herbal supplements and the brain: understanding their...

Praise for Herbal Supplements and the Brain

“Both skeptics and believers in the value of herbal supplements for brainconditions will enjoy the calm objective analysis to which these two expe-rienced pharmacologists put the most popular products. You may notlike their conclusions, but their evidence is convincing.”

—Floyd E. Bloom, MD, Professor Emeritus, Molecular and Integrative Neuroscience Department, TSRI

“Written with authority yet as lucid and enticing as a novel, the Enna/Norton book is certainly the finest volume I know addressing the inter-face of herbs, the brain, and behavior. It will be of value and fun for theeducated layperson as well as the professional.”

—Solomon H. Snyder, M.D., Department of Neuroscience, Johns Hopkins University School of Medicine

“It all began with Adam’s apple. Knowing what you add to your diet maychange your life. Getting a kick from a cup of coffee, fighting depressionwith St. John’s wort, drifting away with valerian, or reaching a ripe oldage with Gingko, this book gives insights into the pros and cons of takingherbal supplements. Excellent and entertaining reading!”

—Hanns Möhler, Professor of Pharmacology, University of Zurich, Switzerland

“If you are someone who takes and believes in herbal supplements, thenthis book is a must-read for you. I’ll bet you will be surprised at some ofthe information. It is written by two extraordinarily qualified authors,who have decades of experience with the effects and toxicities of drugsand supplements. The aim of the book is to use proven criteria to evalu-ate if herbal supplements are effective or not. This information is notalways easy to find, so read on.”

—Michael J Kuhar, Ph.D., Yerkes National Primate Research Centerof Emory University, Candler Professor of Neuropharmacology, School of Medicine, Georgia Research Alliance Eminent Scholar, Center for Ethics of Emory University

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Herbal Supplementsand the Brain

Herbal Supplementsand the Brain

Understanding Their Health Benefits and Hazards

S. J. EnnaStata Norton

Illustrated by Kevin S. Smith

Vice President, Publisher: Tim MooreAssociate Publisher and Director of Marketing: Amy NeidlingerEditorial Assistant: Pamela BolandDevelopment Editor: Russ HallOperations Specialist: Jodi KemperAssistant Marketing Manager: Megan GraueCover Designer: Chuti PrasertsithManaging Editor: Kristy HartProject Editor: Anne GoebelCopy Editor: Geneil BreezeProofreader: Debbie WilliamsIndexer: Erika MillenCompositor: Nonie RatcliffManufacturing Buyer: Dan Uhrig

© 2012 by Pearson Education, Inc.Publishing as FT PressUpper Saddle River, New Jersey 07458

FT Press offers excellent discounts on this book when ordered in quantity for bulk purchasesor special sales. For more information, please contact U.S. Corporate and Government Sales,1-800-382-3419, [email protected]. For sales outside the U.S., please contactInternational Sales at [email protected].

Company and product names mentioned herein are the trademarks or registered trademarksof their respective owners.

All rights reserved. No part of this book may be reproduced, in any form or by any means,without permission in writing from the publisher.

Printed in the United States of America

ISBN-10: 0-13-282497-3ISBN-13: 978-0-13-282497-2

Pearson Education LTD.Pearson Education Australia PTY, Limited.Pearson Education Singapore, Pte. Ltd.Pearson Education Asia, Ltd.Pearson Education Canada, Ltd.Pearson Educación de Mexico, S.A. de C.V.Pearson Education—JapanPearson Education Malaysia, Pte. Ltd.

Library of Congress Cataloging-in-Publication Data

Enna, S. J.Herbal supplements and the brain : understanding their health benefits and hazards /

S.J. Enna, Stata Norton.p. cm.

Includes bibliographical references and index.ISBN 978-0-13-282497-2 (hardback : alk. paper) 1. Herbs—Therapeutic use. 2. Alternative

medicine. 3. Dietary supplements—Therapeutic use. I. Norton, Stata, 1922- II. Title. RM666.H33E55 2013615.3’21—dc23

2012006286

First Printing May 2012 with corrections May 2013

We thank our spouses, Colleen Enna and David Ringle,for the decades they have devoted to encouraging us

to pursue our scientific interests and career goals.Neither this book, nor any of our other accomplishments,would have been possible without their patience, support,

and understanding. This work is dedicated to them.

Contents

Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xvi

Chapter 1 The Gifts of Eden . . . . . . . . . . . . . . . . . . . . . . . 1

Chapter 2 Transforming Plants into Gold . . . . . . . . . . . . . . 7Prehistoric Evidence . . . . . . . . . . . . . . . . . . . . . . . . . 8

Early Documentation . . . . . . . . . . . . . . . . . . . . . . . . 9

Western Culture . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

Alchemy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

Chemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

Chapter 3 Thinking Like a Pharmacologist . . . . . . . . . . . . 17The Origins of Pharmacology . . . . . . . . . . . . . . . . . . 19

Pharmacodynamics . . . . . . . . . . . . . . . . . . . . . . . . 21

Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . 24

In Vitro and In Vivo Studies . . . . . . . . . . . . . . . . . . . 27

Pharmacology and Herbal Supplements . . . . . . . . . . 27

Herbal Supplement Pharmacology Checklist . . . . . . . 28

Chapter 4 The Brain as a Drug Target . . . . . . . . . . . . . . . 33The Human Brain . . . . . . . . . . . . . . . . . . . . . . . . . . 36

Chemical Neurotransmission . . . . . . . . . . . . . . . . . . 39

Neurotransmitter Systems . . . . . . . . . . . . . . . . . . . 41

Behavioral Assays . . . . . . . . . . . . . . . . . . . . . . . . . 45

Clinical Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . 49

Chapter 5 Ginkgo (Ginkgo biloba) . . . . . . . . . . . . . . . . . . 53Botany . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55

Therapeutic Uses . . . . . . . . . . . . . . . . . . . . . . . . . . 55

Constituents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57



Adverse Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . 65

Pharmacological Perspective . . . . . . . . . . . . . . . . . . 66

Chapter 6 St. John’s Wort (Hypericum perforatum) . . . . . . 67Botany . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69


Constituents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71



Adverse Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . 80


Chapter 7 Valerian (Valeriana officinalis) . . . . . . . . . . . . . 83Botany . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84


Constituents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86



Adverse Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . 93


Chapter 8 Lemon Balm (Melissa officinalis) . . . . . . . . . . . 97Botany . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98


Constituents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99

Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . 100

Pharmacodynamics . . . . . . . . . . . . . . . . . . . . . . . 102

Adverse Effects . . . . . . . . . . . . . . . . . . . . . . . . . . 106

Pharmacological Perspective . . . . . . . . . . . . . . . . . 106

Chapter 9 Kava (Piper methysticum) . . . . . . . . . . . . . . . 109Botany . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110

