Cannabis and Cannabinoids Pharmacology, Toxicology, and Therapeutic Potential

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1 Cannabis and Cannabinoids Pharmacology, Toxicology, and Therapeutic Potential Ethan Russo Editors The Haworth Integrative Healing Press An Imprint of The Haworth Press, Inc. New York London Oxford

2 _ CONTENTS About the Editors Contributors Foreword xv xvii xxi Leslie Iversen Preface Definitions and Explanations PART I: BOTANY, TAXONOMY, CHEMISTRY, AND HISTORY xxv xxvii Chapter 1. Botany of Natural Cannabis Medicines 3 Robert C. Clarke David Paul Watson Introduction 3 Natural Life Cycle 3 Agricultural Field Production 5 Vegetative Crop Production 6 Resin Gland Development 7 Cannabis Origins 8 Cannabis Taxonomy 10 Medical Cannabis Today 11 Medical Cannabis Tomorrow 11 Conclusion 12 Chapter 2. Taxonomy of Cannabinoids 15 David W. Pate Phytocannabinoids 15 Synthetic Analogues 16 Anandamide Congeners 19 Receptor Antagonists 22

3 Chapter 3. Chemical Constituents of Cannabis 27 MahmoudA. ElSohly Chemical Constituents 29 Conclusion 35 Chapter 4. History of Cannabis in Western Medicine 37 Manfred Fankhauser Cannabis Before the Birth of Christ 37 Cannabis in the Classical Era 38 Hashish in the Arabic World 39 Hemp in Central Europe 39 Cannabis in European Medicine of the Eighteenth Century 40 Cannabis in Nineteenth-Century Western Medicine 42 The Positive Trend Holds True : The Climax 46 Cannabis As a Medicine in the Twentieth Century 48 An Era Comes to an End 48 Conclusion 49 PART II: PHARMACOLOGY AND PHARMACOKINETICS Chapter 5. Effects of Cannabis and the Cannabinoids 55 Effects on Psyche and Behavior 56 Central Nervous System and Neurochemistry 58 Circulatory System 60 Other Organ Systems and Effects 60 Tolerance 62 Drug Interactions 62 Cannabinoid Interactions 62 Actions of Other Cannabinoids 63 Chapter 6. Pharmacokinetics 67 RudolfBrenneisen General 67 Absorption and Bioavailability 67

4 Distribution 68 Metabolism 69 Excretion 69 Plasma Levels versus Administration Route 70 Chapter 7. Sites and Mechanisms of Action 73 Roger G. Pertwee The Endogenous Cannabinoid System 73 Cannabinoid Receptor Ligands 76 Palmitylethanolamide 80 Inhibitors of Endogenous Cannabinoid Tissue Uptake or Metabolism 80 Other Types of Cannabinoid Receptors 81 Concluding Discussion 81 Chapter 8. Mechanisms of Cannabinoid Analgesia 89 Chris W. Vaughan MacDonald J. Christie Pharmacological Actions of Cannabis sativa 89 Do Cannabinoids Have Analgesic Activity? 89 An Endogenous Cannabinoid Pain Control System 90 Cannabinoids and Central Analgesic Pathways 91 Cellular Actions of Cannabinoids in Pain Pathways 93 Summary 95 Chapter 9. Cannabinoids As Neuroprotectants Against Ischemia 101 Aidan Hampson Introduction 101 Cannabinoids and Ischemia 102 Cannabinoid Receptors and Presynaptic Calcium Channels 102 Cannabinoid Receptors and Postsynaptic Calcium Channels 104 The Cannabinoid System As an Endogenous Regulator of Calcium Influx 105 Cannabinoids and NMDA Receptor Blockade 105 Oxidants and Ischemia 106 Cannabinoids As Neuroprotective Antioxidants 106

5 Chapter 10. Possible Mechanisms in Autoimmune Diseases 111 Robert Melamede PART III: INDICATIONS FOR CANNABIS AND THC Chapter 11. Review of Therapeutic Effects 123 Hierarchy of Therapeutic Effects 124 Indications 125 Surveys 132 Chapter 12. Medical Use of Cannabis: Experience in California 143 Dale Gieringer Effects of Proposition Usage Surveys 144 Chapter 13. Anorexia and Cachexia 153 Martin Schnelle Florian Strasser Anorexia and Cachexia in Cancer Patients 153 Mechanisms of Cancer Cachexia 154 Anorexia and Cachexia in AIDS Patients: Wasting Syndrome 154 Cannabis, A 9 -THC, and Cancer Cachexia/AIDS Wasting 158 Conclusion 161 Chapter 14. Antiemetic Effects of Cannabinoids 165 Terry Plasse Antiemetics in Clinical Use 166 Rationale for the Use of Cannabinoids As Antiemetics 166 Clinical Data 167 Current Role of Cannabinoids As Antiemetics 178

6 Chapter 15. Pain Therapy 181 Anita Holdcroft Pain Disorders and Their Treatments 181 Theoretical and Experimental Data 182 Clinical Trial Data and Case Histories 183 Summary 184 Chapter 16. Migraine 187 Ethan Russo Migraine and Its Symptoms 187 Standard Treatment of Migraine 187 Clinical History of Cannabis in Migraine Treatment 188 Theoretical and Experimental Data with THC Pertinent to Migraine 189 Value and Place of Cannabis in Migraine Treatment 190 Chapter 17. Spastic Disorders 195 Richard E. Musty Paul Consroe Introduction 195 Spasticity and Spastic Disorders 195 Marijuana and Cannabinoids in Spastic Disorders 196 A 9 -THC and Nabilone 197 Preclinical Effects of Cannabinoids 197 Chapter 18. Movement Disorders 205 Kirs ten R. Muller-Vahl Hans Kblbe Udo Schneider Hinderk M. Emrich Gilles de la Tourette Syndrome 206 Huntington's Disease and Other Choreic Disorders 207 Dystonia 208 Parkinson's Disease and Parkinsonian Syndromes 209 Tremor 210 Conclusions 211

