experimental andApplied Sciences (EAS) and is the founder/CSO of IMAGINutrition,Inc., a nutritional technology creation, clinical research, and intellec-tual property-driven think tank/incubator. He has been a coinvestigatoron over 65 university and research institute clinical trials, ranging fromAIDS/HIV to osteoarthritis.Ezra Bjar, PhD, is a phytopharmacologist with more than 15 yearsof experience in the concept development, testing, and launching ofbotanical supplements. He is the principal of Plant Bioassay, a con-sulting company that serves the dietary supplement industry, govern-ment, and academia. Dr. Bjar also acts as adjunct professor in theCollege of Sciences at San Diego State University. He is the authorof two books, several chapters, and numerous scientific articles.Dr. Bjar currently serves as a book review editor for the journalPhytomedicine and as a member of the advisory board of the journalPhytotherapy Research.Joseph M. Betz, PhD, is Director of the Dietary Supplements Meth-ods and Reference Materials Program at the National Institutes ofHealth (NIH) Office of Dietary Supplements. Prior to this, he spent12 years as a research chemist at the Food and Drug Administration(FDA) Center for Food Safety and Applied Nutrition. He has been aprincipal investigator in the National Cancer Institutes (NCI) De-signer Foods program as well as project manager for FDAs PlantToxins and Chemical, Biological, and Toxicological Characteriza-tion of Food Plants research programs. Dr. Betz has a PhD in phar-

macognosy and over 30 publications in the areas of plant toxins andbotanical dietary supplements.Anton Biber, PhD, studied food chemistry at the University ofKarlsruhe. He received his PhD at the University of Wrzburg in1984 and subsequently joined a research group at the University ofMunich. Since 1987 he has been head of the Bioanalytical Depart-ment of Dr. Willmar Schwabe GmbH & Co., Karlsruhe, Germany.His interest is pharmacokinetics of herbal medicinal products.Joerg Gruenwald, PhD, is an international expert in the field of bo-tanicals and natural ingredients and the author of the PhysiciansDesk Reference (PDR) for Herbal Medicines. He is a member of theAd Hoc Advisory Committee of the Office of Dietary Supplements ofthe NIH and chairman of the International Committee of the Ameri-can Herbal Products Association. Dr. Gruenwald is president of Ana-lyze & Realize, Inc. with its subsidiaries Phytopharm Consulting andPhytopharm Research in Berlin. The companies activities rangefrom market analysis, product development, and clinical trials to reg-ulatory affairs for the natural and functional food industry.Loren D. Israelsen, JD, is president of the LDI Group in Salt LakeCity, Utah, a consulting firm specializing in the regulatory and com-mercial development of herbs, dietary supplements, and other naturalproducts. Mr. Israelsen has previously served as president of NaturesWay Products, Inc., and as an advisor to the National Institutes ofHealth, the Food and Drug Administration, and foreign governmentson dietary supplement policy.Uwe Koetter, PhD, is Director of New Product Development withGlaxoSmithKline Consumer Healthcare, where he has been for thepast ten years. He is responsible for development and research ofover-the-counter (OTC) drugs and dietary supplements. Dr. Koetteris the author of 22 publications. He completed his PhD in pharmaceu-tical biology under the supervision of Professor Heinz Schilcher,president of the German Commission E. He is a fully accredited phar-macist, licensed in Germany.Friedrich Lang, PhD, studied chemistry at the University of Heidel-berg and received his PhD in 1980. He is head of the Analytical De-velopment Department of Dr. Willmar Schwabe GmbH & Co.,Karlsruhe, Germany. His special interest is stability testing and bio-pharmaceutical characterization of herbal medicinal products.

Tieraona Low Dog, MD, currently serves as chair of the U.S. Phar-macopeia Dietary Supplements/Botanicals Expert Panel and was amember of the White House Commission on Complementary andAlternative Medicine. A former president of the American HerbalistsGuild, she has researched, practiced, and taught about herbs for morethan twenty years. Dr. Low Dog is in private practice and serveson the executive advisory board for the National Institutes of HealthNational Center for Complementary and Alternative Medicine(NCCAM).Stefan Spiess, RPh, is a pharmacist and food scientist. He is presi-dent of Grunwalder GmbH, a company that sells drugs and supple-ments of mainly natural origin in Europe, is active in the developmentof new products, and provides consulting advice. Prior to this, he heldsenior positions in quality control, research and development, regula-tory, and business development for HEXAL AG. Mr. Spiess is amember of the Gesellschaft deutscher Chemiker Food Chemistrysection, the Arbeitskreis pharmazeutische Verfahrenstechnik, and thePanel for Medical/Pharmaceutical Affairs of the Bundesverband derArzneimittelhersteller.Vijayaraghavan (Srini) Srinivasan, PhD, currently serves as VicePresident of the Dietary Supplement Verification Program of the U.S.Pharmacopeia. Prior to this, Dr. Srinivasan was Director of the OTCDrugs and Dietary Supplements Division of the Information andStandards Development Department in the USP. Dr. Srinivasan hasnumerous publications covering various aspects of nutritional sup-plements such as bioavailability, in vitro dissolution of oral solid dos-age forms, botanicals, aerosols, and synthetic organic chemistry. Hiscurrent interest is the establishment of public standards for in vitrodissolution for botanical dietary supplements.Varro E. Tyler, PhD, was Editor in Chief of The Haworth HerbalPress and Distinguished Professor Emeritus of Pharmacognosy in theSchool of Pharmacy and Pharmacal Sciences at Purdue Universitybefore his recent passing in 2001. A recognized authority on plantdrugs (herbs) and their uses, he was a co-author of Pharmacognosyand Pharmacobiotechnology, the standard U.S. textbook in the field.Dr. Tyler authored over 300 scientific and educational publications,including more than two dozen books. He served as Purdue Univer-sitys Executive Vice President for Academic Affairs for five years,and for 20 years as dean of its School of Pharmacy and PharmacalSciences.

Roy Upton, RH, is the executive director and editor of the AmericanHerbal Pharmacopoeia, an organization dedicated to the develop-ment of quality control standards for botanical medicines. Mr. Uptonis also vice president of the American Herbalists Guild, serves on theboard of directors of the Botanical Medicine Academy, is generalmanager of the herbal company Planetary Formulas, and is a memberof the Standards Committee of the American Herbal Products Asso-ciation. Mr. Upton has also authored several books, including St.Johns Wort and Echinacea, in the Good Herb series of Keats Pub-lishing and the Botanical Safety Handbook published by CRC Press.

