We're all familiar with the idea that plant-derived chemicals can have an impact on the functioning of the human brain. Most of us reach for a cup of coffee or tea in the morning, many of us occasionally eat some chocolate, some smoke a cigarette or take an herbal supplement, and some people use illicit drugs. We know a great deal about the mechanisms by which the psychoactive components of these various products have their effects on human brain function, but the question of why they have these effects has been almost totally ignored. This book sets out to describe not only how, but more importantly why, plant- and fungus-derived chemicals have their effects on the human brain. The answer to this last question resides, in part, with the terrestrial world's two dominant life forms, the plants and the insects, and the many ecological roles the 'secondary metabolite' plant chemicals are trying to play; for instance, defending the plant against insect herbivores whilst attracting insect pollinators. The answer also resides in the intersecting genetic heritage of mammals, plants, and insects and the surprising biological similarities between the three taxa. In particular it revolves around the close correspondence between the brains of insects and humans, and the intercellular signaling pathways shared by plants and humans. Plants and the Human Brain describes and discusses both how and why phytochemicals affect brain function with respect to the three main groups of secondary metabolites: the alkaloids, which provide us with a host of poisons, a handful of hallucinogens, and most drugs of abuse (e.g. morphine, cocaine and nicotine); the phenolics, which constitute a significant and beneficial part of our natural diet; and the terpenes, a group of multifunctional compounds which provide us with the active components of cannabis and a multitude of herbal extracts.

1 From Shamans to Starbucks 3

A Brief History of Psychoactive Plants and Fungi 6

Antiquity 6

Middle Ages (5th to 15th Centuries) 10

Renaissance and the Age of Discovery 11

The Modern Era 19

What Does It All Mean? 23

2 Secondary Metabolites and the Life of Plants 24

The Evolution of Plants and Insects 25

The Evolution of the Synthesis of Secondary Metabolites 28

The Co-evolution of Secondary Metabolites and Insects 31

The Role of Secondary Metabolites in the Life of Plants 34

Defense Against Herbivory 35

Attraction 36

Plant-Microbe Symbiotic Chemical Interactions 39

Plant- Plant Chemical Interactions 39

Defense Against Microbes and Other Stressors 41

A Word About Secondary Metabolite Synthetic Pathways 41

Summary 43

3 More Alike Than We Are Unalike-Why Do Plant Chemicals Affect the Human Brain? 44

The Similarities Between Plants and Animals 45

Receptors and Signaling Cascades 45

Mammalian Neurotransmitters, Neurochemicals,and Receptors? 47

Plant Secondary Metabolites? 51

Immune and Stress Responses 52

Molecular Clocks 54

Similarities in the Insect and Human Central Nervous Systems 55

Neurochemicals and Receptors 56

Insect Models of Human Systems and Behavior 59

Why Do Plant Secondary Metabolites Affect Human Brain Function? 60

4 Alkaloids and the Lives of Plants and Humans 65

Structures and Synthesis 66

I Evolution of Alkaloid Synthesis 67

Ecological Roles of Alkaloids 69

Defense Against Herbivory 69

Antimicrobial Properties 71

Allelopathic Properties 71

Modes of Action 72

Modes of Action Related to Brain Function 72

Alkaloids Derived from L-phenylalanine/L-tyrosine 73

Alkaloids Derived from L-tryptophan 75

Alkaloids Derived from Purine 77

Alkaloids with Activity Unrelated to Common Precursors 78

Alkaloids as Neuropharmacological Probes 79

Alkaloids and the Insect Nervous System 80

Some Conclusions 85

5 The Rewarding or AddJctive Drugs 86

Morphine 87

Ecological Roles of Opiates and Brain Function 90

The Psychostimulants (Cocaine, Ephedrine, Cathinone,Amphetamine, Methamphetamine) 90