Therapeutic Uses . . . . . . . . . . . . . . . . . . . . . . . . . 111

Constituents . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112



Adverse Effects . . . . . . . . . . . . . . . . . . . . . . . . . . 118


x herbal supplements and the brain

Chapter 10 Lavender (Lavandula angustifolia) . . . . . . . . . 123Botany . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124


Constituents . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126



Adverse Effects . . . . . . . . . . . . . . . . . . . . . . . . . . 134


Chapter 11 Kudzu (Pueraria lobata) . . . . . . . . . . . . . . . . . 137Botany . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138


Constituents . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140



Adverse Effects . . . . . . . . . . . . . . . . . . . . . . . . . . 146


Chapter 12 Daffodil (Narcissus pseudonarcissus) . . . . . . . 149Botany . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151


Constituents . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153



Adverse Effects . . . . . . . . . . . . . . . . . . . . . . . . . . 158


Chapter 13 Passion Flower (Passiflora incarnata) . . . . . . . 161Botany . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162


Constituents . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164



Adverse Effects . . . . . . . . . . . . . . . . . . . . . . . . . . 173


contents xi

Chapter 14 Coffee, Tea, and Cocoa . . . . . . . . . . . . . . . . . 175Botany . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177


Constituents . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180



Adverse Effects . . . . . . . . . . . . . . . . . . . . . . . . . . 186


Chapter 15 Epilogue . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189

Endnotes . . . . . . . . . . . . . . . . . . . . . . . . . . . 195

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237

xii herbal supplements and the brain

Acknowledgments

We thank Mr. Kirk Jensen, Mr. Russ Hall, and their colleagues atPearson for their guidance and assistance in creating this volume.Thanks, too, to Mr. Kevin S. Smith for preparing the illustrations andfor contributing his creative talents to this project. We are particularlygrateful to Ms. Lynn LeCount at the University of Kansas MedicalSchool for her editorial and technical assistance. Without her efforts,this work would not have been possible.

About the Authors

A Kansas City native, S. J. Enna received his undergraduate educa-tion at Rockhurst University and his M.S. and Ph.D. degrees in phar-macology from the University of Missouri. Following postdoctoralwork at the University of Texas Southwestern Medical School in Dal-las, F. Hoffmann-LaRoche in Basel, Switzerland, and Johns HopkinsUniversity Medical School, Dr. Enna joined the faculty at the Univer-sity of Texas Medical School in Houston in the departments of Phar-macology and of Neurobiology and Anatomy. In 1986, Dr. Enna wasappointed Scientific Director of Nova Pharmaceutical Corporation inBaltimore. At this time, he also held appointments as a Lecturer inNeuroscience at Johns Hopkins Medical School and Adjunct Profes-sor of Pharmacology at Tulane Medical School in New Orleans. Dr.Enna returned to Kansas City in 1992 as Professor and Chair of Phar-macology at the University of Kansas Medical Center, where he iscurrently Associate Dean for Research and Graduate Education, andProfessor of Pharmacology and of Physiology. Dr. Enna has publishednearly 300 research reports, reviews, and book chapters describinghis research, and has edited or coedited 30 books on various subjectsrelating to neuropharmacology. For decades, he has served as a scien-tific consultant for most of the major pharmaceutical companies andas a board member on government panels and private research foun-dations. He has been appointed to the editorial boards of numerouspharmacology journals and has served as editor of leading journals inthe field, including the Journal of Pharmacology and ExperimentalTherapeutics.

At present, Dr. Enna is editor of Biochemical Pharmacology andPharmacology and Therapeutics, coeditor of Current Protocols inPharmacology, and series editor of Advances in Pharmacology. Dr.Enna has held many elective offices in professional societies, includ-ing the presidency of the American Society for Pharmacology andExperimental Therapeutics. Currently, he is Secretary-General of theInternational Union of Basic and Clinical Pharmacology. He hasreceived numerous awards in recognition of his contributions to thediscipline of pharmacology. Among these are two Research Career

Development Awards from the National Institutes of Health, theJohn Jacob Abel and Torald Sollmann Awards from the AmericanSociety for Pharmacology and Experimental Therapeutics, theDaniel H. Efron Award from the American College of Neuorpsy-chopharmacology, and the PhRMA Foundation Excellence Awardfrom the Pharmaceutical Manufacturer’s Association Foundation. Dr.Enna is internationally recognized for his research in neuropharma-cology, especially his contributions in characterizing the biochemicaland pharmacological properties of neurotransmitter receptors in gen-eral, and the γ-aminobutyric acid (GABA) system in particular.

Dr. Stata Norton received her B.S. degree in Biology from theUniversity of Connecticut, Storrs, her Master’s degree in Zoologyfrom Columbia University in New York, and her Ph.D. degree inZoology and Physiological Chemistry from the University of Wiscon-sin in Madison. After working for over a decade as a neuropharmacol-ogist at the Wellcome Research Laboratories in Tuckahoe, New York,in 1962, she accepted a faculty appointment in Department of Phar-macology, Toxicology, and Therapeutics at the University of KansasMedical School in Kansas City. While at the University of Kansas, shealso served as Professor of Dietetics and Nutrition, Dean of theSchool of Allied Health, and Professor at the Institute for Cell Biol-ogy in Valencia, Spain. Since 1990, she has been Emeritus Professorof Pharmacology at the University of Kansas Medical School.

Dr. Norton was the recipient of a Research Scientist Award fromthe National Institute of Mental Health and was elected to Outstand-ing Educators of America in 1975. She served on the EditorialAdvisory boards for Psychopharmacology, Neurotoxicology, andToxicology and Industrial Health. She was President of the CentralStates Chapter of the Society of Toxicology and a member of the Pre-clinical Psychopharmacology Study Section of the National Instituteof Mental Health. She has published more than 150 scientificresearch articles and reviews in scientific journals and books. Hermain research interests are the development of quantitative methodsfor analyzing animal behavior and the characterization of the effectsof chemicals on behavior. For more than two decades, she authored amajor review on the toxic effects of plants for the reference workToxicology: The Basic Science of Poisons.

about the authors xv

Preface

While for more than 200,000 years humans have been consumingplant materials, such as flowers, fruits, leaves, and roots, for therapeu-tic benefit, it is only in the last 150 years that scientists have been ableto isolate, identify, examine, and categorize the biologically activeconstituents in plants. Many of the compounds identified, or chemi-cal derivatives of them, are now employed as drugs. The ability toobtain such precise scientific information, and to synthesize otheractive compounds, opened the way for legislators in the early twenti-eth century to enact laws regulating the marketing and sale of chemi-cals for therapeutic purposes. The creation of these regulatoryrequirements was spurred by the fact that many inert, and sometimestoxic, products were sold as medications to the public. Current lawsmandate that any substance marketed as a treatment for a particularcondition must first undergo rigorous testing in laboratory animalsand humans to demonstrate its safety and effectiveness.

