ix Preface... v of Companion Volume... xxi PART I LEGAL/REGULATORY ASPECTS OF DIETARY SUPPLEMENTS Chapter 1: Legal/Regulatory Aspects of Dietary Supplements... 3 Melanie Johns Cupp 1.1 Summary... 11 PART II MONOGRAPHS Chapter 1: Androstenedione and Other Over-the-Counter Steroids... 17 Jason L. Duncan, Melanie Johns Cupp, and Timothy S. Tracy 1.1 History... 17 1.2 Chemical Structure... 17 1.3 Current Promoted Uses... 17 1.4 Sources and Chemical Composition... 18 1.5 Products Available... 18 1.6 Physiologic Role... 20 1.7 Clinical Studies... 20 1.8 Pharmacokinetics... 26 1.9 Adverse Effects and Toxicity... 27 1.10 Interactions... 27 1.11 Reproduction... 27 1.12 Chemical and Biofluid Analysis... 28 1.13 Regulatory Status... 29 1.14 Summary... 30 ix
x Chapter 2: Chitosan... 33 Kimberly Novak, Melanie Johns Cupp, and Timothy S. Tracy 2.1 History... 33 2.2 Chemical Structure... 33 2.3 Current Promoted Uses... 33 2.4 Sources and Chemical Composition... 33 2.5 Products Available... 34 2.6 Animal Data... 34 2.7 Clinical Studies... 35 2.8 Pharmacokinetics... 37 2.9 Adverse Effects and Toxicity... 37 2.10 Interactions... 37 2.11 Reproduction... 38 2.12 Chemical and Biofluid Analysis... 38 2.13 Regulatory Status... 39 2.14 Summary... 39 Chapter 3: Chromium Picolinate... 41 Aleshia R. Haslacker, Melanie Johns Cupp, and Timothy S. Tracy 3.1 History... 41 3.2 Chemical Structure... 41 3.3 Current Promoted Uses... 41 3.4 Sources and Chemical Composition... 41 3.5 Products Available... 42 3.6 Animal Data... 42 3.7 Clinical Studies... 42 3.7.1 Lipid Levels... 42 3.7.2 Body Composition and Strength... 43 3.7.3 Diabetes... 44 3.8 Pharmacokinetics... 45 3.9 Adverse Effects and Toxicity... 46 3.10 Interactions... 49 3.11 Reproduction... 49 3.12 Biofluid Analysis... 49 3.13 Regulatory Status... 50 3.14 Summary... 50 Chapter 4: Coenzyme Q10 (Ubiquinone, Ubidecarenone)... 53 Melanie Johns Cupp and Timothy S. Tracy 4.1 History... 53 4.2 Chemical Structure... 53 4.3 Current Promoted Uses... 53 4.4 Sources and Chemical Composition... 54
xi 4.5 Products Available... 54 4.6 Physiologic Role... 55 4.7 In Vitro Effects and Animal Data... 55 4.8 Clinical 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 Doxorubicin-Induced Cardiotoxicity... 64 4.8.6 Hyperlipidemia... 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 Function... 71 4.8.13 Primary Biliary Cirrhosis... 72 4.8.14 Immune Function... 73 4.8.15 Chronic Fatigue Syndrome... 73 4.8.16 Huntington s Disease... 74 4.8.17 Migraine... 74 4.9 Pharmacokinetics... 74 4.10 Adverse Effects and Toxicity... 76 4.11 Interactions... 77 4.12 Reproduction... 80 4.13 Chemical and Biofluid Analysis... 80 4.14 Regulatory Status... 81 4.15 Summary... 81 Chapter 5: Colloidal Silver... 87 Melanie Johns Cupp and Timothy S. Tracy 5.1 History... 87 5.2 Chemical Structure... 87 5.3 Current Promoted Uses... 87 5.4 Sources and Chemical Composition... 87 5.5 In Vitro Effects... 88 5.6 Clinical Data... 88 5.7 Adverse Effects and Toxicity... 88 5.8 Interactions... 88 5.9 Reproduction... 88 5.10 Chemical and Biofluid Analysis... 89 5.11 Regulatory Status... 89 5.12 Summary... 89
xii Chapter 6: Creatine Monohydrate... 91 Nancy Romanchak, Melanie Johns Cupp, and Timothy S. Tracy 6.1 History... 91 6.2 Chemical Structure... 92 6.3 Current 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 Inborn Errors 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 John Edward Pope, Melanie Johns Cupp, and Timothy S. Tracy 7.1 History... 123 7.2 Chemical Structure... 123 7.3 Current 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 7.9 Pharmacokinetics... 134 7.10 Adverse Effects and Toxicity... 138 7.11 Interactions... 141 7.12 Reproduction... 142 7.13 Chemical and Biofluid Analysis... 142 7.14 Regulatory Status... 143 7.15 Summary... 144
