Medicinal Cannabis and CBD in Mental Healthcare

Foreword
Disclaimer
Contents
1: Introduction
	Why This Book?
		The Structure of the Book
		Limitations
		Medicinal Cannabis as Part of a Holistic Therapeutic Approach
		Your Journey
		A Final Note from Dr. Blair
	References
2: Endocannabinoid System
	Introduction
	Purpose of the Endocannabinoid System
	Components of the Endocannabinoid System: Overview
	Endogenous Ligands: Endocannabinoids
		Endocannabinoids in Brief
		Synthesis of AEA and 2-AG
		Binding to Receptors (Extracellular and Intracellular)
			Transport Across the Plasma Membrane
			Intracellular Reservoirs Challenge Classic Understanding of Endocannabinoid On-Demand Synthesis
		Degradation of Endocannabinoids
			AEA Degradation
			2-AG Degradation
			New Signaling Molecules Generated
			A Fine-Tuned Modulation System
		AEA and 2-AG in More Detail
			Anandamide (AEA)
			2-Arachidonylglycerol (2-AG)
		Key Difference Between Endocannabinoids and Phytocannabinoids
		Endocannabinoid-Like Compounds: PEA, OEA, and Oleamide
			N-palmitoylethanolamide (PEA) and Oleoylethanolamide (OEA)
			Oleamide
	Cannabinoid Receptors
		Discovery of Cannabinoid Receptors
		Location of Cannabinoid Receptors
		Location of CB1 Receptors: Overview
			Neuroprotection
		CB1 Receptors in the CNS
			Glutamate and GABAergic Receptors
			CB1 Receptors Are More Abundant than Mu-Opioid Receptors
			CB1 Receptors and Cerebromicrovascular Endothelial Cells
		CB1 Receptors in Peripheral Nervous System and Periphery
			CB1 Receptors in the Peripheral Nervous System
			CB1 Receptors in the Gut
			CB1 Receptors in the Skin
			CB1 Receptors in the Liver
			Contrary Actions in the Periphery Compared with CNS: CB1 Receptors in Adipocytes
			Intracellular CB1 Receptors
			Different Isoforms of CB1 Receptors
		Functions of CB1 Receptors
			Functions of Mitochondrial CB1 Receptors
		CB2 Receptors
			CB2 Receptors and the Immune System
			CB2 Receptors in the Brain
			Unique Features of CB2 Receptors Compared with CB1 Receptors
			CB2 Receptors in Other Organs and Tissues
			CB2 Receptors in Skin
	Mechanisms of Action of the Endocannabinoid System (ECS)
		Classic Understanding of How the ECS Works in the Nervous System
		Complexity of the ECS: Multiple Signaling Pathway Involvement
			Biased Agonism
			Heteromers
		The ECS in Non-neural Cells
		ECS Signal Transmission Via Microvesicles
		Other Receptor Targets for Endocannabinoids
			TRPV1 Receptors
			Peroxisome Proliferator-Activated Receptors (PPARs)
			GPR55 Receptors
	The Endocannabinoid System in Neuroprotection
	Development and the Endocannabinoid System
		The ECS in Early Life
		The Adolescent Brain and the ECS
	Endocannabinoid System Dysfunction and Disease
		The Concepts of Endocannabinoid Tone and Endocannabinoid Deficiency
		Diseases in Which ECS Dysfunction Is Implicated
		Endocannabinoid System Dysfunction and Mental Health
		Omega 3 and 6 PUFAs in the Brain Health
			Diet and Importance of Omega 3 Fatty Acids for a Healthy ECS
			Studies Linking Omega 3 Deficiency and Mental Health Conditions
			Link Between ECS, Omega 3, and Omega 6
			Why Are Omega 3 PUFAs Important for Functioning of the ECS?
			Why Are Dietary Sources of Long-Chain PUFAs Important?