Although prescription and over-the-counter medications are sub-ject to tight federal oversight, there are few regulations concerningthe sale of herbal supplements. In the United States, the chiefrequirement is that no formal claims be made of any therapeutic ben-efit resulting from the use of these products. Nonetheless, consumersare continuously exposed in the lay press and online to reports on thepurported curative properties of certain herbs or how their consump-tion can help prevent disease. Such reports are no doubt responsiblefor driving sales in this multibillion dollar industry. However, like ourancient ancestors, today’s consumer may be purchasing and consum-ing these products for health benefits based solely on the word of oth-ers, not as a result of an independent and objective analysis of thedata supporting the claims. This is understandable, as most lack thetechnical background for making an informed scientific judgment.The aim of this book is to address this need.

Herbal products are used around the world for a variety of pur-poses. Among these is the treatment of central nervous system disor-ders, such as anxiety, insomnia, alcoholism, dementia, and depression.Herbal supplements are also taken to modify brain function in the

treatment of other conditions, such as chronic pain and obesity.Because some of the symptoms of these disorders resolve over timewithout medication, and many have a strong psychological compo-nent, it is often difficult to prove the efficacy of an herbal product as atreatment for these conditions. That is, while the effectiveness of adietary supplement that reduces body weight would be apparent, thecontribution of an herbal product in lessening feelings of depression,or in enhancing cognitive abilities, is more difficult to quantify. Forthis reason, the claims for such benefits may not be supported byexperimental data. In this regard, the consumer may be no differentthan the primitive who ingested a plant material to alter his mentalstatus. Sometimes it worked; often it did not. A change in perceptionor feelings, or in sleep patterns, could be the result of an active con-stituent in the plant, or the power of suggestion. Prolonged consump-tion of any product with no inherent value is not only costly, butpotentially dangerous as anything taken into the body can have toxicconsequences. This volume is devoted to a discussion of herbal sup-plements taken to affect brain function because of the unique chal-lenges associated with assessing the effectiveness of such products.

Written for the nonscientist, the book is informally divided intotwo parts. The first section, chapters 1–4, provides an historical per-spective on the use of plant products to modify central nervous sys-tem function and on the development of the techniques employed fordrug discovery. Included is a discussion of the basic principles ofpharmacology, the science of drugs, as they relate to assessing thepotential effectiveness and safety of an herbal supplement. Descrip-tions are provided of the components of the central nervous systemthat are dysfunctional in neurological and psychiatric disorders, andthe targets of drugs used to treat these conditions. Taking all of theseissues into consideration, a short checklist is provided to assist thepotential consumer in determining, from a scientific standpoint,whether a particular product is likely to contain chemicals that bene-ficially affect brain function. The reader is encouraged to completethe first four chapters before proceeding to those describing individ-ual plant products. The introductory chapters provide the context,concepts, and definitions essential for understanding fully the reason-ing and conclusions drawn in the second part of the book.

preface xvii

Chapters 5 through 15 are devoted to a scientific assessment ofthe claims made for a select group of herbal products that arebelieved to have central nervous system effects. The pharmacologicalprinciples provided in the earlier chapters are applied in this analysis,with the checklist items used to guide the reader in the search for thetruth. In this way, the reader can appreciate how answering a few keyquestions yields powerful insights into the potential benefit of theseproducts.

The primary audience for this book is consumers interested indetermining the value of herbal products purported to influencebrain function. Others who will find this information of interest andvalue are students considering careers in the neurosciences or drugdiscovery, and scientists seeking an updated review of this field. Byhaving the tools needed to make an objective and scientific assess-ment of these products, consumers are in a much better position tomaximize the benefits of herbal supplements. This information willalso make it possible to minimize the risks to one’s health that comeswith consuming these substances without adequate information ontheir effectiveness and safety.

xviii herbal supplements and the brain

The Gifts of Eden

1

1

Adam wasn’t hungry and was apprehensive about the potential con-sequences of eating the forbidden fruit. He was, however, convincedthe plant material could provide benefits beyond its nutritionalvalue. On the one hand, God told him that its consumption would befatal, while the serpent contended the plant would impart newknowledge. Both were right. After eating the fruit Adam lost hishome and immortality, and was made aware of the concepts of goodand evil. He would need this new knowledge to survive in the worldoutside of Eden.

Besides its allegorical importance for Jews, Christians, and Mus-lims, this biblical account provides lessons for those interested in thetherapeutic benefits of herbal supplements, also known as nutritional,dietary, or food supplements. Defined as a product that contains avitamin, mineral, herb or other botanical, an amino acid, an extract,or any combination of these materials, the United States governmentconsiders dietary supplements to be foods rather than drugs. This has

2 herbal supplements and the brain

significant implications with regard to their regulation and the assur-ances provided to consumers. Because of this categorization, poten-tial users must obtain on their own objective data about theseproducts. The aim of this book is to provide such information.

The most fundamental question pertaining to dietary supplementsis whether there is any evidence that they provide benefits beyond pos-sible nutritional value. Written some 2,500 years ago, the Genesisaccount of Adam’s introduction to these products indicates that humanshave been familiar with the possible mystical and therapeutic powers ofplants for quite some time. Moreover, the Old Testament accountdemonstrates that then, as now, there was uncertainty, and thereforerisk, associated with the consumption of plants and plant products forreligious, therapeutic, or, as in Adam’s case, educational purposes.

The fruit consumed by Adam is unknown. In Old English, theword “apple” is simply a synonym for fruit. Regardless, when temptedto eat the plant product, Adam was at a distinct disadvantage totoday’s consumer. There was no historical record on its possibleeffects and no scientific data on its safety. Moreover, as the basic prin-ciples of pharmacology, the science of drugs, had not yet been estab-lished, he was unable to assess these properties himself. Rather,Adam had to rely solely on the word of others.

The constraints experienced by Adam remained for thousands ofyears until written records were maintained on the medicinal value ofplants. More centuries passed before chemists were able to identify,and pharmacologists objectively study, the therapeutically active con-stituents in plant and animal products. Only during the past centuryhas research revealed the diseases and disorders that are mostresponsive to these constituents, and to define precisely the appropri-ate doses to maximize safety and effectiveness in most individuals.