Reviewers of Clinical Trials in Part IIIKarriem Ali, MD, obtained his medical degree with honors in re-search from Stanford University School of Medicine, along with hisresidency in anesthesia, intensive care, and pain management. He hasextensive experience in ethnobotanical field work and is a recognizedconsultant and lecturer in the fields of ethnobiology and rational devel-opment of herbal products. Dr. Ali reviewed trials on dragons blood,ginger, milk thistle, and the formulas Gastrim and Iberogast in con-junction with Dr. Aranda.Richard Aranda, MD, obtained his degree from Stanford UniversitySchool of Medicine and is board certified in internal medicine andgastroenterology. He also obtained advanced training in immunologyat UCLA where he was on the faculty in the Division of DigestiveDiseases. Currently, he holds the position of Associate Director,Clinical Design and Evaluation, Immunology, Bristol-Myers SquibbCo., Princeton, New Jersey. Dr. Aranda reviewed trials on dragonsblood, ginger, milk thistle, and the formulas Gastrim and Iberogast inconjunction with Dr. Ali.Elliot Fagelman, MD, is an attending urologist at Good SamaritanHospital, Suffern, New York, and Nyack Hospital, Nyack, New York.Dr. Fagelman reviewed trials on cranberry, pygeum, saw palmetto,grass pollen, and the formulas Cystone and Prostane in conjunctionwith Dr. Lowe.Deborah A. Goebert, PhD, is assistant professor and associate di-rector of research at the Department of Psychiatry, John A. BurnsSchool of Medicine, University of Hawaii. She has conducted re-search on St. Johns wort, melatonin, and kava as well as traditional

healing and acupuncture. Dr. Goebert reviewed trials on St. Johnswort in conjunction with Dr. Kim.Mary Hardy, MD, a board-certified internist, is the medical directorof the Cedars-Sinai Medical Center program in Integrative Medicine.Her research projects include clinical trials for herbal remedies aswell as participating in an NCCAM-funded project to study barriersto integration of a hospital center of integrative medicine. Most re-cently, Dr. Hardy has been appointed Associate Director for the Cen-ter for Dietary Supplement Research in Botanicals at UCLA. Dr.Hardy obtained her medical degree from Louisiana State UniversitySchool of Medicine in New Orleans and completed her residency ininternal medicine at Tufts-New England Medical Center in Boston.Dr. Hardy reviewed trials on grape seed, hawthorn, and horse chest-nut, as well as the formulas 2nd Wind and Padma.David Heber, MD, PhD, FACP, FACN, is Director of the Center forHuman Nutrition, Professor of Medicine and Public Health, FoundingChief of the Division of Clinical Nutrition in the Department of Med-icine, and Founding Director of the Center for Human Nutrition, all atthe University of California, Los Angeles. Dr. Heber directs the NIHCenter for Dietary Supplement Research in Botanicals, the NCI-funded Clinical Nutrition Research Unit, and the NIH Nutrition andObesity Training grants. He is a director of the American Board ofNutrition and past chair of the Education Committee of the AmericanSociety for Clinical Nutrition. Dr. Heber reviewed trials on artichoke,bilberry, cordyceps, garlic, green tea, and red yeast rice.John Trimmer Hicks, MD, FACP, FACR, is president of Green-wood Regional Rheumatology Center, South Carolina, is on the edito-rial board of the journal Phytomedicine, and is a visiting professor atthe College of Pharmacy, University of Illinois at Chicago. Dr. Hickshas over 20 years of experience in treating patients with various rheu-matologic and arthritic conditions. He orchestrated worldwide clini-cal trials with Smith Kline (now GlaxoSmithKline) and spearheadedtrials as director of the Arthritis Institute in Arlington, Virginia. Hehas been a member of the clinical teaching faculties of GeorgetownUniversity, West Virginia University, and Temple University. Dr.Hicks reviewed trials on cats claw, devils claw, evening primroseoil, and the formula Phytodolor.Hannah L. Kim, MD, is board certified in both child/adolescent psy-chiatry and adult psychiatry and is in private practice in Honolulu.

She is also clinical assistant professor at the Department of Psychia-try, John A. Burns School of Medicine, University of Hawaii. She andcolleagues previously published a review of St. Johns wort clinicalstudies. For this book, Dr. Kim reviewed trials on St. Johns wort inconjunction with Dr. Goebert.Tieraona Low Dog, MD, currently serves as chair of the U.S. Phar-macopeia Dietary Supplements/Botanicals Expert Panel and was amember of the White House Commission on Complementary and Al-ternative Medicine. A former president of the American HerbalistsGuild, she has researched, practiced, and taught about herbs for morethan 20 years. Dr. Low Dog is in private practice and serves on theExecutive Advisory Board for the National Institutes of Health Na-tional Center for Complementary and Alternative Medicine. Dr. LowDog reviewed trials on black cohosh, chaste tree, red clover, and theformula Geriforte.Franklin C. Lowe, MD, MPH, is Associate Professor of ClinicalUrology at Columbia University, College of Physicians and Surgeons,Associate Director of Urology at St. Lukes-Roosevelt Hospital, chair-person of the American Urological Association Committee on Com-plementary and Alternative Medicine, and a member of the AmericanUrological Association Benign Prostatic Hyperplasia Guidelines Com-mittee. He has published extensively on phytotherapy for benign pros-tatic hyperplasia. Dr. Lowe reviewed trials on cranberry, pygeum, sawpalmetto, grass pollen, and the formulas Cystone and Prostane in con-junction with Dr. Fagelman.Richard D. OConnor, MD, is Director of the Department of Clini-cal Research, Director of the Department of Quality Management,and chief of division and staff physician in the Division of Asthma,Allergy, and Clinical Immunology, all at Sharp Rees-Stealy MedicalGroup in San Diego, California. He is also Clinical Professor of Pedi-atrics at the School of Medicine at the University of California, SanDiego. Dr. OConnor has more than 90 publications and has partici-pated as an investigator in over 135 phase II and phase III clinical tri-als. In addition, he was chairperson of the Institutional Review Boardfor Sharp HealthCare for six years and supervised more than 250clinical trials annually. Dr. OConnor reviewed trials on boxwood,butterbur, echinacea, elderberry lemon balm, and the formulas Resis-tex and Sinupret.

