Dietary Supplements - link.springer.com978-1-59259-303-3/1.pdf · DIETARY SUPPLEMENTS TOXICOLOGY and CLINICAL PHARMACOLOGY Edited by Melanie lohns Cupp, PharmO, BCPS and Timothy S

Dietary Supplements

FORENSIC SCIENCE AND MEDICINE

Steven B. Kareh, MD, SERIES EDITOR

DIETARY SUPPLEMENTS: TOXICOLOGY ANO CUNICAL PHARMACOLOGY, edited by Melanie lohns Cupp and Timothy S. Tracy, 2003

BUPRENOPHINE THERAPY OF OPIATE ADDICTION, edited by Pascal Kintz and Pierre Marquet, 2002

BENZODIAZEPINES AND GHB: DETECTION ANO PHARMACOLOGY, edited by Salvatore I. Salamone, 2002

ON-SITE DRUG TESTING, edited by Amanda I. lenkins and Bruce A. Goldberger, 2001

BRAIN IMAGING IN SUBSTANCE ABUSE: RESEARCH, CUNICAL, ANO FORENSIC ApPUCATlONS,

edited by Marc I. Kaufman, 2001

TOXICOLOGY AND CLiNICAL PHARMACOLOGY OF HERBAL PRODUCTS, edited by Melanie lohns Cupp, 2000

CRIMINAL POISONING: INVESTlGATlONAL GUIDE FOR LAW ENFORCEMENT, TOXICOLOGISTS,

FORENSIC SClENTlSTS, ANO ATTORNEYS, by lohn H. Trestrail, 111, 2000

A PHYSIClAN'S GUIDE TO CLiNICAL FORENSIC MEDICINE,

edited by Margaret M. Stark, 2000

DIETARY SUPPLEMENTS TOXICOLOGY and

CLINICAL PHARMACOLOGY

Edited by

Melanie lohns Cupp, PharmO, BCPS

and

Timothy S. Tracy, PhO

West Virginia University Morgantown, WV

SPRINGER SCIENCE+BUSINESS MEDIA, LLC

© Springer Science+Business Media New York 2003 Originally published by Humana Press Inc. in 2003 Softcover reprint ofthe hardcover 1st edition 2003 999 Riverview Drive. Suite 208 Totowa, New Jersey 07512

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Due diligence has been taken by the publishers, editors, and authors ofthis book to ensure the accuracy ofthe 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 in accord with the standards accepted at the time of publication. Notwithstanding, as new research, changes in government regulations, and knowledge from c1inical experiencerelating 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 für 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 health care provider to ascertain the Food and Drug Administration status of each drug or device used in their c1inical practice. The publisher, editors, and authors are not responsible for errors ar omissions or for any consequences from the application ofthe information presented in this book and make no warranty, express or implied, with respect to the contents in this publication.

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Library of Congress Cataloging-in-Publication Data

Dietary supplements: toxicology and c1inical pharmacology 1 edited by Melanie Johns Cupp and Timothy S. Tracy. p. ; cm.- (Forensie science and medicine)

Includes bibliographical references and index. ISBN 978-1-4684-9726-7 ISBN 978-1-59259-303-3 (eBook) DOI 10.1007/978-1-59259-303-3

1. Dietary supplements -Physiological effect. 2. Dietary supplements-Toxicology. 1. Cupp, Melanie Johns. H. Tracy, Timothy S. III. Series.

[DNLM: 1. Dietary Supplements, adverse effects. 2. Pharmacology, Clinical. QU 145.5 D5648 2003] RM258.5 .D545 2003 615'.I-dc21 2002027544

Preface

Sales of dietary supplements have skyrocketed over the past few years. Despite widespread interest in and use of these products, information about the safety and efficacy of dietary supplements in humans is generaIly sparse compared with the information available about prescription drugs. Herbalists and laypersons have used herbs for centuries, but most nonherbal dietary supplements came into vogue only within the past few decades, further limiting the information available about these products. The companion volume, Toxicology and Clinical Pharmacology 0/ HerbaI Products addressed herbai dietary supplements, whereas Dietary Supplements: Toxicology and Clinical Pharmacology focuses on nonherbal dietary supplements. Supplements were chosen for inclusion based on their popularity, toxicity, and the quantity and quality of information available. Some supplements described here are no longer available as dietary supplements (e.g., gammahydroxybutyric acid and related substances, L-tryptophan), but are available through various channels, either legal or illegal. Others are advertised as dietary supplements, although the Food and Drug Administration does not view them as such (e.g., hydrazine sulfate).

The aim of this book is to present, in both comprehensive and summary formats, objective information on nonherbal dietary supplements from the most reliable sources, with an emphasis on information not readily available elsewhere (i.e., detailed descriptions of case reports of adverse effects, pharmacokinetics, and chemical and biofluid analysis). It is not designed to be a prescriber's handbook; the intended audience is both forensic and health care professionals, particularly researchers and clinicians interested in more detailed information than is available in most "herbal" or "natural product" references.