Anecdotal accounts about the potential benefits of dietary sup-plements have existed for thousands of years. Evidence includespollen grains found on Neanderthal (Homo neanderthalensis) gravesthat were from plants lacking showy flowers, such as the yarrow(Achillea millefolium). It is inferred that these plants were placedthere not for adornment, but to provide the departed a supply ofmedications in the afterlife.1 This concept is based, in part, on the factthat many of the plants deposited on Neanderthal gravesites were

chapter 1 • the gifts of eden 3

subsequently described as therapeutics in early medical books, indi-cating that word of their therapeutic powers was passed on for millen-nia. For example, yarrow is mentioned in the Assyrian Herbal (800BC), one of the oldest listings of therapeutically active plant prod-ucts,2 as well as in the Ebers papyrus (1500 BC) from Egypt. TheGreek poet Homer described in The Iliad (800 BC) the use of yarrowto cure wounds, as did the Roman naturalist Pliny the Elder in hiswritings during the first century AD.3

A conservative estimate is that plants have been used as thera-peutics at least since the appearance of modern man, some 200,000years ago. It seems reasonable that as early humans foraged for foodthey would accidently discover the curative powers of some plants ortake note of the fact that consumption of a certain type of seed, root,or fruit produced discernable effects on mood, sensory input, or alle-viated general aches and pains. Indeed, as a species, humans areindebted to the many thousands of forgotten ancestors who becameill or died in the process of identifying plants and animals suitable forconsumption. Thus, through trial and error, early man was able toidentify plants that possess useful medicinal properties.

In addition to using plants to cure disease, they were also con-sumed in the ongoing quest for immortality. Recipes for “elixirs oflife” were described in ancient writings. An example is the Epic ofGilgamesh, the story of a Sumarian hero that was recorded in 2000BC.4 After many travails, Gilgamesh obtained the plant of immortalityfrom deep in the sea. Unfortunately for Gilgamesh, the plant wassubsequently stolen by a serpent. This tale has many of the features ofthe biblical account of Adam and Eve. In the end, Gilgameshreturned home to Sumer to, like the rest of us, spend the remainderof his days as a mortal, awaiting the inevitable.

As in Genesis, ancient medical texts demonstrate that plant prod-ucts have been used for therapeutic purposes for millennia. Duringmost of this time no concerted effort was made to understand thereason for their effectiveness, or, in modern terminology, their mech-anism of action. The first recorded attempts to synthesize therapeu-tics were made by European alchemists during the Middle Ages.5

Besides their efforts to transform base metals into gold, thealchemists were interested in what made substances therapeutically

4 herbal supplements and the brain

useful as they wanted the power to transform basic materials intodrugs. They were hindered in this quest, however, by the prevailingtheories about the nature of matter and the causes of disease.

From the time of Aristotle to the seventeenth century, the use ofplants in European medicine was based on the idea that all naturewas composed of four basic elements: earth, air, fire, and water. Dis-ease resulted from an imbalance of bodily humors. It was believedthis imbalance could be countered by one or more of the four plantclasses—cold, dry, hot, and wet—that corresponded to the four basicelements of nature. Mixtures of plants, usually from the same class,were preferred over a single specimen for treating medical condi-tions. For example, combinations of “cold” plants were used to treatfevers. Given these theories, drug discovery remained an empiricalenterprise for thousands of years, with the identification of activeplants and plant products left solely to chance.

By the seventeenth century, belief in the Aristotelian four ele-ments was being challenged, most notably by the Irish chemistRobert Boyle.6 Boyle understood that the precise identification andclassification of the basic elements of nature were absolutely essentialfor understanding the universe, including drug actions. Thanks to hisefforts, and those of many others, modern chemistry emerged in thenineteenth century. This made it possible to isolate, chemicallydefine, and study the biological responses to plant constituents. As aresult of these efforts, drugs were identified in plants that were firstdiscovered by our distant ancestors. Many of these compounds, ortheir chemical derivatives, are still used today.

Given the historical records, and contemporary scientific data,there is no question that plants produce an abundance of substancesthat provide benefits beyond their nutritional value. However, not allplant constituents have been isolated and properly tested for effec-tiveness, and, unlike drugs, there is no government requirement thata manufacturer demonstrate effectiveness before marketing anherbal supplement. Like Adam, the consumer must rely on the wordof others about the benefits of these products.

This book is designed to address this issue by providing basicinformation needed to assess the potential therapeutic value of plantproducts. Included are fundamental principles of pharmacology and

chapter 1 • the gifts of eden 5

about how drugs and natural products can affect various organs andorgan systems. Explanations and examples are provided about whatdetermines whether an ingested substance will find its way into thebloodstream, and then to the targeted site in the body at a concentra-tion sufficient to have a beneficial effect. Other topics include theways in which natural products may influence the blood levels ofother substances, including drugs, and the likelihood that such inter-actions may diminish the effectiveness of prescription medications oralter normal body chemistry. While the principles described apply toall dietary supplements and drugs, emphasis is placed on factors thatrelate especially to herbal supplements purported to influence brainfunction. Individual chapters are devoted to a discussion of selectednutritional supplements that are said to enhance memory, or to aid inthe treatment of depression, anxiety, insomnia, and alcoholism. Theseproducts were chosen because the promised benefits can be difficultto quantify and are more subject to influence by the power of persua-sion than is the case with other therapeutics. This is why the use ofsuch substances has been exploited over the centuries by shamans tomaintain their social standing, and by charlatans for monetary gain.The properties of these products are described in the context of thebasic principles of pharmacology and the results of scientific studies,both human and laboratory animal, aimed at determining effective-ness and mechanism of action. The approach taken in objectivelyevaluating these products can be used by the reader as a guide forassessing the information available on any dietary supplement. Thiswork is intended for those who are curious about the potential bene-fits and risks associated with the use of food supplements. The infor-mation provided will be of particular value for individuals who, likeAdam, are interested in how drugs and natural products affect us forgood and evil.