Barry S. Oken, MD, has been a member of the faculty at OregonHealth and Science University (OHSU) since 1985, where he is cur-rently Professor in the Departments of Neurology and BehavioralNeuroscience and Director of the Oregon Center for Complementaryand Alternative Medicine (CAM) in Neurological Disorders (www.ohsu.edu/orccamind) whose mission is to facilitate research and edu-cation on the effectiveness and mechanisms of action of CAM thera-pies in the treatment of neurological disorders. Dr. Oken reviewed tri-als on kava and valerian in conjunction with Dr. Shinto.Lynn Shinto, ND, received a degree in naturopathic medicine fromBastyr University, Kenmore, Washington. She is currently a researchassistant professor in the Department of Neurology at Oregon Healthand Science University and a clinical research professor at the Na-tional College of Naturopathic Medicine, Portland, Oregon. Dr.Shinto reviewed trials on kava and valerian in conjunction with Dr.Oken.Keith Wesnes, PhD, founded Cognitive Drug Research in 1986,which has since grown to be the worlds leading provider of auto-mated cognitive function testing facilities for clinical trials. The com-pany was honored to receive the Queens Award for Enterprise for In-ternational Trade in 2002, and the Queens Award in Innovation in2003. Professor Wesnes has published over 100 peer-reviewed re-search articles and chapters and holds several university appoint-ments, including a visiting professorship at the Human CognitiveNeuroscience Unit, University of Northumbria. He is a member ofnumerous advisory boards and frequently speaks at national and in-ternational meetings. Dr. Wesnes reviewed trials on ginkgo and gin-seng.Gloria Y. Yeh, MD, is a faculty member of the Harvard MedicalSchool Division for Research and Education in Complementary andIntegrative Medical Therapies. She has a research interest in comple-mentary approaches to diabetes and cardiovascular disease. She re-ceived her MD from the University of Maryland School of Medicineand completed a Masters in Public Health at Harvard. She is board-certified in internal medicine and practices at an integrative healthclinic in Cambridge, Massachusetts. Dr. Yeh reviewed the Americanginseng trials.

Assistants

Eva Boyd, AB, worked with me in the summer of 2000. She searchedscientific literature databases for clinical trials, retrieved those stud-ies, and entered the information into the database.Julie Dennis, BA, worked with me at the beginning of this project,from June 1999 to January 2000. She made the initial contact withU.S. manufacturers and gathered product information from them.She was also instrumental in establishing the electronic database thatwas used to collect the trial and product information included in thisbook.Eva Dusek, BS, worked with me in 2001. She also collected andsummarized information from clinical studies and entered it into thedatabase.Clea Lopez, BA, worked with me during the last year and a half onthis project, from January 2002 through June 2003. She conductedscientific literature searches, reviewed and extracted information fromclinical trials, and obtained product information from manufacturers.Clea compiled the pharmacopoeial therapeutic information in thesummary sections in Part III of the book. She also assisted in editingthe chapters in Part I, Part II, and the summary sections in Part III.

PrefacePreface

I believe that if herbal medicine is to play a significant role in fu-ture health care, the therapeutic effects of the individual herbsmust be carefully evaluated by well-designed, randomized, double-blind, placebo-controlled studies involving a significant numberof human subjects.

Varro E. Tyler (1999)Phytomedicines: Back to the Future

In Journal of Natural ProductsBackground of the Project

The genesis of the idea for this book came from a conversationwith my childhood physician, Larry Posner, MD, at a party in Sep-tember 1998. He told me of his interest in botanicals due to the num-ber of patients he had taking dietary supplements and of the limitedknowledge he had of those products. He knew of my work with me-dicinal herbs and asked me to speak to him in his language regardingthe evidence for these herbs. I inquired what language that might beand he replied, double-blind, controlled, randomized clinical trials.My response was that quite a few studies have been conducted onherbal remedies, probably more than he realized. Thus, the idea ofthis book was born.

Purpose and Scope of the BookThis book provides consumers and health professionals with a

means to distinguish those herbal products that have the backing ofclinical evidence to substantiate claims of efficacy. It includes prod-uct descriptions provided largely from label information. In addition,this book describes in detail the trials associated with those productsand provides an assessment of the quality of those trials.

Only products that have undergone controlled clinical trials are in-cluded, as this research design is considered the most persuasive andis generally given the most weight by researchers and practitioners.Many herbal preparations commonly sold on the market are not in-cluded in this text, as they have not been subjected to controlled clini-cal trials.

The book lists products, made with 32 herbs and ten formulas, thathave been studied in a total of 369 clinical trials. Attempts were madeto be systematic and inclusive in gathering products and trials; how-ever, due to the magnitude of the effort and the amount of time re-quired to complete the project, I acknowledge that it is essentially asnapshota sampling of the existing products and their clinical trialsat the time when we were doing research for the book.

It is my hope that this snapshot will assist in the evaluation of theclinical science behind botanical medicine and will help with theevaluation of the evidence for herbal product efficacy. I also hope thatthis book will help to bridge the gap between herbal medicine andstandard Western therapies by using the language of the latter to de-scribe the former. Ultimately it is my desire that this book will assistin establishing an appropriate place for botanical medicine alongsidestandard Western therapies in the medicine cabinet.

The chapters in Part I: Fundamentals of Herbal Medicine providebackground as well as context for the product and trial summariesthat follow. These chapters provide information on the regulatory sta-tus of botanicals in the United States, the characterization and stan-dardization of products, as well as the means to establish bioavail-ability, efficacy, and safety. Also included is a discussion on theborrowing of science from one product to support claims of effi-cacy for another. In addition, there is a discourse on the motives forconducting trials in the United States and in Europe, particularly inGermany. Finally, a chapter on pharmacopoeial monographs de-scribes what they are and what information they provide.

Part II: Methods describes the methods used to gather informationon products and clinical studies. It includes the criteria for entry intothe book and the means used to evaluate the efficacy of the individualtrials.

Part III: Botanical Profiles contains information on products andclinical trials. Products are grouped according to the principal botani-cal ingredient. If the products are multi-ingredient formulas, without

a primary ingredient, then they are listed separately. Each botanicalsection is headed by a summary review of the products and trials.This summary section contains an at-a-glance table listing the prod-ucts included in that section, the indications addressed by the clinicalstudies, and the number and quality of those studies. The summarysection also includes information from therapeutic monographs withuse information for that herb. The summary section is followed bydetails on the products, which is in turn followed by a detailed ac-count of the clinical trials for each product.

Indexes allow for easy access to the product and trial informationthrough the botanical common and scientific names, as well as byproduct and manufacturer names and therapeutic indication.

AcknowledgmentsAcknowledgments

This book was a long time in the making, and like many large proj-ects, it has gone through several stages. Many people have given meadvice and/or assistance over that time and to mention all of themwould be prohibitive. I will therefore mention a few and hope thatthose whose names do not appear will forgive me.

When I embarked on this book, I had only a vague sort of notion asto what it would entail. Initial encouragement from Joerg Gruenwaldregarding the idea of this book resulted in a joint attempt to contactU.S. manufacturers. We asked manufacturers if they had productswhose efficacy was supported by clinical studies. The scant responserevealed to us that it would not necessarily be easy to obtain this prod-uct information and the project was abandoned.