Although information about dietary supplements is widely available on the Internet, it is usuaIly provided by product distributors and is designed to seIl products rather than provide objective information about product efficacy and toxicity. Even reviews of dietary supplements in journals, newsletters, books, and electronic databases can be biased or incorrect. In compiling information to be included in Dietary Supplements: Toxicology and Clinical Pharmacology, emphasis was placed on original studies published in reputable, peer-reviewed journals. Older studies as weIl as more current literature were utilized for completeness. Where appropriate, information was obtained from metaanalyses, systematic reviews, or other high-quality reviews such as those written by recognized experts. Case reports of adverse effects and interactions, although anecdotal

v

vi Preface

in nature, were used to identify and describe uncommon, but potentially serious, adverse events that may not have been noted in controlled studies because of small sampIe size or short duration. The detail in which studies in this section is described is a function of the popularity of the supplement, the extent to which study results conflict with each other and with advertised efficacy claims, the attention recent supplement studies have received in both lay and medical news, and other factors described in the text.

This volume begins with an updated discussion of the legal aspects of dietary supplements. Each of the following supplement monographs includes a review of the product's history, current promoted uses, sources and chemical composition, and descriptions of available products, which are kept general owing to the myriad of everchanging products on the market. Product quality is also discussed in this section. For those supplements that are endogenous to humans, the physiologic role is then described. The pharmacologic effects of the products, divided into in vitro/animal data and clinical studies, are reviewed. The in vitro/animal data included were chosen to provide an explanation for the product's clinical effects in humans and to show the rationale for clinical studies. 1t should be noted that because of the nature of dietary supplement claims (see Part I, LegallRegulatory Aspects), some promoted product uses might not have been studied in humans; conversely, known pharmacologic and therapeutic effects might not be promoted commercially. As a result, in most chapters there is amismatch between the information in the Current Promoted Uses and Clinical Studies sections.

The Pharmacokinetics section covers absorption, tissue distribution, elimination, and body fluid concentrations. Such pharmacokinetic information is not usually included in other sources and may be useful in forensic investigations, or in the clinical setting when the product is used in patients with renal or hepatic insufficiency. A section on Adverse Effects and Toxicity follows, which includes detailed information on case reports of adverse reactions to the supplement. The Interactions section discusses interactions between the supplement and drugs or foods, as weIl as the effects of drugs on endogenous levels of the supplement if it is an endogenous compound. The Reproduction section is generally limited, owing to lack of information. Methods of Chemical and Biofluid Analysis are included for forensic professionals and for those investigating the product in clinical studies. Each mono graph ends with a discussion of Regulatory Status of the product. The amount of information included in each of these sections varies according to availability.

At the end of each monograph is a summary presenting key information in bulleted form. A table at the end of the book summarizes supplement toxicities and adverse effects, drug interactions, and use in special populations (e.g., pregnancy and lactation, renal and hepatic impairment). The source ofthis information (animal data, in vitro effects, clinical trials, case reports, and theoretical concerns) are given. This section is intended for quick reference, and readers should refer to the chapter for more detailed discussion.

Adverse reactions to dietary supplements appear to be uncommon compared with those attributed to prescription drugs. This may be a function of health care and forensic professionals' unfamiliarity with a product's pharmacology and toxicology or assumption that a product is "natural" and therefore safe. Thus, an adverse reaction may go

Preface vii

unrecognized or be attributed to aprescription medication. It is hoped that the information in Dietary Supplements: Toxicology and Clinical Pharmacology will be used to solve c1inical or forensic problems involving dietary supplements, to promote dialog between health care professionals and patients, and to stimulate intellectual curiosity about these products, fostering further research on their therapeutic and adverse effects.

Melanie lohns Cupp

Contents

Preface ................................................................................................................ v

Contents of Companion Volume ...................................................................... xxi

PART I LEGALIREGULATORY ASPECTS OF DIETARY SUPPLEMENTS

Chapter 1: LegallRegulatory Aspects of Dietary Supplements .......................... 3 Melanie lohns Cupp

1.1 Summary ....................................................................................................... 11

PARTII~ONOGRAPHS

Chapter 1: Androstenedione and Other Over-the-Counter Steroids ................. 17 lason L. Duncan, Melanie lohns Cupp, and Timothy S. Tracy