Index

237

Aacetaldehyde, 145acetoxyvalerenic acid, 89acetylcholine, 22, 42-44acetylcholine neurotransmission,

effects of lavender (Lavandulaangustiolia) on, 133

acetylcholine nicotinic receptorsystem, 155

acetylcholinesterase, 103, 133-134, 155-156

acetylsalicylic acid (aspirin), 21Achillea millefolium (yarrow)

presence in Neanderthal graves,2, 8

use in Greco-Roman era, 3adenosine, 42-43, 185Adlumia fungosa, 43adverse effects

of cocoa (Theobroma cacao),186-187

of coffee (Coffea arabica), 186-187

of daffodil (Narcissuspseudonarcissus), 158-159

of ginkgo (Ginkgo biloba), 65-66

of kava (Piper methysticum),118-120

of kudzu (Pueraria lobata), 146-147

of lavender (Lavandulaangustiolia), 134-135

of lemon balm (Melissaofficinalis), 106

of passion flower (Passifloraincarnata), 173

of St. John’s wort (Hypericumperforatum), 80-81

of tea (Camellia sinensis), 186-187

of Valeriana officinalis(Valerian), 93-94

aglycones, 140-142agonists, 23alchemy, 3-4, 13-15alcohol withdrawal, therapeutic

use of kudzu (Pueraria lobata)for, 143-146

alcoholism, therapeutic use ofkudzu (Pueraria lobata) for,143-146

aldehyde dehydrogenase-2, 144-145

238 index

alkaloids, 192-193caffeine

adverse effects, 186-187chemical structure of, 181historical use of, 175-177pharmacodynamics, 184-186pharmacokinetics, 182-184pharmacological

perspective, 187-188therapeutic uses, 178-180

definition of, 149in daffodil. See daffodil

(Narcissus pseudonarcissus)in passion flower (Passiflora

incarnata), 164theobromine, 180-181

adverse effects, 186-187pharmacodynamics,

184-186pharmacokinetics, 182-184pharmacological

perspective, 187-188therapeutic uses, 179

theophylline, 180-181adverse effects, 186-187pharmacodynamics,

184-186pharmacokinetics, 182-184pharmacological

perspective, 187-188therapeutic uses, 179

alpha-pinene, 73alprazolam, interaction with

St. John’s wort, 80Althea, presence in Neanderthal

graves, 8Alzheimer’s disease, 37, 47

Neuropsychiatric Inventory andAlzheimer’s DiseaseAssessment Scale, 50

therapeutic use of ginkgo(Ginkgo biloba), 64

therapeutic use of lemon balm(Melissa officinalis), 103

therapeutic use of lavender(Lavandula angustiolia), 130-132

therapeutic use of galantamine,155-157

Amaryllidaceae, 151-153amitriptyline, interaction with St.

John’s wort, 80amphetamine, 46, 191amygdala, 37analgesia, therapeutic use of

lavender (Lavandulaangustiolia) for, 130-131

analgesic effectof daffodil (Narcissus

pseudonarcissus), 156of passion flower (Passiflora

incarnata), 171Andrea (Jesuatti Friar), 21Andrea, Giovanni, 14anecdotal reports, 49Anethum graveolens (dill

seed), 12animal test models, 46-48antagonists, 23anthrones, 72anti-inflammatory effect

of daffodil (Narcissuspseudonarcissus), 157

of passion flower (Passifloraincarnata), 172

index 239

anticonvulsant effectof lavender (Lavandula

angustiolia), 130of passion flower extract, 170

antimicrobial properties oflavender (Lavandulaangustiolia), 131

antioxidant activity of lemonbalm (Melissa officinalis), 104

antitumor activity of daffodil (Narcissuspseudonarcissus), 157

anxietytherapeutic use of kava (Piper

methysticum), 116-117therapeutic use of lemon balm

(Melissa officinalis), 102-105therapeutic use of lavender

(Lavandula angustiolia), 129-134

therapeutic use of passionflower (Passiflora incarnata),168-170

therapeutic use of Valerian(Valeriana officinalis), 90-93

apigenin, 164-169apolinaris (Hyoscyamus), 13apoptosis, effect of ginkgo

(Ginkgo biloba) on, 62Aristotle, 12aromatase, 172Ascyrum (St. Peter’s wort), 70aspirin (acetylsalicylic acid), 21assays, behavioral, 45-48Assyrian Herbal, 3, 10-11Atropa belladonna, 23awaine, 118axo-axonic synapses, 40axo-dendritic synapses, 40axons, 36

BBacon, Francis, 15barbiturates, 43, 83behavioral assays, 45-48Ben Cao Pin Hui Jing Yao (Liu

Wen-Tai), 54-55benzodiazepines, 43, 83beta-amyloid, 47, 103beta-caryophyllene, 73beta-myrcene, 73bianthraquinone, 72Biblical mention of herbal

supplements, 1bicuculline, 43bilobalide, 58-60bioavailability, 24-26, 59-60bornyl acetate, 87-88botany




of ginkgo (Ginkgo biloba), 55of kava (Piper methysticum),

110-111of kudzu (Pueraria lobata),

138-139of lavender (Lavandula

angustiolia), 124-125of lemon balm (Melissa

officinalis), 98of passion flower (Passiflora

incarnata), 162-163of St. John’s wort (Hypericum

perforatum), 69-70of tea (Camellia sinensis),

177-178

240 index

of Valerian (Valerianaofficinalis), 84-85

Boyle, Robert, 4, 15brain

chemical neurotransmisson, 39-41

neurotransmitter systems, 41-45nucleus accumbens, 114sigma receptors, 77structure of, 36-39

Ccaffeic acid, 182caffeine

adverse effects, 186-187chemical structure of, 181historical use of, 175-177pharmacodynamics, 184-186pharmacokinetics, 182-184pharmacological perspective,

187-188therapeutic uses, 178-180

Camellia japonica, 177-179Camellia sinensis (tea), 11

adverse effects, 186-187botany, 177-178constituents, 180-182historical use of, 175-177pharmacodynamics, 184-186pharmacokinetics, 182-184pharmacological perspective,


camphor, 126cannabinoids, 191Cannabis, 191Cannabis sativa, 11, 191catechins, 182-185categorization of herbal

supplements, 1, 18

Catha edulis, 190caudate nucleus, 38Celsus, 12Centaurea (century plant), 8central nervous system, 33-35.

See also braincentral nervous system

depressants, 83central nervous system

disorders, 34century plant (Centaurea), 8cerebellum, 37-38cerebral cortex, 37-38challenges of pharmacological

analysis of herbal supplements,27-28

chemical neurotransmission, 39-41

chemistry, development of, 4, 15-16

chlordiazepoxide (Librium®), 83chlorogenic acid, 182chocolate. See cocoachrysin, 164-169, 172cingulate cortex, 37Cistus laudanifer, 20citral, 99-104citronellal, 99-104Clark, A. J., 24clinical depression, 67clinical studies, 49-51clovamide, 182Clusiaceae, 69cocaine, 191cocoa (Theobroma cacao)

adverse effects, 186-187botany, 177-178constituents, 180-182historical use of, 175-177pharmacodynamics, 184-186pharmacokinetics, 182-184

index 241

pharmacological perspective,187-188

therapeutic uses, 178-180codeine, 190Coffea arabica (coffee)



Coffea canephora, 175coffee (Coffea arabica)



Commiphora myrrha, 9Cook, James, 109Corey, Elias James, 57corpus striatum, 38Crataeus, 12crossover studies, 49Culpepper, Nicholas, 124cyclosporine, interaction with St.