However, Dr. Varro (Tip) Tyler approached me regarding a con-tract with The Haworth Herbal Press in June 1999, starting the pro-cess anew. With the assistance of Julie Dennis, we expanded ourmailing list and contacted approximately 200 manufacturers, initiallyasking only for a sign of interest. This time, with the publishers nameclearly on the letterhead, we got better results. We set out to collectnot only those products which had been tested in clinical studies, butalso those which had similar specifications. Julie tirelessly collectedinformation on 300 products, designed and established a database forthat information, and entered the information into the database. Herenthusiasm and positive attitude were a boon throughout this stage ofthe project.

In the meantime, conversations with Loren Israelsen, UlrichMathes, and others revealed to me the complexity of evaluating prod-uct equivalency and the issues behind borrowing the science forone product to support the efficacy of another. I soon realized that Icould include only products that had themselves been tested in clini-cal trials. However, now I was seven months into the project, hadspent most of the generous grant from The Haworth Press, and, insome ways, was starting over. I began to concentrate on the clinicaltrials themselves: retrieving studies from scientific databases and

then specifically contacting manufacturers who made those products.Both Eva Boyd and Eva Dusek helped tremendously with the massivejob of identifying and collecting clinical trials as well as enteringthem into the database.

Conversations with Marie Mulligan, MD, and others helped mewith ideas regarding the evaluation of the quality of clinical studies.Paramount in these conversations were those methodological quali-ties required by the medical community for a trial to be consideredcredible. Thankfully, Tieraona Low Dog, MD, stepped in and de-signed the checklist used to evaluate the trials. Her guidance was alsoinstrumental in the overall concept and design of the book.

With the trials gathered and the checklist in place, I began to sendthose trials out to MDs for review. I am deeply indebted to all thosewho reviewed trials, for this is not a quick process. Concurrent withthe gathering and evaluation of trials was the writing of Part I of thebook, encompassing the fundamentals of herbal medicine. I am in-debted to the authors of those chapters for their contributions. In addi-tion, I am grateful to Mitch Bakos for his computer advice and assis-tance with the database. Also, the advice of Cathirose Petrone, whotaught me how to juggle many tasks at the same time with a minimumof stress, was a blessing.

Thinking that I had only a few months left before finishing thebook, I asked Clea Lopez to assist me. Those several months turnedinto a year and a half. Clea assisted with just about every aspect of thebook during that time. With her help, we again conducted literaturesearches, looking for trials that had been published since our initialsearch. Her editing skills were a very pleasant surprise to me, with awonderful ability to spot where the text needed to be clearer or whereI needed to provide additional information. Her excellent editorialadvice and attention to detail has made this book a much better onethan it would have been without her.

EDITORS NOTE

The purpose of this book is informational. It is not intended as aguide to self-medication or as a substitute for the advice of a healthpractitioner.

The production of this book was partially supported by a grantfrom The Haworth Press. No monetary assistance was provided byany manufacturer whose product is, or is not, included in the book.

This book is not meant to promote any product(s) in particular. Thepurpose of the book is to examine the scientific data supporting theefficacy of herbal preparations. As therapeutic equivalence of theseproducts has not been proven, examining the clinical evidence cannotbe done without profiling individual products.

Manufacturers who wish to submit their product(s) for inclusion infuture editions of this book should contact the editor via e-mail at or via the Internet at .

PART I:FUNDAMENTALS

OF HERBAL MEDICINE

Chapter 1

History and Regulation of Botanicals in the United StatesHistory and Regulation of Botanicalsin the United States

Loren D. IsraelsenMarilyn Barrett

INTRODUCTION

At least four regulatory classifications are now possible for botani-cals in the United States: (1) food, (2) dietary supplement, (3) over-the-counter (OTC) drug, and (4) prescription (Rx) drug. However,most botanical products are regulated as dietary supplements accord-ing to provisions in the Dietary Supplement Health and EducationAct (DSHEA) of 1994. This chapter gives a brief description of howbotanicals were historically regulated in the United States, the subse-quent genesis of DSHEA, and the means that DSHEA provides toregulate herbs and other botanicals. It also briefly covers the regula-tions regarding botanicals as drugs, either sold without a doctors pre-scription over-the-counter or requiring a doctors prescription.

HISTORY

Plants have, at one time, supplied virtually all cultures with food,clothing, shelter, and medicines. It is estimated that approximately 10to 15 percent of the roughly 300,000 species of higher plants have ahistory of use in traditional medicine. By contrast, only 1 percent ofplant species have a history of food use (McChesney, 1995).

One hundred years ago, herbs were well established as medicinesin the United States. They were widely listed in the United States

Pharmacopeia (USP) and prescribed by physicians. Herbal tinctures,extracts, salves, and so forth, were the materia medica of the day.

Regulation of medicines in this country began when the authorityto set and enforce drug safety standards was given to the Food andDrug Administration (FDA) in 1938. The passage of the Food, Drug,and Cosmetic Act gave the FDA the responsibility to prosecute theadulteration or misbranding of foods, drugs, and cosmetics.

Herbal preparations soon gave way to single-entity chemical drugs.World War II created a demand for more powerful drugs of all kinds,particularly antibiotics and trauma treatment agents. The federal gov-ernment urged drug companies, then largely botanical crude-drughouses, such as Merck, Lily, and Parke-Davis, to invest in new syn-thetic chemistry-based research. Single-entity chemicals were moreconsistent, easier to measure, and judged more specific in their thera-peutic focus than botanical preparations.

In 1951, Congress passed the Durham-Humphrey Act which de-fined a prescription drug as any drug that because of its toxicity orother potential for harmful effect or method of use is not safe for useexcept under the supervision of a practitioner licensed by law to ad-minister such a drug (Young, 1995). Manufacturers at that time had toposition their drugs as either Rx or OTC.

In 1962, the Food, Drug, and Cosmetic Act was expanded to re-quire all drugs marketed at that time to be proven both safe and effec-tive. The FDA then issued guidelines for safety and efficacy testingrequirements for new drugs. As a result, new drugs now required theFDAs approval before marketing. Old drugs were permitted to re-main on the market as long as their ingredients and labeling remainedunchanged.

In 1972, the FDA began a comprehensive review of all OTC drugproducts to assess their safety and efficacy. Drug ingredients found tobe generally recognized as safe and effective (GRASE) were placedinto Category I and approved for marketing. Those determined to beunsafe or ineffective were placed in Category II and banned from usein any OTC drug. If safety and efficacy could not be determined dueto a lack of information, then the ingredient went into Category III.With few commercial sponsors to conduct safety and efficacy studies,many botanicals, listed as possible or known ingredients in OTCproducts, were relegated to Category II status and some were placedin Category III. With few herbs retaining drug status after the OTC re-

view, the botanical industry had no other regulatory option but to of-fer their products as foods.