7 Chapter 19. Glaucoma and Cannabinoids 215 David W. Pate Cannabinoids As Ocular Hypotensives 216 Mechanisms of Action 217 Chapter 20. Dependency and Cannabis 225 Tod H. Mikuriya Pre-Prohibition 225 Cannabis and Mood Disorders 226 Cannabis Substitution for More Harmful Nonmedical Drugs 226 Cannabis Use in Treatment of Psychological and Emotional Trauma 227 Drug Policy, Dependencies, and Cannabis 228 PART IV: RISKS AND SIDE EFFECTS Chapter 21. Review of Unwanted Actions of Cannabis and THC 233 Overall Toxicity 234 Acute Effects 234 Chronic Effects 235 Legal Consequences 241 Extrapolation of Animal Data to Humans 241 Comparison of Cannabis and Other Drugs 243 Chapter 22. Acute Effects of Cannabis and the Cannabinoids 249 F. Markus Leweke Acute Effects on the Central Nervous System 249 Effects of Cannabinoids on Peripheral Systems 252 Chapter 23. Cannabis and Dependence 257 Wendy Swift Wayne Hall Tolerance and Withdrawal 257 Cannabis Dependence 259 Tolerance, Dependence, and Therapeutic Cannabinoid Use 262

8 Chapter 24. Pregnancy 269 Peter A. Fried Impact on the Course of Pregnancy 270 Impact upon Growth and Neonatal and Infant Behavior 271 Impact Beyond Infancy 272 Impact upon Executive Function 273 Conclusion 275 Chapter 25. Immune System 279 GuyA.Cabral Immune System and Cannabinoid Receptors 279 Animal Studies 281 In Vitro Studies _, 282 Human Data with Cannabis/THC 283 Relevance for the Therapeutic Situation in Therapeutic Doses 284 Chapter 26. Hormonal System and Reproduction 289 Laura L. Murphy Reproductive Endocrine System 289 Stress Hormone Axis 292 Other Hormones 293 Chapter 27. Long-Term Effects of Cannabis on Psyche and Cognition 299 Nadia Solowij Brin F. S. Grenyer Effects on the Central Nervous System 299 Evidence from Animal Research 299 Evidence from Human Research 301 Relevance for Therapeutic Use of Cannabis 306 Chapter 28. Cannabis and Alcohol in Motor Vehicle Accidents 313 Gregory B. Chesher Marie Longo How Cannabis Pharmacokinetics Presents More Problems 316 Results of Culpability Studies 318 Conclusion 322

9 Chapter 29. Respiratory Risks from Marijuana Smoking 325 Donald P. Tashkin Introduction 325 Chronic Bronchitis and Emphysema 325 Respiratory Cancer 328 Respiratory Tract Infection 330 Other Potential Respiratory Complications of Marijuana Smoking 331 Monitoring for Respiratory and Infectious Complications of Medicinal Marijuana 332 Chapter 30. Contaminants and Adulterants in Herbal Cannabis 337 John M. McPartland Introduction 337 Natural Contaminants 337 Adulterants 340 Chapter 31. Practical Hints 345 Dosing 345 Restrictions on Use and Helpful Hints 346 Treatment of an Acute Overdose 347 Interactions 347 Cannabis or THC 349 Smoking or Eating 350 Storage 351 Cultivation 351 PART V: OTHER CANNABINOIDS Chapter 32. Overview of Cannabinoids Under Investigation 357

10 Chapter 33. Cannabidiol: Possible Therapeutic Application 359 Antonio W. Zuardi Francisco S. Guimardes Viviane M. C. Guimardes Elaine A. Del Bel Anxiolytic Properties of CBD 360 Antipsychotic Effect of CBD 361 Fos-hike Immunoreactivity Expression Induced by CBD 362 Conclusions 363 Chapter 34. Anandamides: Potential Glaucoma Medicine? 371 David W. Pate Cyclodextrin Structure and Function 372 Ocular Drug Delivery Barriers 373 Intraocular Pressure Studies 374 Mechanisms of Action 375 Conclusions 376 Chapter 35. Therapeutic Potential of Ajulemic Acid (CT3) 381 Sumner H. Burstein Background Stereospecificity Cannabinoid Acids Do Not Bind to CB, or CB 2 Anti-Inflammatory Effects of Ajulemic Acid Analgesic Effects of Ajulemic Acid Future Directions Chapter 36. HU-211: A Cannabinoid Neuroprotective Agent Raphael Mechoulam Ester Shohami Introduction In Vitro Effects of HU-211 In Vivo Effects of HU

11 Drug Development 395 Summary 396 PART VI: OTHER CONSTITUENTS OF CANNABIS Chapter 37. Noncannabinoid Components 401 John M. McPartland Vito Mediavilla Introduction 401 Terpenoids 401 Flavonoids 404 Conclusions 406 Chapter 38. Hemp Seed and Hemp Oil 411 Gero Leson Petra Pless Introduction 411 Composition of Hemp Oil 413 Nutritional and Therapeutic Benefits of Hemp Oil 418 Body Care 422 Resources 427 Index 429

Research on Cannabis and PD: Is there any evidence?

Research on Cannabis and PD: Is there any evidence? Benzi M. Kluger, MD, MS Associate Professor of Neurology and Psychiatry Director Movement Disorders Center University of Colorado Denver DISCLOSURES