xiii Chapter 8: Dimethylglycine (N,N-Dimethylglycine)... 149 Melanie Johns Cupp and Timothy S. Tracy 8.1 History... 149 8.2 Chemical Structure... 149 8.3 Current Promoted Uses... 150 8.4 Sources and Chemical 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 Enhanced Athletic 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 Chemical and Biofluid Analysis... 158 8.13 Regulatory Status... 159 8.14 Summary... 159 Chapter 9: Fish Oil... 161 Laura Martin, Melanie Johns Cupp, and Timothy S. Tracy 9.1 History... 161 9.2 Chemical Structures... 161 9.3 Current Promoted Uses... 161 9.4 Sources and Chemical 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 9.8 Pharmacokinetics... 167 9.9 Adverse Effects and Toxicity... 167 9.10 Interactions... 168 9.11 Reproduction... 169 9.12 Chemical and Biofluid Analysis... 169 9.13 Regulatory Status... 170 9.14 Summary... 170
xiv Chapter 10: γ-hydroxybutyric Acid (GHB), γ-butyrolactone (GBL), and 1,4-Butanediol (BD)... 173 Betsy Meredith, Melanie Johns Cupp, and Timothy S. Tracy 10.1 History... 173 10.2 Chemical Structures... 174 10.3 Current Promoted Uses... 174 10.4 Sources and Chemical Composition... 174 10.5 Products Available... 174 10.6 In Vitro Effects and Animal Data... 176 10.7 Clinical Studies... 176 10.8 Pharmacokinetics... 177 10.9 Adverse Effects and Toxicity... 179 10.9.1 GHB... 179 10.9.2 GBL... 183 10.9.3 BD... 185 10.9.4 Carcinogenicity/Mutagenicity... 188 10.9.5 Pharmacologic Treatment... 188 10.10 Interactions... 189 10.11 Reproduction... 190 10.12 Chemical and Biofluid Analysis... 190 10.13 Regulation... 191 10.14 Summary... 192 Chapter 11: Germanium... 197 Thomas A. Chase, Melanie Johns Cupp, and Timothy S. Tracy 11.1 History... 197 11.2 Chemical Structure... 197 11.3 Current Promoted Uses... 197 11.4 Sources and Chemical Composition... 197 11.5 Products Available... 198 11.6 In Vitro Effects... 198 11.7 Clinical Studies... 199 11.8 Pharmacokinetics... 199 11.9 Adverse Effects and Toxicity... 199 11.10 Interactions... 204 11.11 Reproduction... 205 11.12 Chemical and Biofluid Analysis... 205 11.13 Regulatory Status... 206 11.14 Summary... 206 Chapter 12: Glucosamine and Chondroitin... 209 Melanie Johns Cupp and Timothy S. Tracy 12.1 History... 209 12.2 Chemical Structures... 209
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 Pharmacokinetics... 232 12.9 Adverse Effects and Toxicity... 236 12.9.1 Allergic 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 I. Jacknowitz and Timothy S. Tracy 13.1 History... 245 13.2 Chemical 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 Johns 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 14.6 In Vitro 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-Hydroxy-L-Tryptophan, L-5-Hyroxytryptophan, Ocitriptan)... 267 Kerry Bowers, Melanie Johns 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-Methoxytryptamine)... 277 Ann Sullivan, Melanie Johns Cupp, and Timothy S. Tracy 16.1 History... 277 16.2 Chemical Structure... 277 16.3 Current Promoted Uses... 277 16.4 Physiologic Role... 277 16.5 Products Available... 278 16.6 In Vitro and Animal Studies... 278 16.7 Clinical Studies... 279 16.7.1 Sleep... 279 16.7.2 Neurological 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