In the late 1970s, the FDA began to apply the food additive provi-sions of the Food, Drug, and Cosmetic Act to botanicals. Under pro-visions added to the Federal Food, Drug, and Cosmetic Act of 1958,food additives already on the market in 1958 were accepted withoutFDA review. However, substances added to the food supply after thisdate were required to gain FDA approval prior to marketing, unlessthey were considered GRAS (generally recognized as safe). A fairnumber of herbs were included on a list of GRAS food additives thathad been prepared by the Flavor and Extract Manufacturers Associa-tion as flavorings for alcoholic beverages. However, the FDA viewedcommonly used herbs as unapproved food additives and thereforesubject to FDA approval prior to marketing. This interpretation led toa series of bitterly fought court cases and several herbs being takenoff the market.

Congress passed the Nutrition Labeling Education Act of 1990(NLEA) to reform food labeling and to allow, for the first time, a newclass of health claims based on disease-nutrient relationships. For themost part, this legislation did not apply to botanicals because of theway it was written and the way it was interpreted by the FDA.

With lawsuits between herbal manufacturers and the FDA com-monplace, a group of leading herb companies met with Senator OrrinG. Hatch (R-Utah) and Congressman Bill Richardson (D-New Mex-ico) who drafted legislation that became the Dietary SupplementHealth and Education Act of 1994. This law was passed by Congressand signed into law by President Clinton on October 25, 1994. Thiswas the first time a U.S. law defined the terms herb or botanical.

DSHEA EXPLAINED

As with most federal laws, the legislative language of DSHEA isarcane, if not mystifying. The core provisions of the act, however, arestraightforward and create an expansive framework for all dietarysupplements. The following summary of DSHEA is an herbs-onlyinterpretation which provides a useful tool for those wishing to seehow DSHEA creates a new architecture for the manufacture, sale,and promotion of herbs.

DefinitionDSHEA defines the term dietary supplement as an herb or other

botanical or concentrate, constituent, extract, or combination of anybotanical that is intended for ingestion as a tablet, capsule, or liquid,is not represented for use as a conventional food or as a sole item of ameal or the diet, and is labeled as a dietary supplement. This includesnew drugs that were marketed as botanicals prior to such approval; itdoes not include a botanical approved as a new drug, or authorized forinvestigation as a new drug, and not previously marketed as a dietarysupplement. Botanicals are not classified as food additives.

SafetyDietary supplement products are allowed to contain botanicals that

have been present in the food supply and in a form in which the food(botanical) has not been chemically altered. Dietary supplement in-gredients marketed in the Unites States before October 15, 1994, areregarded as safe because of their long history of use. Those ingredi-ents not marketed before then are new ingredients. At least 75 daysbefore introduction into commerce, manufacturers must provide theFDA with information that shows the new botanical can reasonablybe expected to be safe under conditions of use or labeling.

DSHEA states that a botanical is considered unsafe under one oftwo conditions: (1) it presents a significant or unreasonable risk of ill-ness or injury under conditions of use recommended or suggested inlabeling, or (2) it is a new botanical for which inadequate informationexists to provide reasonable assurance that it does not present a sig-nificant or unreasonable risk of illness or injury. In any case, the FDAshall have the burden of proof to show that a botanical is unsafe.

Good Manufacturing PracticesA botanical is also considered unsafe if it is prepared, packed, or

held under conditions that do not meet current good manufacturingpractice regulations (GMPs). For the moment, the preparation andpackaging of dietary supplements is covered by the same GMPs thatapply to conventional foods. However, DSHEA authorizes the FDAto establish separate GMPs for dietary supplements, and rule makingby the FDA is imminent.

Labeling

The label must identify the product by the term dietary supple-ment. Botanical dietary supplement labels must list the name of eachingredient, the quantity of such ingredients, or, if a proprietary blend,the total quantity of all ingredients. The label must also identify anypart of the plant from which the ingredient is derived.

Botanical dietary supplements are misbranded if they are repre-sented as conforming to such official compendium as USP and fail todo so, fail to have the identity and strength which they represent tohave, or fail to meet the quality, purity, or compositional specifica-tions, based on validated assays or other appropriate methods, whichthey are represented to meet.

Literature, including an article, a chapter in a book, or an officialabstract of a peer-reviewed scientific publication which appears in anarticle shall not be defined as labeling when used in connection withthe sale of botanicals to consumers provided that it is not false or mis-leading, does not promote a particular manufacturer or brand of bo-tanical, is displayed or presented with other items on the same subjectmatter so as to present a balanced view of the available scientific in-formation on a botanical, and, if displayed in an establishment, isphysically separate from the botanical and does not have appended toit a sticker or other method that associates it with the product.

Claims of Benefit or Statements of Nutritional SupportAllowed in Labeling

Under DSHEA, a statement for a botanical dietary supplementmay be made if the statement describes how a botanical is intended toaffect the structure or function of humans, characterizes the docu-mented mechanism by which a botanical acts to maintain such struc-ture or function, or describes general well-being from consumptionof a botanical. The statement must contain, prominently displayedand in bold-faced type, the following: This statement has not beenevaluated by the Food and Drug Administration. This product is notintended to diagnose, treat, cure or prevent any disease.

The FDA published a final rule in the Federal Register on February7, 2000 (docket No. 98N-0044), which describes how the agency willdistinguish disease claims from structure/function claims. The rule

permits health maintenance claims (maintains a healthy circulatorysystem), other nondisease claims (for muscle enhancement, helpsyou relax), and claims for common, minor symptoms associatedwith life stages (for common symptoms of PMS, for hot flashes).It does not allow for claims regarding diseases (prevents osteoporo-sis) or implied disease claims (prevents bone fragility in post-menopausal women) (FDA, 2000).

As with all food labeling, statements must be truthful and not mis-leading. Statements of nutritional support may be made without priorFDA review, but the manufacturer must notify the FDA within 30days of marketing a product with a new claim and must have substan-tiation for the claim. Criteria for substantiating a claim are not yet de-fined by the FDA. However, advertising guidelines for benefit state-ments for dietary supplements have been published by the FederalTrade Commission (1998) and can be found on their Web site (www.ftc.gov).

DSHEA establishes that a botanical is not a drug solely because itslabel or labeling contains a statement of nutritional support. Also, abotanical shall not be deemed misbranded if its label or labeling con-tains directions or conditions of use or warnings.