1.1 History ........................................................................................................... 17 1.2 Chemieal Strueture ........................................................................................ 17 1.3 Current Promoted Uses ................................................................................. 17 1.4 Sourees and Chemieal Composition ............................................................. 18 1.5 Produets Available ......................................................................................... 18 1.6 Physiologie Role ........................................................................................... 20 1.7 Clinieal Studies ............................................................................................. 20 1.8 Pharmaeokineties .......................................................................................... 26 1.9 Adverse Effeets and Toxicity ........................................................................ 27 1.10 Interaetions .................................................................................................... 27 1.11 Reproduetion ................................................................................................. 27 1.12 Chemical and Biofluid Analysis .................................................................... 28 1.13 Regulatory Status .......................................................................................... 29 1.14 Summary ....................................................................................................... 30

ix

x Contents

Chapter 2: Chitosan .......................................................................................... 33 Kimberly Novak, Melanie lohns Cupp, and Timothy S. Tracy

2.1 History ........................................................................................................... 33 2.2 Chemical Structure ........................................................................................ 33 2.3 Current Promoted Uses ................................................................................. 33 2.4 Sources and Chemie al Composition ............................................................. 33 2.5 Produets Available ......................................................................................... 34 2.6 Animal Data .................................................................................................. 34 2.7 Clinieal Studies ............................................................................................. 35 2.8 Pharrnaeokineties .......................................................................................... 37 2.9 Adverse Effeets and Toxicity ........................................................................ 37 2.10 Interactions .................................................................................................... 37 2.11 Reproduetion ................................................................................................. 38 2.12 Chemieal and Biofluid Analysis .................................................................... 38 2.13 Regulatory Status .......................................................................................... 39 2.14 Summary ....................................................................................................... 39

Chapter 3: Chromium Picolinate ...................................................................... 41 Aleshia R. Haslacker, Melanie lohns Cupp, and Timothy S. Tracy

3.1 History ........................................................................................................... 41 3.2 Chemieal Strueture ........................................................................................ 41 3.3 Current Promoted Uses ................................................................................. 41 3.4 Sources and Chemieal Composition ............................................................. 41 3.5 Produets Available ......................................................................................... 42 3.6 Animal Data .................................................................................................. 42 3.7 Clinieal Studies ............................................................................................. 42

3.7.1 Lipid Levels .......................................................................................... 42 3.7.2 Body Composition and Strength .......................................................... 43 3.7.3 Diabetes ................................................................................................ 44

3.8 Pharmaeokineties .......................................................................................... 45 3.9 Adverse Effeets and Toxicity ........................................................................ 46 3.10 Interactions .................................................................................................... 49 3.11 Reproduetion ................................................................................................. 49 3.12 Biofluid Analysis ........................................................................................... 49 3.13 Regulatory Status .......................................................................................... 50 3.14 Summary ....................................................................................................... 50

Chapter 4: Coenzyme QlO (Ubiquinone, Ubidecarenone) ............................... 53 Melanie lohns Cupp and Timothy S. Tracy

4.1 History ........................................................................................................... 53 4.2 Chemieal Strueture ........................................................................................ 53 4.3 Current Promoted Uses ................................................................................. 53 4.4 Sources and Chemical Composition ............................................................. 54

Contents xi

4.5 Produets Available ......................................................................................... 54 4.6 Physiologie Role ........................................................................................... 55 4.7 In Vitro Effeets and Animal Data .................................................................. 55 4.8 Clinieal Studies ............................................................................................. 56

4.8.1 Heart Failure ...................................................................................... 57 4.8.2 Heart Surgery .................................................................................... 60 4.8.3 Hypertension ..................................................................................... 63 4.8.4 Cancer ................................................................................................ 64 4.8.5 Doxorubiein-Indueed Cardiotoxicity ................................................ 64 4.8.6 Hyperlipidernia .................................................................................. 65 4.8.7 Diabetes ............................................................................................. 66 4.8.8 Exercise Capacity .............................................................................. 66 4.8.9 Myopathies ........................................................................................ 68 4.8.10 Periodontal Disease ........................................................................... 71 4.8.11 Photoaging ......................................................................................... 71 4.8.12 Sperm Funetion ................................................................................. 71 4.8.l3 Primary Biliary Cirrhosis .................................................................. 72 4.8.14 Immune Funetion .............................................................................. 73 4.8.15 Chronic Fatigue Syndrome ................................................................ 73 4.8.16 Huntington's Disease ......................................................................... 74 4.8.17 Migraine ............................................................................................ 74

4.9 Pharmaeokineties .......................................................................................... 74 4.10 Adverse Effeets and Toxicity ........................................................................ 76 4.11 Interactions .................................................................................................... 77 4.12 Reproduetion ................................................................................................. 80 4.l3 Chemical and Biofluid Analysis .................................................................... 80 4.14 Regulatory Status .......................................................................................... 81 4.15 Summary ....................................................................................................... 81

Chapter 5: Colloidal Silver ............................................................................... 87 Melanie lohns Cupp and Timothy S. Tracy