John’s wort, 80cytochrome P450 enzymes, 26

Ddaffodil (Narcissus

pseudonarcissus), 149-151adverse effects, 158-159

botany, 151-152constituents, 153-154historical use of, 152pharmacodynamics, 155-158pharmacokinetics, 154-155pharmacological

perspective, 159therapeutic uses, 152

daidzein, 140-142, 146daidzin, 140, 144Darwin, Charles, 109De Medicina (Celcus), 12dehydrogenase, 145delta-9-tetrahydrocannabinol,

191dementia. See

Alzheimer’s diseasedendrites, 36depression, therapeutic use of St.

John’s wort for, 67-71, 75-80desmethoxyyangonin,

112-114, 120dextromethorphan, interaction

with St. John’s wort, 80Dian Nan Ben Cao (Lan

Mao), 54diazepam (Valium®), 43, 83, 89Dicentra cucullaria (Dutchman’s

britches), 43Dietary Supplement Health and

Education Act of 1994, 18diffusion, 25Digenea simplex, 43digoxin

interaction with lemon balm(Melissa officinalis), 101

interaction with St. John’s wort(Hypericum perforatum), 80

dihydrokavain, 112-114dihydromethysticin, 112-114, 120

242 index

dill seed (Anethum graveolens), 12

donepezil, 156dopamine, 36, 42-44double-blind studies, 49Dr. Willmar Schwabe GmbH &

Company, 57, 132drug receptors, discovery of,

22-24Dutchman’s britches (Dicentra

cucullaria), 43

Eearly documentation of herbal

supplements, 3, 9-11Ebers papyrus, 3, 9Ebers, George, 9EGb 761, 57Ehrlich, Paul, 22elements, periodic table of, 16elevated plus maze, 46emetic effect of

daffodil (Narcissuspseudonarcissus), 157

endocannabinoids, 191endogenous depression, 67English lavender. See lavender

(Lavandula angustiolia)Enquiry into Plants

(Theophrastus), 151enterovirus 71, 157enzymes

acetylcholinesterase, 133, 155-156

aldehyde dehydrogenase-2, 144-145

aromatase, 172cytochrome P450 enzymes, 265-lipoxygenase, 77

nitric oxide synthase, 77phosphodiesterase, 184

Ephedra, 11Ephedra equisetina, 190Ephedra sinica, 190presence in Neanderthal

graves, 8ephedrine, 8, 190-191Epic of Gilgamesh, 3epigallocatechin-3-gallate, 182,

185-187Erythroxylon coca, 191ethanol, 83ethyl alcohol, 83excitatory neurotransmitters, 40extrapyramidal system, 38

FFDA (Food and Drug

Administration)establishment of, 17lack of oversight over herbal

supplements, 18-19role of, 17-18

Federal Food, Drug, andCosmetic Act, 17

fennel (Foeniculum vulgare), 125-lipoxygenase, 77flavokawain B, 118-119flavonoids

bioavailability of, 59-60in cocoa (Theobroma

cacao), 182in coffee (Coffea arabica), 182in ginkgo standardized

extract, 58in kudzu (Pueraria lobata),

140-141

index 243

in passion flower (Passifloraincarnata), 164-168

in tea (Camellia sinensis), 182flavonol glycosides in ginkgo

standardized extract, 58-60flavonols in St. John’s wort,

73, 77fluoxetine (Prozac®), 75, 116Foeniculum vulgare (fennel), 12Food and Drug Administration.

See FDA (Food and DrugAdministration)

Forester, Johann, 109four basic elements of nature

(Aristotle), 12French lavender (Lavandula

stoechas), 123-124French spikenard (Valeriana

celtica), 84

GGABA (γ-aminobutyric acid),

42, 171GABA receptors, 90-91GABA transaminase, 102galantamine, 152-159

adverse effects, 158-159anti-inflammatory activity, 157chemical structure of, 153therapeutic use for Alzheimer’s

disease, 155-157pharmacodynamics, 155-156pharmacokinetics, 154-155

galanthine, 153Galanthus woronowi, 152Galen, 84γ-aminobutyric acid (GABA), 42Ge Gen. See kudzu (Pueraria

lobata)

GEM (Ginkgo Evaluation ofMemory) study, 64

genistein, 140-142, 146genistin, 140geranial, 99Gerard, John, 12, 70, 99, 125,

151-152ginkgo (Ginkgo biloba)

adverse effects, 65-66botany, 55contituents, 57-59historical use of, 53-54pharmacodynamics, 61-65pharmacokinetics, 59-61pharmacological perspective, 66popularity of, 53standardized extract, 58-59therapeutic uses, 55-57

Ginkgo Evaluation of Memory(GEM) study, 64

Ginkgoaceae, 53ginkgolide B, 57-58Ginkgophyla, 53Giovanni Andrea (friar), 124glia, 36globus pallidus, 38glutamic acid, 42Glycininae, 139glycitein, 142glycosides in kudzu (Pueraria

lobata), 140-143government oversight of herbal

supplements, lack of, 18-19Graminae, 151Greco-Roman era, herbal

supplements in, 3, 11-13growth of herbal supplement

market, 18Gymnosperm, 55

244 index

Hhaemanthamine, 153half-life, 25haloperidol, 46hangover, effectiveness of kudzu

(Pueraria lobata) for, 145harmaline, 164harmalol, 164harmane, 164harmol, 164Hatshepsut, 10hepatotoxicity associated with

kava (Piper methysticum), 118-119

herbal supplement pharmacologychecklist, 28-32

heroin, 190hippocampus, 37Hippocrates, 11, 84historical development of

pharmacology, 19-21historical use of herbal

supplementsalchemy, 3-4, 13-15Biblical mention of herbal

supplements, 1chemistry, 4, 15-16cocoa (Theobroma cacao),

175-177coffee (Coffea arabica), 175-177early documentation, 3, 9-11ginkgo (Ginkgo biloba), 53-54Greco-Roman era, 3, 11-13kava (Piper methysticum),

109-110kudzu (Pueraria lobata),

137-138lavender (Lavandula

angustiolia), 123-124

lemon balm (Melissa officinalis), 97-98

passion flower (Passifloraincarnata), 161-162

prehistoric evidence, 2, 8St. John’s wort (Hypericum

perforatum), 67-69tea (Camellia sinensis), 175-177Valerian (Valeriana officinalis),

83-84HMS Beagle, 109HMS Endeavour, 109Homer, 3, 9homoorientin, 164-166hydrophilic compounds, 24hydroxylated phenylpropionic

acid, 101hydroxyvalerenic acid, 89hyoscyamine, 23Hyoscyamus (apolinaris), 11-13Hyoscymus niger, 23hyperforin, 72-73, 76hypericin, 71-72, 76hypericins, 72Hypericum attenuatum, 69Hypericum maculatum, 69Hypericum perforatum (St.