Commission on Dietary Supplement Labels

DSHEA established a presidential commission to study and pro-vide recommendations for the regulation of label claims and state-ments for botanicals, including the use of literature in connectionwith the sale of botanicals, and procedures for evaluation of suchclaims. The seven members of the Commission on Dietary Supple-ment Labels were appointed by the president to evaluate how best toprovide truthful and scientifically valid information about dietarysupplements to consumers. The commissions final report, which wassubmitted to the president and Congress in November 1997, includedguidance regarding statements of nutritional support and the substan-tiation of such claims. The commission recognized that underDSHEA, botanical products should continue to be marketed as di-etary supplements, when properly labeled. However, they recom-mended that a review panel be established to review claims for OTCdrug uses (Commission on Dietary Supplement Labels, 1997).

Office of Dietary Supplements

DSHEA also established an Office of Dietary Supplements (ODS)within the National Institutes of Health (NIH). The purposes of theoffice are to explore the potential ability of botanicals to improvehealth care and to promote scientific study of the benefits of botani-cals in maintaining health and preventing chronic disease.

The director of the ODS is to conduct and coordinate scientific re-search relating to botanicals that can limit or reduce the risk of dis-eases such as heart disease, cancer, birth defects, osteoporosis, cata-racts, or prostatism, collect results of scientific research related tobotanicals and compile a database, and serve as a principal advisor tothe NIH, the Centers for Disease Control and Prevention (CDCP),and the commissioner of the FDA on issues relating to botanicals andscientific issues arising in connection with the labeling and composi-tion of botanicals.

Currently the ODS, in collaboration with the National Center forComplementary and Alternative Medicine (NCCAM), sponsors sixbotanical research centers. The ODS Web site hosts two databases: onecontaining information regarding federally funded research on dietarysupplements (CARDS, Computer Access to Research on DietarySupplements) and the other containing scientific literature regardingdietary supplement ingredients (IBIDS, International BibliographicInformation on Dietary Supplements) (http://dietary-supplements.info.nih.gov). The ODS is also conducting systematic reviews of the litera-ture in order to determine areas needing research and to assist in the de-velopment of clinical guidelines. Fact sheets with information on themost commonly used botanicals are in preparation. The ODS, again inconjunction with NCCAM, has sponsored clinical trials on St. Johnswort and ginkgo. Several dozen other trials on botanicals are currentlylisted on the NCCAM Web site (nccam. nih.gov). The ODS is also cur-rently supporting the development of validated analytical methods,standards, and reference materials for the most commonly used botani-cals.

DRUGS: OTC AND RX

Before a botanical product is marketed as a drug with a claim to di-agnose, treat, cure, or prevent a disease, it must first be approved bythe FDA. The revision of the Food, Drug, and Cosmetic Act in 1962required all drugs marketed after that time to be proven both safe andeffective. This revision presented the FDA with the challenge of up-dating its approval of hundreds of drugs already on the market thathad not been proven effective. The FDA set up panels of experts to re-view the active ingredients of these drugs, many of which were soldover-the-counter. However, many herbal products were found to beeither unsafe, ineffective, or simply lacking sufficient evidence toevaluate (Tyler, 1993).

In order to obtain drug status for a new botanical product, or forone that failed a previous evaluation, manufacturers must submit aNew Drug Application (NDA) to the FDA. This requirement holdswhether the new drug is to be sold as an OTC or Rx drug. The NDAmust contain evidence of the products safety and efficacy. This evi-dence is usually in the form of pharmacological studies, ranging inscope from in vitro assays and small animal studies to randomized,double-blinded clinical trials in humans, with an emphasis on theclinical studies. The benefit to pharmaceutical firms which manufac-ture synthetic chemical drugs is that their research is rewarded by pat-ent protection for a substantial period of time. However, as mostherbs have previously been marketed in a traditional form, and thusare not new or unique, they are not eligible for patent protection.There are some exceptions when a botanical is prepared in a uniqueform (for example, the ginkgo extract EGb 761) or for a previouslyunknown use. Without patent protection, most manufacturers are un-willing to spend the money necessary to conduct the research re-quired for a new drug application. In addition, manufacturers mayfind it easier to forego scientific studies as they can easily sell theirproducts as dietary supplements.

The Commission on Dietary Supplement Labels (1997) recom-mended that the FDA establish a review panel for OTC claims forbotanical products that are proposed by manufacturers for drug uses(p. 57). However, in April 1998 the FDA published a notice respond-ing to the commission report, indicating that the agency considers

such a review to be premature at this time. The FDA did not give anexplanation for their decision (FDA Notice, 1998).

Petitions formally requesting that valerian and ginger be recog-nized as old OTC drug ingredients were filed with the FDA in 1994.Nearly six years later, the agency issued a response provisionally ac-cepting the supporting data, which was largely European, but onlyunder very stringent conditions. Valerian and ginger have yet to be-come OTC drugs.

Numerous experts agree that a select number of botanicals areproper candidates for OTC drug status. Although this would meanthat some plant extracts would be available both as dietary supple-ments and OTC drugs, it is likely that many American consumerswho currently would not use a certain herb as a dietary supplementwould accept and use that same herb if it were offered as a drug thathas received FDA (government) approval. Likewise, physicians, phar-macists, and other health care providers would be far more inclined torecommend, or at least not discourage, the use of an herbal OTC drug.The reasons being that OTC drugs are manufactured under strictergood manufacturing practices, and OTC products have mandatory la-beling which includes dosage recommendations, cautions, and warn-ings. Although manufacturers of botanical products are welcome tosubmit their products for review under the new drug approval pro-cess, it does not appear that the FDA is prepared to actively welcomeOTC applications for botanicals as old drug ingredients. That is, for abotanical to achieve OTC status, it must have all the scientific re-search required for a new drug. It is unlikely to be grandfathered inas an old drug without that documentation.

PROSPECTUS

Canada has created a natural health products category, which is in-termediate between the formal OTC drug review process and the lessformal dietary supplement regime in the United States. Many in theherbal industry now feel that such a category would be beneficial forthe United States as well. However, this would require a new regula-tory category to be created.

In the meantime, it is entirely possible for a botanical to be mar-keted and sold as a food, a dietary supplement, and a drug at the same

time, depending on its label claim. For example, ginger root can besold as a food ingredient, as a dietary supplement to maintain a calmstomach, or (if approved by the FDA) as an OTC drug to preventand treat nausea or motion sickness.

REFERENCES

Commission on Dietary Supplement Labels (1997). Commission on Di-etary Supplement Labels Report to the President, the Congress and theSecretary of the Department of Health and Human Services. Final Re-port, November 24.

Dietary Supplement Health and Education Act (DSHEA) (1994). PublicLaw 103-417, October 25.

Food and Drug Administration (FDA) (2000). Regulations on StatementsMade for Dietary Supplements Concerning the Effect of the Product onthe Structure or Function of the Body. Federal Register 65 (4): 1000-1050.

Food and Drug Administration (FDA) Notice (1998). Dietary supplements:Comments on report of the Commission on Dietary Supplement Labels.Federal Register 63: 23633-23637 (April 29).

