Cannabinoids as Therapeutics (eBook)

Contents 6
List of contributors 8
Preface 10
Cannabis in India: ancient lore and modern medicine 12
Introduction: Ayurvedic medicine 12
Cannabis: its history in the medicine of India 13
A nexus with Western medicine 17
Politics and cannabis collide 20
Cannabis in contemporary Ayurvedic medicine 22
The scientific basis of Indian cannabis claims 23
Cannabis in India in context 27
References 28
Cannabinoid chemistry: an overview 34
Introduction 34
Natural cannabinoids 34
Endogenous cannabinoids 36
Synthetic cannabinoid receptors agonists/antagonists 38
1 47
2, 47
3 48
4 48
5 48
6 49
7 49
8 49
9 49
8 50
9 50
10 50
11) 50
12) 50
Conclusions 51
References 52
Cannabidiol as a potential medicine 58
Introduction 58
Epilepsy 59
Other central motor disorders 63
Anxiety 63
Psychotic illnesses 64
Neurotoxicity 65
Inflammation 66
Other potential therapeutic targets 68
Concluding discussion 70
References 71
Endocannabinoids and regulation of fertility 77
Introduction 77
Endocannabinoid degradation during pregnancy 78
FAAH and human reproduction 82
FAAH and the regulation of spermatogenesis 84
Conclusions and perspectives 85
References 86
Cannabinoids in neurodegeneration and neuroprotection 89
Introduction 89
Mechanisms involved in neuroprotection by cannabinoids 91
Cannabinoids in acute neurodegeneration 98
Cannabinoids in chronic neurodegeneration 100
Concluding remarks and future perspectives 110
References 111
Role of the endocannabinoid system in learning and memory 120
Introduction 120
Behavioral effects of cannabinoid agonists in learning paradigms 120
Endocannabinoid modulation of cognitive processes 128
Neuroanatomical locus of effects 133
Cellular effects/interactions with other transmitter systems 135
Role of endocannabinoids in synaptic plasticity 137
Conclusions on the effects of endocannabinoids on cognition 140
References 141
Cannabinoids and anxiety 150
Introduction 150
Anxiolytic effects of CB1 receptor antagonists 150
Cannabinoid receptor agonists 151
CB1 receptor- knockout studies 152
Anandamide hydrolysis and anxiety 152
Discussion of animal studies 152
Human studies 153
Discussion 155
References 155
Cannabinoid targets for pain therapeutics 157
Introduction 157
Effects of direct-acting cannabinoid receptor agonists 158
Brain action of cannabinoid agonists 158
Spinal action of cannabinoid agonists 159
Peripheral action of cannabinoid agonists 159
Effects of cannabinoid CB2- specific agonists 160
Effects of cannabinoid agonists in humans 160
Development of non-psychotropic cannabinoids 163
Development of inhibitors of FAAH 164
Development of inhibitors of cellular transport of endogenous cannabinoids 165
Synergism between cannabinoid and opioid agonists 165
Summary and conclusions 166
References 166
Potential use of cannabimimetics in the treatment of cancer 173
Introduction 173
Cannabinoid receptor stimulation causes inhibition of cancer growth through multiple intracellular mechanisms and pathways 175
Cannabinoid receptor stimulation leads to inhibition of tumor angiogenesis and metastasis 178
The endocannabinoid system attempts to provide protection from the growth and spread of cancer 179
Non- CB1/-CB2 receptors are also involved in ( endo) cannabinoid anti- tumor actions 180
Substances targeting the endocannabinoid system in cancer therapy – pros and cons 182
References 184
Cannabinoids: effects on vomiting and nausea in animal models 190
Introduction 190
Cannabinoids as anti-emetics 191
Anti-emetic effects of cannabinoids in human clinical trials 192
Effects of cannabinoids on emesis in animals 193
Conditioned gaping in shrews: a model for ANV 198
Conditioned gaping in rats: a model of nausea 199
Conclusions 202
References 203
The skeleton: stone bones and stoned heads? 208
Introduction 208
Strategy 209
Expression of cannabinoid receptors in bone 209
Cannabinoid ligands regulate bone cell differentiation and activity 210
Cannabinoid receptor signalling regulates bone mass 210
Summary 210
References 211
Cannabinoids and drugs of abuse 214
Introduction 214
Tolerance 215
Physical dependence 216
Behavioral sensitization 216
Drug discrimination 217
Self-administration 218
Conditioned place preference 219
Neurochemical correlates of cannabinoid rewarding properties 219
Cannabinoid system and drug addiction 220
References 222
Cannabinoids in appetite and obesity 226
Introduction 226
Cannabinoid agonists and appetite 226
Cannabinoid antagonists and obesity 228
1) 230
Mechanism of action of cannabinoid ligands on food intake and energy balance 231
Conclusion 233
References 234
The development of Sativex – a natural cannabis-based medicine 238
History of the development 238
The endogenous cannabinoid system 240
Cannabinoid receptor ligands 241
Classification of cannabinoids 241
Production of cannabis-based medicines 242
Rationale for the development of a cannabis-based medicine as a whole- plant extract 242
Regulatory requirements 243
Breeding of cannabis plants for generation of cannabis extracts 244
Cultivation of chemovars for generation of cannabis extracts 246
BDS content 248
Characterization, control and specification of BDS 250
Finished product – BDP: formulation and filling 251
Administration of Sativex 251
achieving the therapeutic window 251
Clinical effects of Sativex 252
Clinical programme results 254
Phase II data 254
Phase III data 254
Neuropathic pain in MS 256
Neuropathic pain in brachial plexus avulsion 258
Symptoms of MS 259
Effect on sleep 260
What do patients want? 261
Long-term data 262
Safety 262
Intoxication 263
Dosing 265
Conclusion 266
References 267
Index 271