5.1 History ........................................................................................................... 87 5.2 Chemieal Strueture ........................................................................................ 87 5.3 Current Promoted Uses ................................................................................. 87 5.4 Sources and Chemieal Composition ............................................................. 87 5.5 In Vitro Effeets .............................................................................................. 88 5.6 Clinieal Data .................................................................................................. 88 5.7 Adverse Effeets and Toxicity ........................................................................ 88 5.8 Interactions .................................................................................................... 88 5.9 Reproduetion ................................................................................................. 88 5.10 Chemieal and Biofluid Analysis .................................................................... 89 5.11 Regulatory Status .......................................................................................... 89 5.12 Summary ....................................................................................................... 89

xii Contents

Chapter 6: Creatine Monohydrate .................................................................... 91 Nancy Romanchak, Melanie lohns Cupp, and Timothy S. Tracy

6.1 History ........................................................................................................... 91 6.2 Chemical Structure ........................................................................................ 92 6.3 CUITent Promoted Uses ................................................................................. 92 6.4 Sources and Chemical Composition ............................................................. 92 6.5 Products Available ......................................................................................... 92 6.6 Physiologic Role ........................................................................................... 93 6.7 In Vitro Effects and Animal Data .................................................................. 93 6.8 Clinical Studies ............................................................................................. 96

6.8.1 Inbom EITors of Metabolism ............................................................. 96 6.8.2 Enhancement of Athletic Performance .............................................. 96 6.8.3 Cardiovascular Effects .................................................................... 104

6.9 Pharmacokinetics ........................................................................................ 106 6.10 Adverse Effects and Toxicity ...................................................................... 109 6.11 Interactions .................................................................................................. 113 6.12 Reproduction ............................................................................................... 114 6.13 Chemical and Biofluid Analysis .................................................................. 114 6.14 Regulatory Status ........................................................................................ 116 6.15 Summary ..................................................................................................... 116

Chapter 7: Dehydroepiandrosterone (DHEA) (Prasterone) ............................ 123 lohn Edward Pope, Melanie lohns Cupp, and Timothy S. Tracy

7.1 History ......................................................................................................... 123 7.2 Chemical Structure ...................................................................................... 123 7.3 CUITent Promoted Uses ............................................................................... 124 7.4 Sources and Chemical Composition ........................................................... 124 7.5 Products Available ....................................................................................... 124 7.6 Physiologic Effects ...................................................................................... 125 7.7 In Vitro Effects and Animal Data ................................................................ 126 7.8 Clinical Studies ........................................................................................... 126

7.8.1 Exercise Performance ...................................................................... 126 7.8.2 Systemic Lupus Erythematosus ...................................................... 127 7.8.3 Replacement in Aging ..................................................................... 130 7.8.4 Depression ....................................................................................... 133 7.8.5 HIV/AIDS ....................................................................................... 134 7.8.6 Other Clinical Studies ..................................................................... 134


Contents xiii

Chapter 8: Dimethylglycine (N,N-Dimethylglycine) ..................................... 149 Melanie lohns Cupp and Timothy S. Tracy

8.1 History ......................................................................................................... 149 8.2 Chemical Structure ...................................................................................... 149 8.3 Current Promoted Uses ............................................................................... 150 8.4 Sources and Chernical Composition ........................................................... 150 8.5 Products Available ....................................................................................... 150 8.6 Animal Data ................................................................................................ 150

8.6.1 Anticonvulsant Activity ................................................................... 150 8.6.2 Exercise Performance ...................................................................... 151 8.6.3 Immunomodulating Effects ............................................................. 151

8.7 Clinical Studies ........................................................................................... 152 8.7.1 EnhancedAth1etic Performance ...................................................... 152 8.7.2 Anticonvulsant Activity ................................................................... 153 8.7.3 Immunomodulating Effects ............................................................. 155 8.7.4 Autism ............................................................................................. 155

8.8 Pharmacokinetics ........................................................................................ 157 8.9 Adverse Effects and Toxicity ...................................................................... 157 8.10 Interactions .................................................................................................. 158 8.11 Reproduction ............................................................................................... 158 8.12 Chernical and Biofluid Analysis .................................................................. 158 8.13 Regulatory Status ........................................................................................ 159 8.14 Summary ..................................................................................................... 159

Chapter 9: Fish Oil ......................................................................................... 161 Laura Martin, Melanie lohns Cupp, and Timothy S. Tracy

9.1 History ......................................................................................................... 161 9.2 Chernical Structures .................................................................................... 161 9.3 Current Promoted Uses ............................................................................... 161 9.4 Sources and Chernical Compositions .......................................................... 161 9.5 Products Available ....................................................................................... 162 9.6 In Vitro Effects and Animal Data ................................................................ 163 9.7 Clinical Studies ........................................................................................... 163