Cocaine 92

Ephedrine 93

Amphetamine/Methamphetarnine 94

Cathinone 95

Ecological Roles of Psychostimulant Secondary Metabolites and Brain Function 96

Caffeine 97

Ecological Roles of Caffeine and Brain Function 100

The Paradox of Drug Reward 101

6 The Hallucinogens 104

A Common Mechanism of Action? 105

Ecological Roles of Hallucinogens-Some General Observations 107

The Phenethylarnines 108

Mescaline (3,4,5-Trimethoxy-phenethylarnine) 108

Ergot Alkaloids: Lysergic Acid Derivatives 111

Lysergic Acid Diethylamide (LSD) 112

Lysergic Acid Amide 113

Ecological Roles of Ergot Alkaloids and Brain Function 115

Simple Tryptarnines 116

Psilocybin/Psilocin 116

Dimethyltryptamine and Derivatives 119

Ibogaine 122

Ecological Roles of Simple Tryptamines and Brain Function 123

The Deliriants-The Nightshade (Solanaceae) Family 125

Nicotine 126

Ecological Roles of Nicotine and Brain Function 129

Hyoscyarnine, Scopolamine, and Atropine 131

Ecological Roles of the Tropane Alkaloids and Brain Function 136

The antidote to Hyoscyamine, Scopolamine, and Atropine:The Cholinesterase Inhibitors 137

8 Phenolics and the Lives of Plants and Animals 143

Phenolics in the Life of Plants-Ecological Roles 146

Phenolics in the Life of Humans 149

What Have the Plants Ever Done for Us?-Vitamins 153

Why Do Polyphenols Have Beneficial Effects on Human Brain Function? 156

Similarities in Hormonal Stress Signaling Between Plants and Animals 156

The Plant Signaling Roles of Polyphenols 158

Cross-Kingdom Signaling Between Plants and Humans by Polyphenols and Other Phenolics 160

What Relevance Does This Have to the Effects of Polyphenols on Human Brain Function? 164

Some Conclusions 166

9 Phenolics and the Human Brain 168

Mechanisms of Action- Flavonoids 168

Cognitive Function 168

Neuroinflarnmation and Neuroprotection 170

Flavonoids, Other Polyphenols, and Human Brain Function 171

Flavanols 171

Anthocyanins 175

lsoflavones (and Other) Phytoestrogens 176

Non-flavonoid Polyphenols 179

Resveratrol 179

Curcumin 181

Phenolic Acids 181

Atypical Phenolics 182

Kavalactones (from Piper methysticum) 182

Hypericum perforntum (St. John's Wort) 183

Intervention Studies with Phenolics: Some Conclusions 184

The Ecological (or Primary) Roles of Phenolics and the Human Brain 185

Unintentional Cross-Kingdom Signaling? 185

Unintended Targets of Intentional Cross-Kingdom Signaling? 186

And Finally, a Few More Conclusions 189

10 Terpenes and the Lives of Plants and Animals 193

Terpenes and the Lives of Plants:-Ecological Roles 195

Defense 195

Attraction 200

Terpenes and the Lives of Humans 203

Terpenes and Human Brain Function 205

Some Conclusions 209

11 The Lamiaceae Subtribe Salviinae-The Sa.lvia, Rosmarin us,and Melissa Genera 210

The Salvia genus: Sage 212

European Sage: Salvia officinalis and Salvia lavandulaefolia 212

Salvia divinorum 214

Some Other Salvia Species 218

Melissa officinalis (Lemon Balm) 219

Rosmarinus officinalis 221

Ecological Roles of the Salviinae Terpenes and Brain Function 223

Some Conclusions 225

12 Cannabis and the Cannabinoids 227

Cannabis and Reward 233

The Ecological Roles of Cannabinoids and Brain Function 234

13 Some Miscellaneous Terpenes 237

The Adaptogens-Modified Triterpenes from the Panax,Withania, and Bacopa Genera 237

The Panax Genus-Panax ginseng, Panax quinquefolius 239

Withania somnifera 241

Bacopa monnieri 243

Ecological Roles of the Terpene Adaptogens and Brain Function 244

Ginkgo biloba

Ecological Roles of Ginkgolides and Bilobalide and Brain Function 250

Valeriana officinalis (Valerian) 251

Ecological Roles of Valerian Secondary Metabolites and Brain Function 252

14 In Conclusion: Comparing and Contrasting the Alkaloids,Phenolics, and Terpenes 253

Future Directions? 260

References 263

Index 345

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