John’s wort)adverse effects, 80-81botany, 69-70constituents, 71-74historical use of, 67-69pharmacodynamics, 75-80pharmacokinetics, 74-75pharmacological perspective,


hypothalamus, 37

index 245

IIlex paraguariensis (maté), 177The Iliad (Homer), 3, 9in vitro studies, 27in vivo studies, 27inhibitory neurotransmitters, 40insomnia, therapeutic use of

Valerian (Valeriana officinalis)for, 93

ironwort (Sideritis heraclea), 13isoflavones in kudzu (Pueraria

lobata), 140-143isoorientin, 164isorhamnetin in ginkgo

standardized extract, 58isoschaftoside, 164-165isovaleric acid, 87isovitexin, 164-166

J-Kkaempferol

in ginkgo standardized extract, 58

in St. John’s wort, 73, 77kainic acid, 43kava (Piper methysticum)

adverse effects, 118-120botany, 110-111constituents, 112historical use of, 109-110pharmacodynamics, 114-117pharmacokinetics, 112-114pharmacological perspective,

120-121therapeutic uses, 111

kavain, 112-114kavalactones, 112-119ketamine, 43kew. See ginkgo (Ginkgo biloba)

kudzu (Pueraria lobata)adverse effects, 146-147botany, 138-139constituents, 140-141historical use of, 137-138pharmacodynamics, 143-146pharmacokinetics, 141-143pharmacological perspective,


LLabiatae, 98Lamiaceae, 98, 124Lan Mao, 54Langley, John, 22large scale clinical trials, 49laudanum, 20Lavandula angustiolia (lavender)



Lavandula latifolia (spikelavender), 123-124

Lavandula stoechas (Frenchlavender), 123-124

Lavandula x intermedia, 124lavandulin, 125lavender (Lavandula angustiolia)

adverse effects, 134-135botany, 124-125constituents, 126-127historical use of, 123-124

246 index

pharmacodynamics, 129-134pharmacokinetics, 127-129pharmacological perspective,


legislationDietary Supplement Health and

Education Act of 1994, 18Federal Food, Drug, and

Cosmetic Act, 17United States Pure Food and

Drug Act, 17Leguminosae, 139lemon balm (Melissa officinalis)

adverse effects, 106botany, 98constituents, 99-100historical use of, 97-98pharmacodynamics, 102-105pharmacokinetics, 100-102pharmacological perspective,


Li Shih-Chen, 54-55, 139Librium® (chlordiazepoxide), 83Liliaceae, 151limbic system, 37-38linalool, 126-131linalyl acetate, 126-128, 131linalys acetate, 126Linnaeus, Carl, 97lipid peroxidation, 104lipophilic compounds, 24Liu Wen-Tai, 54liver toxicity associated with kava

(Piper methysticum), 118-119Logianaceae, 23London Pharmacopeia, 125lorazepam, 132

luteolin, 167-168lycorine, 153-154, 157-158Lycoris (spider lily), 153

MMa Huang, 190maidenhair. See ginkgo

(Ginkgo biloba)major depression, 67malaria, historical use of St.

John’s wort for, 70maltol, 164Mandragora, 11Manerix®, 75MAO (monoamine oxidase)

inhibition by kava, 116marijuana, 191-192maté (Ilex paraguariensis), 177maypop. See passion flower

(Passiflora incarnata)Medicina Antiqua, 70medulla, 37megaleion, 9Melissa officinalis (lemon

balm), 11adverse effects, 106botany, 98constituents, 99-100historical use of, 97-98pharmacodynamics, 102-105pharmacokinetics, 100-102pharmacological perspective,


memoryscopolamine-induced memory

impairment, 48therapeutic use of ginkgo

(ginkgo biloba) for, 64

index 247

Mendeleev, Dmitri, 16, 20mendeleium, 16mercuries (alchemy), 15meta-coumaric acid, 101methylxanthine alkaloids

adverse effects, 186-187pharmacodynamics, 184-186pharmacokinetics, 182-184pharmacological perspective,


methysticin, 112-114Mithridates, King of Pontus, 12mithridatum, 12, 124Moclobemide, 75The Mode of Action of Drugs on

Cells (Clark), 24Modern Herbal (Grieve), 125monoamine oxidase (MAO)

inhibition by kava, 116Monocotyledonae, 151monoterpenes

in lemon balm (Melissaofficinalis), 99

in lavender (Lavandulaangustiolia), 126

Morpheus, 20morphine, 20, 70, 190Morris water maze assay, 47Muscari, presence in

Neanderthal graves, 8myrrh, 9-10

Nnapthodianthrone, 72Narcissus poeticus, 151Narcissus pseudonarcissus

(daffodil), 149-151adverse effects, 158-159botany, 151-152

constituents, 153-154historical use of, 152pharmacodynamics, 155-158pharmacokinetics, 154-155pharmacological

perspective, 159therapeutic uses, 152

Narcissus serotinus, 151Nardostachys jatamansi

(spikenard), 84nardus. See lavender (Lavandula

angustiolia)National Formulary, 164Natural History (Pliny), 97Neanderthal use of herbal

supplements, 2, 8neopallium, 37neral, 99neurokinin, 158neurons, 36neuropharmacology

behavioral assays, 45-48brain structure, 36-39chemical neurotransmission,

39-41clinical studies, 49-51definition of, 35neurotransmitter systems, 41-45

Neuropsychiatric Inventory andAlzheimer’s DiseaseAssessment Scale, 50

neurotransmissionacetylcholine, 44adenosine, 43dopamine, 44explained, 39-41GABA (γ-aminobutyric acid), 42glutamic acid, 42neurotransmitter systems, 36,

41-45serotonin, 44

248 index

NF-kappaB inhibition by kava, 116

nitric oxide, 77nitric oxide synthase, 77norepinephrine, 75, 190Norpramin® (desipramine), 116Novum Organum, or New

Method (Bacon), 15nucleus accumbens, 37, 114

Ooleanolic acid, 99-1011,8-cineole, 126-127open-label clinical trials, 49opium, 20-21opium poppy, 190orientin, 164-167oxygen radicals, 185

PPAF (platelet-activating

factor), 63paleopallium, 37Papaver somniferum, 11, 20,

70, 190Papaveraceae, 43Paracelsus, 14, 20Parkinson’s disease, 39Passiflora incarnata (passion

flower)adverse effects, 173botany, 162-163constituents, 164-165historical use of, 161-162pharmacodynamics, 168-172pharmacokinetics, 166-168pharmcological perspective,