9.7.1 Cardiovascular Indications .............................................................. 164 9.7.2 Diabetes ........................................................................................... 166 9.7.3 Psychiatric Indications .................................................................... 166 9.7.4 Other Uses ....................................................................................... 166


xiv Contents

Chapter 10: y-Hydroxybutyric Acid (GHB), y-Butyrolactone (GBL), and 1,4-Butanediol (BD) ................................................................................ 173

Betsy Meredith, Melanie lohns Cupp, and Timothy S. Tracy

10.1 History ......................................................................................................... 173 10.2 Chemie al Struetures .................................................................................... 174 10.3 Current Promoted Uses ............................................................................... 174 10.4 Sources and Chemical Composition ........................................................... 174 10.5 Produets Available ....................................................................................... 174 10.6 In Vitro Effeets and Animal Data ................................................................ 176 10.7 Clinieal Studies ........................................................................................... 176 10.8 Pharmaeokineties ........................................................................................ 177 10.9 Adverse Effeets and Toxicity ...................................................................... 179

10.9.1 GHB ................................................................................................ 179 10.9.2 GBL ................................................................................................. 183 10.9.3 BD ................................................................................................... 185 10.9.4 CareinogenicitylMutagenicity ......................................................... 188 10.9.5 Pharmaeologic Treatment ................................................................ 188

10.10 Interactions .................................................................................................. 189 10.11 Reproduetion ............................................................................................... 190 10.12 Chemieal and Biofluid Analysis .................................................................. 190 10.13 Regulation ................................................................................................... 191 10.14 Summary ..................................................................................................... 192

Chapter 11: Germanium ................................................................................. 197 Thomas A. Chase, Melanie lohns Cupp, and Timothy S. Tracy

11.1 History ......................................................................................................... 197 11.2 Chemie al Strueture ...................................................................................... 197 11.3 Current Promoted Uses ............................................................................... 197 11.4 Sources and Chemieal Composition ........................................................... 197 11.5 Produets Available ....................................................................................... 198 11.6 In Vitro Effeets ............................................................................................ 198 11.7 Clinieal Studies ........................................................................................... 199 11.8 Pharmaeokineties ........................................................................................ 199 11.9 Adverse Effeets and Toxicity ...................................................................... 199 11.10 Interactions .................................................................................................. 204 11.11 Reproduetion ............................................................................................... 205 11.12 Chemical and Biofluid Analysis .................................................................. 205 11.13 Regulatory Status ........................................................................................ 206 11.14 Summary ..................................................................................................... 206

Chapter 12: Glucosamine and Chondroitin .................................................... 209 Melanie lohns Cupp and Timothy S. Tracy

12.1 History ......................................................................................................... 209 12.2 Chemieal Struetures .................................................................................... 209

Contents xv

12.3 Current Promoted Uses ............................................................................... 209 12.4 Sources and Chemical Composition ........................................................... 209 12.5 Products Available ....................................................................................... 210 12.6 In Vitro Effects and Animal Data ................................................................ 212 12.7 Clinical Studies ........................................................................................... 213

12.7.1 Glucosamine vs Placebo for Osteoarthritis ..................................... 215 12.7.2 Glucosamine vs Ibuprofen for Osteoarthritis .................................. 220 12.7.3 Chondroitin Sulfate for Osteoarthritis ............................................. 224 12.7.4 Glucosamine and Chondroitin ......................................................... 229

12.8 Pharrnacokinetics ........................................................................................ 232 12.9 Adverse Effects and Toxicity ...................................................................... 236

12.9.1 Allergie Reactions ........................................................................... 236 12.9.2 Insulin Resistance ............................................................................ 237 12.9.3 Manganese Toxicity ........................................................................ 237

12.10 Interactions .................................................................................................. 238 12.11 Reproduction ............................................................................................... 238 12.12 Chemical and Biofluid Analysis .................................................................. 238 12.13 Regulatory Status ........................................................................................ 240 12.14 Summary ..................................................................................................... 240

Chapter 13: Huperzine .................................................................................... 245 Arthur l. lacknowitz and Timothy S. Tracy

13.1 History ......................................................................................................... 245 13.2 Chemie al Structure ...................................................................................... 245 13.3 Current Promoted Uses ............................................................................... 245 13.4 Sources and Clinical Composition .............................................................. 246 13.5 Products Available ....................................................................................... 246 13.6 In Vitro Effects and Animal Studies ............................................................ 246 13.7 Clinical Studies ........................................................................................... 248 13.8 Pharmacokinetics ........................................................................................ 249 13.9 Adverse Effects and Toxicity ...................................................................... 249 13.10 Interactions .................................................................................................. 250 13.11 Reproduction ............................................................................................... 250 13.12 Chemical and Biofluid Analysis .................................................................. 250 13.13 Regulatory Status ........................................................................................ 251 13.14 Summary ..................................................................................................... 251