Federal Trade Commission (1998). Dietary Supplements: An AdvertisingGuide for Industry. Federal Trade Commission, Bureau of ConsumerProtection (www.ftc.gov).

McChesney (1995). Botanicals, Historical Role. Presented at the Drug In-formation Association (DIA) Alternative Medicine Workshop on Bo-tanicals, March 30-31.

Office of Dietary Supplements (ODS) Web site: .

Tyler VE (1993). The Honest Herbal, A Sensible Guide to the Use of Herbsand Related Remedies, Third Edition. Binghamton, NY: PharmaceuticalProducts Press.

Young JH (1995). Federal Drug and Narcotic Legislation. Pharmacy inHistory 37 (2): 59-67; citation of amendments to sections 303(c) and503(b) of the Federal Food, Drug, and Cosmetic Act, 82nd Congress,First Session, October 26, 1951, 65 U.S. Statutes 648.

Chapter 2

Product Definition Deficiencies in Studies of Herbal MedicinesProduct Definition Deficiencies in ClinicalStudies of Herbal Medicines

Varro E. Tyler

Clinical studies and case reports of herbal medicines have recentlybegun to appear in major medical journals of the United States. Theclinicians responsible for these publications are apparently unawarethat no standards of quality exist for herbal products in this and manyother countries. Accustomed to working with drugs that must con-form to official specifications, these authors often fail to define ade-quately the botanicals employed, and their failure to do so raises morequestions than are answered. The following examples, some of themselected from the special November 11, 1998, alternative medicineissue of the Journal of the American Medical Association, will illus-trate this problem.

One of the major clinical trials published in that issue was a studyconducted in Australia by Bensoussan et al. (1998), involving thetreatment of irritable bowel syndrome with a multi-ingredient Chi-nese herbal formula. None of the 20 botanicals employed was identi-fied by its correct Latin binomial (genus, species; followed by authorcitation) nor was any assurance provided that the identification givenonly as a Latin drug title was confirmed in any way (botanical orchemical characterization).

The quantities of the herbs were provided only as a percentage ba-sis (presumably by weight), and the amount administered was statedonly as five capsules (size not specified) three times daily. On the ba-sis of the data provided, the study could never be replicated or its pur-

Chapter 2 originates from The Scientific Review of Alternative Medicine, by Varro E.Tyler, Product Definition Deficiencies in Clinical Studies of Herbal Medicines, Vol.4, No. 2 (Fall/Winter 2000), pp. 17-21. Reprinted by permission of the publisher.

ported results verified. Further, no follow-up was conducted to deter-mine which of the herbs contributed to the reported positive effectsand which were merely adjuvants, correctives, or flavors.

A letter to the editor by Grush et al. (1998) in the same issue warnsagainst the use of St. Johns wort during pregnancy as a result of ob-servations on two gravid women. Both of them were said to be con-suming 900 mg/day of the herb. Because the dose of St. Johns wortranges from 2 to 4 g, what is probably being referred to here is 900 mgof a St. Johns wort concentrated extract standardized to contain 0.3percent hypericin. There is a considerable difference between thisand the crude herb. Further, no botanical or chemical studies verify-ing that the herbal product labeled St. Johns wort was indeed Hyperi-cum perforatum L. were apparently conducted.

Garges, Varia, and Doraiswamy (1998) attribute a case of cardiaccomplications and delirium to the withdrawal of valerian root extract,even though the patient was consuming seven other medications plusminerals and vitamins. Although the designation valerian root iscommonly misused to described both the rhizome (underground stem)and roots of the plant, no data were presented to assure readers thatthe extract was prepared from Valeriana officinalis L. as specified.Several species of valerian are commonly employed as central ner-vous system depressants.

Further, the preparation involved is defined only as an extract,without specifying the solvents used to prepare it or the degree ofconcentration. It was apparently consumed in substantial quantities,ranging from 30 mg to 2 g per dose five times daily. The authors con-clude that in view of the multiple factors involved (e.g., numerousother drugs, surgery) we cannot causally link valerian root to hissymptoms. This statement contradicts an earlier one, which reporteda case of serious cardiac complications and delirium associated withthe withdrawal of valerian roots. It also renders inaccurate the simi-larly worded title of the publication. In actuality, information pro-vided in the paper is inadequate to allow any firm conclusion as towhat herbal product was being consumed.

A letter from Lawson (1998) in the same issue of JAMA com-mented on the negative results achieved with a steam-distilled garlicoil (Allium sativum L.) preparation tableted in combination with beta-cyclodextrin. The author pointed out that the prepared garlic oil haslittle hypocholesterolemic activity in the first place and that only

about 25-40 percent of it was ever released from the binder. Some ofthe tablets were compressed so compactly that they passed throughthe intestinal tract of human intact or in large pieces.

Although the authors of the original paper replied that the bindingof the oil to the beta-cyclodextrin was intentional, thus providing aslow release of activity, they failed to address the more difficult prob-lem of whether therapeutic levels of allyl sulfides were ever attained(Berthold, Sudhop, and von Bergmann, 1998). In their minds, thiswas considered unnecessary because convincing evidence of lipid-lowering effects of any garlic preparation is still lacking. No refer-ence in support of this assertion is provided. The 17 positive of 20 to-tal studies cited by Lawson are dismissed as lacking rigorous design,but the defects are not specified. They do concede that conclusionsof our study apply only to the preparation we used. . . . Unfortu-nately, that was not the way it was reported in the popular press,which labeled all garlic preparations ineffective for blood lipid reduc-tion.

Berthold and colleagues (1998) could have precluded much of theconcern about their original study simply by including in it a betterdefinition of the product utilized. Characterization of the proven ac-tivity (or lack thereof) of allyl sulfides, quantitative figures regardingthe slow release of these principles from the beta-cyclodextrin binderwith estimates of predictable blood levels, and data on tablet disinte-gration time under controlled conditions should certainly have beenpresented. This study is an excellent example of the pronounced effectdosage form design can have on the purported activity of an herbal prod-uct.

In the report of their clinical trial on Garcinia cambogia Desr. forweight loss, Heymsfield et al. (1998) made more than the usual effortto define the product utilized. However, something went awry. Theauthors indicate that caplets containing the plant extract (50 percenthydroxycitric acid) plus added hydroxycitric acid were administeredin daily doses totaling 3000 mg of extract and 1500 mg of hydroxy-citric acid. The problem here is that hydroxycitric acid (HCA) doesnot exist in that form in nature. Instead, it occurs as a lactone whichlacks the ability to inhibit ATP-citrate lyase (Clauatre and Rosen-baum, 1994). That enzyme is responsible for the formation of acetyl-CoA, the metabolite necessary for fatty acid and cholesterol bio-synthesis. Lacking this inhibiting activity, the plant extract could not

be expected to have any antiobesity activity and, of course, none wasfound.

