Page i Toxicology and Clinical Pharmacology of Herbal Products Page ii Forensic Science and Medicine Steven B. Karch, MD, S ERIES E DITOR T OXICOLOGY AND C LINICAL P HARMACOLOGY OF H ERBAL P RODUCTS, edited by Melanie Johns Cupp, 2000 CRIMINAL POISONING: INVESTIGATIONAL GUIDE FOR LAW ENFORCEMENT, T OXICOLOGISTS, F ORENSIC S CIENTISTS, AND A TTORNEYS, by John H. Trestrail, III, 2000 A PHYSICIAN'S GUIDE TO CLINICAL FORENSIC MEDICINE, edited by Margaret M. Stark, 2000 Page iii Toxicology and Clinical Pharmacology of Herbal Products Edited by Melanie Johns Cupp, PHARMD, BCPS West Virginia University Morgantown, WV Humana Press Totowa, New Jersey Page iv © 2000 Humana Press Inc. 999 Riverview Drive, Suite 208 Totowa, New Jersey 07512 All rights reserved. No part of this book may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, microfilming, recording, or otherwise without written permission from the Publisher. The content and opinions expressed in this book are the sole work of the authors and editors, who have warranted due diligence in the creation and issuance of their work. The publisher, editors, and authors are not responsible for errors or omissions or for any consequences arising from the information or opinions presented in this book and make no warranty, express or implied, with respect to its contents. Due diligence has been taken by the publishers, editors, and authors of this book to assure the accuracy of the information published and to describe generally accepted practices. The contributors herein have carefully checked to ensure that the drug selections and dosages set forth in this text are accurate and in accord with the standards accepted at the time of publication. Notwithstanding, as new research, changes in government regulations, and knowledge from clinical experience relating to drug therapy and drug reactions constantly occurs, the reader is advised to check the product information provided by the manufacturer of each drug for any change in dosages or for additional warnings and contraindications. This is of utmost importance when the recommended drug herein is a new or infrequently used drug. It is the responsibility of the treating physician to determine dosages and treatment strategies for individual patients. Further it is the responsibility of the health care provider to ascertain the Food and Drug Administration status of each drug or device used in their clinical practice. The publisher, editors, and authors are not responsible for errors or omissions or for any consequences from the application of the information presented in this book and make no warranty, express or implied, with respect to the contents in this publication. This publication is printed on acid-free paper. ANSI Z39.48-1984 (American Standards Institute) Permanence of Paper for Printed Library Materials. Cover design by Patricia F. Cleary. For additional copies, pricing for bulk purchases, and/or information about other Humana titles, contact Humana at the above address or at any of the following numbers: Tel: 973-256-1699; Fax: 973-256- 8341; E-mail: humana@humanapr.com, or visit our Website at www.humanapress.com Photocopy Authorization Policy: Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by Humana Press Inc., provided that the base fee of US $10.00 per copy, plus US $00.25 per page, is paid directly to the Copyright Clearance Center at 222 Rosewood Drive, Danvers, MA 01923. For those organizations that have been granted a photocopy license from the CCC, a separate system of payment has been arranged and is acceptable to Humana Press Inc. The fee code for users of the Transactional Reporting Service is: [0-89603-791-6/00 $10.00 + $00.25]. Printed in the United States of America. 10 9 8 7 6 5 4 3 2 1 Library of Congress Cataloging in Publication Data Toxicology and clinical pharmacology of herbal products / edited by Melanie Johns Cupp. p. ; cm.—(Forensic science and medicine) Includes bibliographical references and index. ISBN 0-89603-791-6 (alk. paper) 1. Herbs—Toxicology. 2. Materia medica, Vegetable—Toxicology. I. Title:Herbal products. II. Cupp, Melanie Johns. III. Series. [DNLM: 1. Herbs adverse effects. 2. Plants, Medicinal adverse effects. 3. Pharmacology. QV 767 T755 2000] RA 1250 .T68 2000 615.9'52—dc21 99-046505 Page v FOREWORD The herbal medicine industry is growing at an astounding rate. Trade group estimates suggest that total sales exceeded $4 billion dollars in 1999. Herbal remedies are for sale not just in health food stores, but in supermarkets, drug stores, and even discount warehouses. Along with the proliferation in sales has come a proliferation of information sources. Not all of the sources are equally reliable, or even intelligible. Traditional herbalists classify thistle and mugwort as "cholagogues," substances used to make the gallbladder contract and release bile. Medical school graduates are unlikely to have ever heard the term, or even accept the notion that most right-sided abdominal pain is a result of diminished bile flow. Heroin and cocaine may not be the only drugs to come from plants, but a practicing physician or toxicologist might be forgiven for thinking so. In 1998, 1264 papers were published about cocaine and only 17 about kava kava, an abused herb that is not without toxic side effects. Unfortunately, the majority of the papers about kava kava were published in journals not found in ordinary hospital libraries. In recognition of this fact, and of the obvious need for a reliable reference work on herbal toxicology, The Toxicology and Clinical Pharmacology