Chapter 14: Hydrazine Sulfate ....................................................................... 253 Ona Dingess, Melanie lohns Cupp, and Timothy S. Tracy

14.1 History ......................................................................................................... 253 14.2 Chemical Structure ...................................................................................... 253 14.3 Current Promoted Uses ............................................................................... 253 14.4 Sources and Chemical Composition ........................................................... 254 14.5 Products Available ....................................................................................... 254

xvi Contents

14.6 In Vitra Effects and Animal Data ................................................................ 254 14.7 Clinical Studies ........................................................................................... 255 14.8 Pharmacokinetics ........................................................................................ 260 14.9 Adverse Effects and Toxicity ...................................................................... 260 14.10 Interactions .................................................................................................. 262 14.11 Reproduction ............................................................................................... 263 14.12 Chemical and Biofluid Analysis .................................................................. 264 14.13 Regulatory Status ........................................................................................ 264 14.14 Summary ..................................................................................................... 265

Chapter 15: 5-Hydroxytryptophan (5-HydraxY-L-Tryptophan, L-5-Hydroxytryptophan, Oxitriptan) .............................................................. 267

Kerry Bowers, Melanie lohns Cupp, and Timothy S. Tracy

15.1 History ......................................................................................................... 267 15.2 Chemical Structure ...................................................................................... 267 15.3 Current Promoted Uses ............................................................................... 267 15.4 Products Available ....................................................................................... 267 15.5 Sources and Chemical Composition ........................................................... 268 15.6 Clinical Studies ........................................................................................... 268 15.7 Pharmacokinetics ........................................................................................ 268 15.8 Adverse Effects and Toxicity ...................................................................... 269 15.9 Interactions .................................................................................................. 271 15.10 Reproduction ............................................................................................... 273 15.11 Chemical and Biofluid Analysis .................................................................. 273 15.12 Regulatory Status ........................................................................................ 274 15.13 Summary ..................................................................................................... 274

Chapter 16: Melatonin (N-acetyl-5-Methoxytryptarnine) .............................. 277 Ann Sullivan, Melanie lohns Cupp, and Timothy S. Tracy

16.1 History ......................................................................................................... 277 16.2 Chemical Structure ...................................................................................... 277 16.3 Current Pramoted Uses ............................................................................... 277 16.4 Physiologic Role ......................................................................................... 277 16.5 Products Available ....................................................................................... 278 16.6 In Vitra and Animal Studies ........................................................................ 278 16.7 Clinical Studies ........................................................................................... 279

16.7.1 Sleep ................................................................................................ 279 16.7.2 Neuralogical Disease ....................................................................... 283 16.7.3 Cancer .............................................................................................. 283 16.7.4 Other Uses ....................................................................................... 286

16.8 Pharmacokinetics ........................................................................................ 286 16.9 Adverse Effects and Toxicity ...................................................................... 287 16.10 Interactions .................................................................................................. 289 16.11 Reproduction ............................................................................................... 291 16.12 Chemical and Biofluid Analysis .................................................................. 291

Contents xvii

16.13 Regulatory Status ........................................................................................ 292 16.14 Summary ..................................................................................................... 292

Chapter 17: Methylsulfonylmethane (Dimethylsulfone) ................................ 297 Timothy S. Tracy and Melanie lohns Cupp

17.1 History ......................................................................................................... 297 17.2 Chemieal Strueture ...................................................................................... 297 17.3 Current Promoted U ses ............................................................................... 297 17.4 Sources and Chemieal Composition ........................................................... 297 17.5 Produets Available ....................................................................................... 298 17.6 In Vitro Effeets and Animal Studies ............................................................ 298 17.7 Clinieal Studies ........................................................................................... 299 17.8 Pharmaeokineties ........................................................................................ 299 17.9 Adverse Effeets and Toxieity ...................................................................... 299 17.10 Interactions .................................................................................................. 300 17.11 Reproduetion ............................................................................................... 300 17.12 Chemie al and Biofluid Analysis .................................................................. 300 17.13 Regulatory Status ........................................................................................ 300 17.14 Summary ..................................................................................................... 301

Chapter 18: Pyruvate ...................................................................................... 303 Melanie lohns Cupp and Timothy S. Tracy

18.1 History ......................................................................................................... 303 18.2 Chemieal Strueture ...................................................................................... 303 18.3 Current Promoted Uses ............................................................................... 303 18.4 Produets Available ....................................................................................... 303 18.5 In Vitro Effeets and Animal Studies ............................................................ 304 18.6 Clinieal Studies ........................................................................................... 305

18.6.1 Weight LosslMaintenanee and Body Composition ......................... 305 18.6.2 Antilipemic Effeets ......................................................................... 307 18.6.3 Exereise ........................................................................................... 307 18.6.4 Diabetes ........................................................................................... 308