Passiflora lutea, 162Passifloraceae, 162passion flower (Passiflora

incarnata)adverse effects, 173botany, 162-163constituents, 164-165historical use of, 161-162pharmacodynamics, 168-172pharmacokinetics, 166-168pharmcological perspective,


passive diffusion, 25Pen Ts’ao Kang Mu (Li Shih-

Chen), 54Peonia, 11peptides, 158Periodic Table of Elements,

development of, 16, 20pharmacodynamics

challenges of assessing herbalsupplements, 27-28




development of, 22-23drug receptors, discovery of,

22-24explained, 21-24of ginkgo (Ginkgo biloba), 61-65of kava (Piper methysticum),



angustiolia), 129-134

index 249

of lemon balm (Melissaofficinalis), 102-105

of passion flower (Passifloraincarnata), 168-172

pharmacology checklist forherbal supplements, 28-32

of plant aklaloids, 192-193of St. John’s wort (Hypericum

perforatum), 75-80of tea (Camellia sinensis),

184-186of Valeriana officinalis

(Valerian), 90-93pharmacokinetics

bioavailability, 24-26challenges of assessing herbal

supplements, 27-28of cocoa (Theobroma cacao),

182, 184of coffee (Coffea arabica),

182-184of daffodil (Narcissus

pseudonarcissus), 154-155explained, 24-27of ginkgo (Ginkgo biloba), 59-61half-life, 26of kava (Piper methysticum),



angustiolia), 127-129of lemon balm (Melissa

officinalis), 100-102of passion flower (Passiflora

incarnata), 166-168of plant aklaloids, 192-193of tea (Camellia sinensis),

182-184

of Valeriana officinalis(Valerian), 88-90


of St. John’s wort (Hypericumperforatum), 74-75


phenobarbital, 43, 83phosphodiesterase, 184phytoestrogens, 141, 146Piper methysticum (kava)

adverse effects, 118-120botany, 110-111constituents, 112historical use of, 109-110pharmacodynamics, 114-117pharmacokinetics, 112-114pharmacological perspective,


Piper nigrum, 110Piper wickmanni, 110Piperaceae, 110pipermethystine, 118placebos, 51platelet-activating factor

(PAF), 63Pliny, 68, 97, 152Pliny the Elder, 3plus maze test, 92polyphenols, 181pons, 37postsynaptic neurons, 40prefrontal cortex, 37prehistoric evidence of herbal

supplement use, 2, 8presynaptic receptors, 40primary motor area (cerebral

cortex), 38

250 index

proteinsbeta amyloid, 47transporter proteins, 25-26

Prozac® (fluoxetine), 75, 116Psuedo-Apuleius, 13psychiatric disorders, therapeutic

use of ginkgo (Ginkgo biloba)for, 64

psychotherapeutics, challenges intesting, 50-51

Pueraria chinensis, 139Pueraria lobata (kudzu)



Pueraria montana, 139puerarin, 140-146purple passion flower. See

passion flower (Passifloraincarnata)

putamen, 38pyriform cortex, 37

Q-Rquercetin

in ginkgo standardized extract, 58

in St. John’s wort, 73, 77

receptors, discovery of, 22-24regulation of herbal

supplements, lack of, 18-19Rhazes, 14rivastigmine, 156

Rome, historical use of herbalsupplements, 3, 11-13

rosmarinic acid, 99-103rosuvastatin, interaction with

lemon balm (Melissaofficinalis), 101

Rubiaceae, 178

Ssalicin, purification of, 21salicylic acid, 21Salix spp., 21salts (alchemy), 15The Sceptical Chymist

(Boyle), 15schaftoside, 164-165sciatica, historical use of St.

John’s wort for, 70scopolamine-induced memory

impairment, 48Senecio, presence in

Neanderthal graves, 8sensory cortex, 38septum, 37serotonin, 36, 42-44, 75sertraline, 79Serturner, Freidrich, 20sesquiterpenes, 87-90Shen Nong Ben Cao Jing, 54side effects. See adverse effectsSideritis heraclea (ironwort), 13sigma receptors, 77silexan, 1326,7-epoxy-linalool, 128Solanaceae, 10spider lily (Lycoris), 153spike lavender (Lavandula

latifolia), 123-124spikenard (Nardostachys

jatamansi), 84

index 251

squill (Urgenia maritima), 13St. John’s wort (Hypericum

perforatum), 74-75adverse effects, 80-81botany, 69-70constituents, 71-74historical use of, 67-69pharmacodynamics, 75-80pharmacokinetics, 74pharmacological perspective,


St. Peter’s wort (Ascyrum), 70standardized extract of ginkgo

(Ginkgo biloba), 58Strychnos, 23substantia nigra, 38sulfurs (alchemy), 15swertisin, 164swertismarin, 165symptom scales, 50synapses, 36synaptic cleft, 36

Tt1/2 (half life), 26tacrine, 156tannins in St. John’s wort, 73tea (Camellia sinensis)



tectoridin, 144terpene trilactones in ginkgo

standardized extract, 58-60, 63-64

thalamus, 37-38Theobroma cacao (cocoa)



theobromine, 180-181adverse effects, 186-187pharmacodynamics, 184-186pharmacokinetics, 182-184pharmacological perspective,


Theophrastus, 9, 97, 151theophylline, 180-181

adverse effects, 186-187pharmacodynamics, 184-186pharmacokinetics, 182-184pharmacological perspective,


thiopental, 83Tincture of Opium, 20transient receptor potential

channels (TRPC), 76transmitters

acetylcholine, 44adenosine, 43dopamine, 44explained, 39-41GABA (γ-aminobutyric acid), 42

252 index

glutamic acid, 42neurotransmission, 40serotonin, 44

transporter proteins, 25-26trigonelline, 182triterpenes in lemon balm

(Melissa officinalis), 99TRPC (transient receptor

potential channels), 76

UUnited States Food and Drug

Administration. See FDA (Foodand Drug Administration)

United States NationalFormulary, 164

United States Pure Food andDrug Act, 17

Urgenia maritima (squill), 13ursolic acid, 99-101

Vvalepotriates, 87-90valerenic acid, 88-92Valerian (Valeriana officinalis)



valerian epoxy triesters, 87Valeriana, 11

Valeriana celtica (Frenchspikenard), 84

Valeriana ciliata, 85Valeriana officinalis (Valerian)



Valeriana pauciflora, 85Valeriana septentrionalis, 85Valeriana uliginosa, 85Valerianaceae, 84Valium® (diazepam), 43, 83vesicles, 40vestibular nuclei, 38vitexin, 164-166

W-X-Y-Zwild apricot. See passion flower

(Passiflora incarnata)willow bark extract, 21yangonin, 112-114yarrow (Achillea millefolium)

presence in Neanderthal graves,2, 8

use in Greco-Roman era, 3yellow passion flower (Passiflora

lutea), 162

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