of Herbal Products was an early addition to our new series in Forensic Science and Medicine. It is very badly needed. The reason that herbalists and physicians use different terminology, and the reason that most herbal medicine books are of little use to the physician confronted with a desperately ill patient, is that herbalists and traditional physicians think about diseases (and the medicines used to treat them) differently. Of course many of the drugs first used in modern medicine are extracted from plants. But herbalists use whole plants and traditional physicians use purified ingredients derived from plants. Traditional physicians and scientists generally believe that, if a plant has any medicinal value at all, it is because it con- Page vi tains one "active" ingredient that must be isolated and purified. Herbalist believe results are better when the whole herb is used, because different components of the plant act synergistically. There are risks and benefits to both approaches. If an "active" ingredient is isolated, then it can be given in a more concentrated form. This means that the effects, both therapeutic and toxic, will be exaggerated. On the other hand, if the whole plant (or leaves, or roots, depending on the plant) is used, the concentration of the active ingredient may or may not be sufficient to produce the desired therapeutic result, but the chances for toxicity are decreased. The low concentration of active ingredients may explain why, given the enormous numbers of people taking herbal products, relatively few toxic reactions have been reported. Coca leaf is a good example. Indians who chew the leaves never achieve blood cocaine concentrations high enough to produce serious toxicity. But the results of recent studies suggest that coca leaf chewers do absorb other ingredients from the leaves that prevent high- altitude sickness. Herbalists also believe that combining herbs improves efficacy and reduces adverse effects. When compounded by knowledgeable practitioners, some of the remedies do make sense. The combination of Devil's claw, white willow, and tumeric, all agents with antiinflammatory effects, is rational, and quite probably effective. But combining St. John's Wort, which contains a selective serotonin reuptake inhibitor, with Ephedra, which causes increased catecholamine release, is both dangerous and ill advised. Whether a particular combination of herbs produces good or bad results depends on who is doing the compounding. Under current US laws, anyone is free to market any combination of ingredients, no matter how misguided the underlying science. Herbalists are not the only ones who combine agents. So do patients. And they often forget to tell their physicians about it. Occassionally, this leads to dire results. Terpenoids contained in Gingko biloba interact with platelet-activating factor. Fatal brain hemorrhages have occurred in anticoagulated patients who self-medicated with gingko. Traditional physicians generally avoid drugs in combination, because combinations often turn out to be counterproductive or, as in the case of gingko, outright dangerous. For example, tetracycline and penicillin would never be given at the same time, because the former slows bacterial growth, while the later exerts its bactericidal effects only in growing bacteria. Even without isolating the active principle, some herbal products are very toxic. Comfrey may be an effective treatment for bruises and sprains, but it also contains pyrrazolidine alkaloids which can cause severe liver damage. The alkaloid content is higher in comfrey's roots than in its leaves and higher Page vii in plants grown in Europe than in the United States. Yet neither the alkaloid content, the country of origin, nor the portion of the plant used is likely to be indicated on the product label. Dr. Cupp and her coauthors are to be congratulated for having done an excellent job in combing the scientific literature for reliable, peer-reviewed, information about the most widely used herbal products. They have also done a very good job in presenting that information in such a way that it is easily accessible to practicing physicians and laboratory scientists, not to mention consumers who would be well advised to read about any remedy, whether it is prescribed by their physician or their herbalist. The 28 subsections of this book deal with the herbs that are most often encountered. Hundreds of other herbs exist, but reliable information about them is difficult to acquire. As more is learned, it will be incorporated into future editions. STEVEN B. KARCH, MD BERKELEY, CA Page ix PREFACE Sales of herbal products have increased dramatically over the past five years. Unfortunately, the knowledge base devoted to the adverse effects of these products has not grown in proportion to their increased usage. Data of questionable accuracy, often designed to sell products rather than to provide objective information, can be found in the print and electronic media, most notably on the Internet. Even in medical journals, misleading information about the beneficial and adverse effects of herbs can be found. Toxicology and Clinical Pharmacology of Herbal Products is designed to provide medical examiners, toxicologists, and health care providers with an objective review of the available information on the pharmacology and toxicology of commonly used herbs. Clinical and pathological findings from case reports of herbal adverse effects are described in detail. Sections on the relevant pharmacokinetics, chemical analysis, and analysis of