18.7 Pharmaeokineties ........................................................................................ 309 18.8 Adverse Effeets and Toxicity ...................................................................... 309 18.9 Interactions .................................................................................................. 309 18.10 Reproduetion ............................................................................................... 309 18.11 Chemie al and Biofluid Analysis .................................................................. 310 18.12 Regulatory Status ........................................................................................ 310 18.13 Summary ..................................................................................................... 310

Chapter 19: Red Yeast Rice Extract.. .............................................................. 313 Tim Berry, Melanie lohns Cupp, and Timothy S. Tracy

19.1 History ......................................................................................................... 313 19.2 Chemieal Strueture ...................................................................................... 313 19.3 Current Promoted Uses ............................................................................... 313

XVIII Contents

19.4 Sourees and Chemie al Composition ........................................................... 313 19.5 Produets Available ....................................................................................... 315 19.6 In Vitro Effeets and Animal Studies ............................................................ 315 19.7 Clinieal Studies ........................................................................................... 316 19.8 Pharmaeokineties ........................................................................................ 317 19.9 Adverse Effeets and Toxieity ...................................................................... 318 19.10 Interaetions .................................................................................................. 318 19.11 Reproduetion ............................................................................................... 318 19.12 Chemie al and Biofluid Analysis ................................................................... 319 19.13 Regulatory Status ........................................................................................ 319 19.14 Summary ..................................................................................................... 320

Chapter 20: SAMe (S-adenosyl-L-methionine) .............................................. 321 Micheie Brula, Melanie lohns Cupp, and Timothy S. Tracy

20.1 History ......................................................................................................... 321 20.2 Chemieal Strueture ...................................................................................... 321 20.3 Current Promoted Uses ............................................................................... 321 20.4 Sourees and Chemie al Composition ........................................................... 321 20.5 Produets Available ....................................................................................... 322 20.6 Physiologie Role ......................................................................................... 322 20.7 In Vitro Effeets and Animal Data ................................................................ 323 20.8 Clinieal Studies ........................................................................................... 323

20.8.1 Depression ....................................................................................... 323 20.8.2 Alzheimer's Disease ........................................................................ 325 20.8.3 Fibromyalgia ................................................................................... 326 20.8.4 Osteoarthritis ................................................................................... 327 20.8.5 Liver Disease ................................................................................... 328

20.9 Pharmaeokineties ........................................................................................ 329 20.10 Adverse Effeets ........................................................................................... 329 20.11 Interaetions .................................................................................................. 330 20.12 Reproduetion ............................................................................................... 331 20.13 Chemical and Biofluid Analysis .................................................................. 331 20.14 Regulatory Status ........................................................................................ 332 20.15 Summary ..................................................................................................... 332

Chapter 21: Shark Cartilage ........................................................................... 335 Kerri l. Pettrey, Melanie lohns Cupp, and Timothy S. Tracy

21.1 History ......................................................................................................... 335 21.2 Chemie al Strueture ...................................................................................... 335 21.3 Current Promoted Uses ............................................................................... 335 21.4 Sourees and Chemieal Composition ........................................................... 335 21.5 Produets Available ....................................................................................... 336 21.6 In Vitro Effeets and Animal Studies ............................................................ 336 21.7 Clinieal Studies ........................................................................................... 337

Contents xix

21.8 Pharmacokinetics ........................................................................................ 338 21.9 Adverse Effects and Toxicity ...................................................................... 338 21.10 Interactions .................................................................................................. 339 21.11 Reproduction ............................................................................................... 339 21.12 Chernical and Biofluid Analysis .................................................................. 339 21.13 Regulatory Status ........................................................................................ 340 21.14 Summary ..................................................................................................... 340

Chapter 22: L-Tryptophan ............................................................................... 341 Beth McDermitt Knapp, Melanie lohns Cupp, and Timothy S. Tracy

22.1 History ......................................................................................................... 341 22.2 Chernical Structure ...................................................................................... 341 22.3 Current Promoted Uses ............................................................................... 341 22.4 Sources and Chemical Composition ........................................................... 341 22.5 Products Available ....................................................................................... 342 22.6 In Vitro Effects and Animal Studies ............................................................ 342 22.7 Clinical Studies ........................................................................................... 343

22.7.1 Premenstrual Dysphoric Disorder ................................................... 343 22.7.2 Seasonal Affective Disorder ............................................................ 343 22.7.3 Smoking Cessation .......................................................................... 344 22.7.4 Depression (Unipolar and Bipolar) ................................................. 345 22.7.5 Insornnia .......................................................................................... 354 22.7.6 Pain .................................................................................................. 354 22.7.7 Fatigue ............................................................................................. 356

22.8 Pharmacokinetics ........................................................................................ 357 22.9 Adverse Effects and Toxicity ...................................................................... 359