xvii 16.13 Regulatory Status... 292 16.14 Summary... 292 Chapter 17: Methylsulfonylmethane (Dimethylsulfone)... 297 Timothy S. Tracy and Melanie Johns Cupp 17.1 History... 297 17.2 Chemical Structure... 297 17.3 Current Promoted Uses... 297 17.4 Sources and Chemical Composition... 297 17.5 Products Available... 298 17.6 In Vitro Effects and Animal Studies... 298 17.7 Clinical Studies... 299 17.8 Pharmacokinetics... 299 17.9 Adverse Effects and Toxicity... 299 17.10 Interactions... 300 17.11 Reproduction... 300 17.12 Chemical and Biofluid Analysis... 300 17.13 Regulatory Status... 300 17.14 Summary... 301 Chapter 18: Pyruvate... 303 Melanie Johns Cupp and Timothy S. Tracy 18.1 History... 303 18.2 Chemical Structure... 303 18.3 Current Promoted Uses... 303 18.4 Products Available... 303 18.5 In Vitro Effects and Animal Studies... 304 18.6 Clinical Studies... 305 18.6.1 Weight Loss/Maintenance and Body Composition... 305 18.6.2 Antilipemic Effects... 307 18.6.3 Exercise... 307 18.6.4 Diabetes... 308 18.7 Pharmacokinetics... 309 18.8 Adverse Effects and Toxicity... 309 18.9 Interactions... 309 18.10 Reproduction... 309 18.11 Chemical and Biofluid Analysis... 310 18.12 Regulatory Status... 310 18.13 Summary... 310 Chapter 19: Red Yeast Rice Extract... 313 Tim Berry, Melanie Johns Cupp, and Timothy S. Tracy 19.1 History... 313 19.2 Chemical Structure... 313 19.3 Current Promoted Uses... 313
xviii 19.4 Sources and Chemical Composition... 313 19.5 Products Available... 315 19.6 In Vitro Effects and Animal Studies... 315 19.7 Clinical Studies... 316 19.8 Pharmacokinetics... 317 19.9 Adverse Effects and Toxicity... 318 19.10 Interactions... 318 19.11 Reproduction... 318 19.12 Chemical and Biofluid Analysis... 319 19.13 Regulatory Status... 319 19.14 Summary... 320 Chapter 20: SAMe (S-adenosyl-L-methionine)... 321 Michele Brula, Melanie Johns Cupp, and Timothy S. Tracy 20.1 History... 321 20.2 Chemical Structure... 321 20.3 Current Promoted Uses... 321 20.4 Sources and Chemical Composition... 321 20.5 Products Available... 322 20.6 Physiologic Role... 322 20.7 In Vitro Effects and Animal Data... 323 20.8 Clinical 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 Pharmacokinetics... 329 20.10 Adverse Effects... 329 20.11 Interactions... 330 20.12 Reproduction... 331 20.13 Chemical and Biofluid Analysis... 331 20.14 Regulatory Status... 332 20.15 Summary... 332 Chapter 21: Shark Cartilage... 335 Kerri J. Pettrey, Melanie Johns Cupp, and Timothy S. Tracy 21.1 History... 335 21.2 Chemical Structure... 335 21.3 Current Promoted Uses... 335 21.4 Sources and Chemical Composition... 335 21.5 Products Available... 336 21.6 In Vitro Effects and Animal Studies... 336 21.7 Clinical Studies... 337
xix 21.8 Pharmacokinetics... 338 21.9 Adverse Effects and Toxicity... 338 21.10 Interactions... 339 21.11 Reproduction... 339 21.12 Chemical and Biofluid Analysis... 339 21.13 Regulatory Status... 340 21.14 Summary... 340 Chapter 22: L-Tryptophan... 341 Beth McDermitt Knapp, Melanie Johns Cupp, and Timothy S. Tracy 22.1 History... 341 22.2 Chemical 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 Insomnia... 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 LD 50...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 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
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