However, the authors state that the extract used was found to con-tain 50 percent hydroxycitric acid by analysis. This is almost cer-tainly inaccurate because HCA is an unstable hygroscopic compoundthat reverts to the inactive lactone over time. Probably the HCA waspresent in the extract as a more stable salt of some type. This raisesconcerns about the absorbability and ultimate activity of the unde-fined salt. Presumably the HCA administered with the plant extractwas also in the form of a salt rather than the free acid.

Once again, failure to define precisely the nature of the herbal ex-tract utilized has resulted in confusion. Replication of the study onthe basis of the published data would be impossible.

Confusion in the medical literature due to inadequate herbal prod-uct definition is certainly not confined to one journal, nor is it of re-cent origin. In 1989, MacGregor et al. published a report in the Brit-ish Medical Journal of four women who suffered hepatotoxic effectsafter consuming two different proprietary herbal remedies. Both ofthese remedies presumably contained scullcap (Scutellaria lateriflora L.)and valerian (Valeriana officinalis), and the authors concluded thatthe deleterious effects noted probably resulted from the consumptionof these two herbs. This assumption was based in part on the reportedtoxicity of valepotriates in valerian. No analysis of the products wasconducted to determine if they actually contained the two herbs inquestion.

Since that time, it has been determined that the unstable iridoidcompounds known as valepotriates are not found in significantamounts in commercial valerian preparations. Further, in Britain theknown hepatotoxic herb germander (Teucrium chamaedrys L.) is of-ten substituted for scullcap, and this substitution was, in all likeli-hood, the cause of the observed effects (Tyler, 1993). Once again,failure to characterize an herbal product properly resulted in a falsereport of potential toxicity of two herbs.

Probably more confusion has been produced in the herbal litera-ture by so-called Siberian ginseng, better designated eleuthero, thanany other herb. Eleuthero is not a true ginseng, a designation properlyreserved for species of Panax. Botanically, it is Eleutherococcussenticosus (Rupr. and Maxim.) Maxim., and although it belongs tothe same family as ginseng, the Araliaceae, its constituents are very

different. Family relationships of botanicals do not necessarily reflectsimilar constituents or activities. Potatoes (Solanum tuberosum L.)and the deadly nightshade (Atropa belladonna L.) are both membersof the Solanaceae.

Eleuthero is seldom obtainable in this country in the form of piecessufficiently large to allow identification by means of organolepticevaluation. Instead, it is usually seen either as a powder, which ismore difficult to identify, or as an extract. In China, where much ofthe herb originates, it is known as wujia, a name also applied to en-tirely different plants, especially Chinese silk vine (Periploca sepiumBunge) (Keville, 1992). Eleuthero is utilized in various herbal mix-tures touted to enhance athletic performance, so it is also subject toadulteration with stimulants.

In 1990, Koren et al. published a report of a mother whose new-born infant suffered from neonatal androgenization. They attributedthe effect to the mothers consumption of pure ginseng and dis-cussed the literature on ginsengs (Panax ginseng C.A. Mey.) effecton hormones. In fact, the product consumed was labeled Siberianginseng, but the authors failed to recognize the difference between itand ginseng.

Unfortunately, the product actually consumed was no longer avail-able for analysis, but additional samples of the same lot from the orig-inal supplier were subsequently shown to be Chinese silk vine (Awang,1991). Additional analyses of various specimens revealed one thatwas actually eleuthero, but it contained caffeine, which is not a nor-mal constituent of that herb (Tyler, 1994). Moreover, none of the nat-ural constituents of either species is known to induce androgeni-zation. The hairy baby case has thus become an infamous example ofpoor herbal quality. One herb, eleuthero, was mistaken for another,ginseng, but eleuthero was replaced by Chinese silk vine, which inturn was almost certainly adulterated with an androgen. This entiremuddle could have been avoided if the dosage form initially utilizedhad been properly analyzed and defined prior to publication.

Eleuthero substituted with Chinese silk vine has also been impli-cated in a case involving elevated digoxin levels in a cardiac patient.McRae, the attending physician, reported that eleutherosides in Sibe-rian ginseng may have been converted to digoxin in vivo, thus caus-ing the increased serum levels (McRae, 1996).

No eleutheroside is known to be related chemically to digoxin or tohave cardiotonic properties, but Chinese silk vine has related com-pounds with such properties. Therefore, as Awang has surmised, theapparent rise in serum digoxin levels was probably due to the substi-tution of P. sepium for E. senticosus (Awang, 1996). The erroneousattribution of digitalis-like effects to constituents of eleuthero couldhave been avoided if the dosage form utilized had been tested for thepresence of eleutherosides, thus assuring its identity before publica-tion.

A particularly egregious case of inadequate product definition ap-peared in a 1998 article by DiPaola et al. in the New England Journalof Medicine. An eight-herb formula designated PC-SPES, promotedfor the treatment of prostate cancer, was defined as consisting in partof five plants designated by common names only. These includedchrysanthemum, licorice, scutellaria (scullcap), isitis, and saw pal-metto. Of these, the first three may be obtained from at least two dif-ferent species, so the composition of the formula is unclear. The re-maining three botanicals in the formula were designated by Latinbinomials but without author citations.

The formula was said to have been purchased from a commercialsource in four different batches, each of which was analyzed. Exactlywhat the products were analyzed for, how they were analyzed, andthe results of the analyses are not stated in the paper. The concentra-tion of each of the eight herbs in the total formula is likewise not men-tioned. Stock solutions of the formula and other herbs studied wereprepared by exposing them to alcohol for 24 hours. Nowhere is themethod of exposure explained.

Rather than continuing to describe examples of inadequate herbalproduct characterization in the medical literature, it seems more prof-itable to review exactly what is necessary to provide adequate herbalproduct definition. First of all, the botanical should be identified byits Latin binomial, followed on the first citation by the name of the au-thor who assigned that designation. This latter specification, oftenoverlooked by those unfamiliar with botanical nomenclature, is nev-ertheless important because it increases the clarity and accuracy ofthe designation (Laurence, 1995).

Plants often have more than one scientific name, each assigned bya different author. The long-used medicinal herb chamomile has atleast 12 scientific names, each more or less accurate depending on

ones interpretation of its characteristics. Matricaria recutita L. (theL. is an abbreviation of Linnaeus) is now considered the most appro-priate binomial, but other authors have assigned it to different generaand utilized different specific epithets. The genera include Chamo-milla, Chrysanthemum, Leucanthemum, and Athemis, in addition toMatricaria (List and Hrhammer, 1976). Unless