22.9.1 Adverse Effects Noted in Clinical Trials ......................................... 359 22.9.2 LDso ........................................................................................................................................................................ 360 22.9.3 Eosinophilia-Myalgia Syndrome ..................................................... 361 22.9.4 Sexual Dysfunction ......................................................................... 369 22.9.5 Pregnancy ........................................................................................ 370 22.9.6 Carcinogenesis ................................................................................ 370 22.9.7 Bladder Tumors ............................................................................... 371

22.10 Interactions .................................................................................................. 373 22.11 Reproduction ............................................................................................... 377 22.12 Chemical and Biofluid Analysis .................................................................. 378 22.13 Regulatory Status ........................................................................................ 379 22.14 Summary ..................................................................................................... 380

Chapter 23: Vanadyl Sulfate ........................................................................... 387 Timothy S. Tracy

23.1 History ......................................................................................................... 387 23.2 Chemical Structure ...................................................................................... 387 23.3 Current Promoted Uses ............................................................................... 387

xx Contents

23.4 Products Available ....................................................................................... 388 23.5 Animal Studies ............................................................................................ 388 23.6 Clinical Studies ........................................................................................... 388 23.7 Pharmacokinetics ........................................................................................ 390 23.8 Adverse Effects and Toxicity ...................................................................... 390 23.9 Interactions .................................................................................................. 391 23.10 Reproduction ............................................................................................... 391 23.11 Biofluid Analysis ......................................................................................... 391 23.12 Regulatory Status ........................................................................................ 392 23.13 Summary ..................................................................................................... 392

Appendix: Summary Table on Dietary Supplements ..................................... 395

Index ............................................................................................................... 401

CONTENTS OF THE COMPANION VOLUME

Toxicology and Clinical Pharmacology 01 Herbai Products

PART I LEGALIREGULATORY ASPECTS OF HERB AL PRODUCTS

Chapter 1: Legal/Regulatory Aspeets of HerbaI Produets Melanie lohns Cupp

PARTII~ONOGRAPHS

Chapter 1: Ma Huang and the Ephedra Alkaloids Steven B. Karch

Chapter 2: Kava Shawn Reeder and Melanie lohns Cupp

Chapter 3: Ginkgo biloba Forouzandeh Mahdavi and Melanie lohns Cupp

Chapter 4: Valerian Marlea Givens and Melanie lohns Cupp

Chapter 5: St. lohn's Wort lohn T. Schwarz and Melanie lohns Cupp

Chapter 6: Chamomile Melanie lohns Cupp

Chapter 7: Eehinaeea lulie Davis and Melanie lohns Cupp

Chapter 8: Feverfew Brian Schuller and Melanie lohns Cupp

Chapter 9: Garlie lames Allman and Melanie lohns Cupp

xxi

xxii Contents of the Companion Vo/ume

Chapter 10: Ginger Charity Metz and Melanie lohns Cupp

Chapter 11: Saw Pairnetto Amy Meadows and Melanie lohns Cupp

Chapter 12: Panax Ginseng Angela Morgan and Melanie lohns Cupp

Chapter 13: Cranberry Angela 1. Lawson and Melanie lohns Cupp

Chapter 14: Borage Melanie lohns Cupp

Chapter 15: Calamus Melanie lohns Cupp

Chapter 16: Chaparral Kim Melgarejo and Melanie lohns Cupp

Chapter 17: Coltsfoot Amanda Dailey and Melanie lohns Cupp

Chapter 18: Comfrey David Burch and Melanie lohns Cupp

Chapter 19: Scullcap lennijer Schumacher and Melanie lohns Cupp

Chapter 20: Licorice Michael Newton and Melanie lohns Cupp

Chapter 21: Pokeweed Heather Knight-Trent and Melanie lohns Cupp

Chapter 22: Sassafras David Hutson and Melanie lohns Cupp

Chapter 23: Hawthom lennijer Annon and Melanie lohns Cupp

Chapter 24: Aloe Tara Dalton and Melanie lohns Cupp

Contents of the Cornpanion Vo/urne

Chapter 25: Senna Melanie lohns Cupp

Chapter 26: Cascara Sagrada Amy Renner and Melanie lohns Cupp

Chapter 27: Dong Quai Rayna De Rosa and Melanie lohns Cupp

Chapter 28: Cat's Claw Melissa Dawn Bostic and Melanie lohns Cupp

PART III SUMMARY OF TOXICITIES AND DRUG INTERACTIONS

Chapter 1: Summary of Toxicities and Drug Interactions Melanie lohns Cupp

xxiii

Documents

Dietary Supplements - link.springer.com978-1-59259-303-3/1.pdf · DIETARY SUPPLEMENTS TOXICOLOGY and CLINICAL PHARMACOLOGY Edited by Melanie lohns Cupp, PharmO, BCPS and Timothy S