biofluids are unique to this volume, and will be of use to pathologists and forensic scientists, as well as to clinicians. Animal, human, and in vitro data are presented on the known pharmacologic and toxicologic effects of each herb, arranged by organ, organ system, or therapeutic/toxicologic effect. A good deal of pharmacology and therapeutics information is included in this section, not only because toxicology is an extension of pharmacology, but also to make the book useful for a wide variety of applications by professionals with various interests. Adverse effects noted in clinical trials are noted in this section as well. At the end of the book, a summary table lists herbal toxicities by affected organ, provides a list of herbs involved in drug interactions, and indicates the type of data supporting the reported toxicities. Each herbal monograph begins with a discussion of the herb's uses, products, and the dosage forms available. This information, in conjuction with color photographs 1 of some of the most popular products, can be of assistance in those situations where the identity of an herbal product is in question. [...]... legal aspects of herbal products provides an overview of the regulation of herbal products in the US and abroad In addition, each herbal monograph reviews the herb's status internationally, including approved uses The incidence of adverse effects associated with the use of herbal products is unknown, and may be underreported Without a foundation of knowledge upon which to inquire whether an herbal product... cause of a given finding, further exploration of the possibility of an herb-induced toxicity might not be undertaken Even if an herbal product is suspected of causing an adverse outcome, without information about similar cases, toxicological analysis of biofluids, or the pharmacologic or toxicologic effects of the herb, further investigation might prove difficult or impossible Toxicology and Clinical Pharmacology. .. Legal/Regulatory Aspects of Herbal Products Chapter 1: Legal/Regulatory Aspects of Herbal Products Melanie Johns Cupp 3 Part II Monographs Chapter 1: Ma Huang and the Ephedra Alkaloids Steven B Karch 11 1.1 Sources 11 1.2 History and Traditional Uses 11 1.3 Current Promoted Uses 12 1.4 Available Products 13 1.5 Pharmacology 15 1.5.1 Introduction 15 1.5.2 Pharmacologic Effects 16 1.5.3 Metabolism and Elimination... Antihyperglycemic Effects 182 16.5 Case Reports of Toxicity Due to Commercially Available Products 182 16.6 Drug Interactions 187 16.7 Pharmacokinetics 187 16.8 Chemical Analysis/Analysis of Biofluids 188 16.9 Regulatory Status 188 Chapter 17: Coltsfoot Amanda Dailey and Melanie Johns Cupp 191 17.1 History and Traditional Uses 191 17.2 Current Promoted Uses 191 17.3 Products Available 192 17.4 Pharmacologic/Toxicologic... Mutagenicity/Carcinogenicity 90 7.4.7 Reproduction 90 7.5 Case Reports of Toxicity Due to Commercially Available Products 90 7.6 Chemical Analysis 91 7.7 Regulatory Status 91 Chapter 8: Feverfew Brian Schuller and Melanie Johns Cupp 95 8.1 History and Traditional Uses 95 8.2 Current Promoted Uses 95 8.3 Products Available 96 8.4 Pharmacology /Toxicology 97 8.4.1 Neurologic Effects 97 8.4.2 Anti-Inflammatory... of Toxicity Due to Commercially Available Products 136 11.6 Pharmacokinetics/Toxicokinetics 137 11.6.1 Absorption 137 11.6.2 Distribution 137 11.6.3 Metabolism/Excretion 137 11.7 Analysis of Biofluids 137 11.8 Chemical Analysis 138 11.9 Regulatory Status Chapter 12: Panax Ginseng Angela Morgan and Melanie Johns Cupp 138 141 12.1 History and Traditional Uses 141 12.2 Current Promoted Uses 142 12.3 Products. .. investigation might prove difficult or impossible Toxicology and Clinical Pharmacology of Herbal Products is designed to provide the necessary knowledge base upon which such investigations may efficaciously proceed MELANIE JOHNS CUPP 1I want to acknowledge Mark Branciaroli of Elkins, WV for producing the photographs of the herbal products Page xi CONTENTS Foreword by Steven B Karch Preface Contributors Product... Pharmacokinetics/Toxicokinetics 38 2.8.1 Absorption 38 2.8.2 Metabolism/Elimination 38 2.9 Analysis of Biofluids 38 2.10 Chemical Analysis 39 2.11 Regulatory Status 39 Chapter 3: Ginkgo biloba Forouzandeh Mahdavi and Melanie Johns Cupp 43 3.1 History and Traditional Use 43 3.2 Current Promoted Use 43 3.3 Products Available 43 3.4 Pharmacologic/Toxicologic Effects 44 3.4.1 Nervous System Effects 44 3.4.2... Effects 114 9.5 Case Reports of Toxicity 115 9.6 Drug Interactions 118 9.7 Pharmacokinetics/Toxicokinetics 118 9.7.1 Absorption 118 9.7.2 Distribution 118 9.7.3 Metabolism/Elimination 118 9.8 Analysis of Biofluids 120 9.9 Regulatory Status 120 Chapter 10: Ginger Charity Metz and Melanie Johns Cupp 123 10.1 History and Traditional Uses 123 10.2 Current Promoted Uses 124 10.3 Products Available 124 10.4... Effects 47 3.5 Case Reports of Toxicity Due to Commercially Available Products 47 3.6 Drug Interactions 48 3.7 Pharmacokinetics/Toxicokinetics 48 Page xiii 3.7.1 Absorption 48 3.7.2 Distribution 49 3.7.3 Metabolism/Elimination 49 3.8 Chemical Analysis 49 3.9 Analysis of Biofluids 50 3.10 Regulatory Status 50 Chapter 4: Valerian Marlea Givens and Melanie Johns Cupp 53 4.1 History and/ Traditional Uses 53 . recognition of this fact, and of the obvious need for a reliable reference work on herbal toxicology, The Toxicology and Clinical Pharmacology of Herbal Products . States of America. 10 9 8 7 6 5 4 3 2 1 Library of Congress Cataloging in Publication Data Toxicology and clinical pharmacology of herbal products