			The Problem with the Western Diet
			Hemp Seeds Have a Very Good Ratio of Omega 6/Omega 3 PUFAs
	Conclusion
	References
3: The Endocannabinoid System, Stress, and Mental Health
	Introduction
	Key Brain Structures Involved in the Regulation of Stress
		Corticolimbic System
			Roles of the Components of the Corticolimbic System
		Hypothalamic-Pituitary-Adrenal (HPA) Axis
		Other Areas
	The Stress Response
		The Autonomic Stress Response
			Sympathetic Nervous System Mechanisms of Action
			Parasympathetic Nervous System Neuroanatomical Connections
			Measurement of ANS Activity
		Neuroendocrine Stress Response
			The HPA Axis in Stress
			Measurement of Neuroendocrine Activity
			Sex Differences in the Stress Response System Along the HPA Axis
	When the Stress Response Becomes Pathological
	Stress and Inflammation
		How Does Stress Activate Inflammatory Changes?
	Endocannabinoid System and Stress Regulation
		Several Lines of Evidence that the ECS Is a Regulator of the Stress Response
		Bidirectional Relationship Between Stress and the ECS
		ECS and the Autonomic Nervous System Stress Response
		ECS, the Corticolimbic System, and the HPA Axis
			ECS and Regulation of the HPA Axis
		How Is the ECS Involved in Acute and Chronic Stress?
			Acute Stress
			Chronic Stress
		The Endocannabinoidome (Extended ECS) and Stress
		Genes, Stress, and the Endocannabinoid System
			Social Isolation
			Environmental Enrichment
	Early Life Stress and the Endocannabinoid System
		Early Life Stress, Corticolimbic System, and HPA Axis Development
		Stress Responsivity
		Findings from Animal Models
		Early Life Stress and Genetic Patterns in Humans
		Sex Differences in How Early Life Stress Affects the ECS
	The Gut and Stress
		The Gut Microbiome and Stress
		Microbiota Changes and Stress
		The Gut Regulates the HPA Axis
		Leaky Gut and Mental Health
		The Endocannabinoidome, the Gut, and Links to Mental Health
		Inflammation, the Gut, and the ECS
	Cannabis Exposure and Stress Responsivity
	Conclusion
	References
4: Overview of Medicinal Cannabis
	Introduction
	Definition of Medicinal Cannabis
	Taxonomy: What Is in a Name?
		Hemp
		Hemp Oil and Hemp Seed Oil
	Historical Use of Cannabis as Medicine
		Cannabis in China
		Cannabis in Other Ancient Cultures
		Medicinal Cannabis in the Western World
	Regulations in the USA
	Active Constituents of Cannabis
		Where Are the Phytocannabinoids and Terpenes Found?
		Entourage Effect
		Cannabis Strains/Cultivars and Active Constituent Profiles
			Genes and Environmental Conditions
		A Word of Caution About Reductionism
	Phytocannabinoids: Overview
	Cannabidiol
		Therapeutic Actions of CBD
			What Conditions Can CBD Potentially Treat?
		Mechanisms of Action of CBD
			CBD Modulates Endocannabinoid Tone and Adenosine Tone
			CBD Modulates Multiple Signalling Systems
			Immunological and Anti-Inflammatory Effects
			Antioxidant Activity
			Anti-Bacterial Effect
			Cellular Benefits in the Central Nervous System
			Effects on Cardiovascular System
			Anti-Cancer Activity and Exosomes
		CBD Antagonism and Potentiation of THC
			Potentiation
			Antagonism
		Cannabidiolic Acid (CBDA)
	Tetrahydrocannabinol (THC)
		Therapeutic Actions of THC
		Mechanism of Action of THC
			Anti-Inflammatory Effects
			Anti-Ageing Effects
		THCA-A
	Other Phytocannabinoids
		Cannabichromene (CBC)
		Tetrahydrocannabivarin (THCV)
	Terpenes
		Actions of Terpenes
	Forms of Medicinal Cannabis
		Oils Are Not Oils
		A Gap in Our Knowledge: Lack of Studies in Whole Plant Extracts
			Superiority of Whole Spectrum CBD Over Pure CBD Isolate Demonstrated
			Dangers of Meta-Analyses
	Routes of Delivery and Pharmacokinetics
		Inhalation
		Oral Route
		Topical Route, Other Routes
		Bioavailability of CBD
		Bioavailability and Onset and Duration of Action of THC
	Safety
	Going Forward: The United Nations and the Single Convention
	Conclusion
	References
5: Anxiety
	Introduction
	Anxiety: Overview
		Types of Anxiety Disorder
		Associated Comorbidities
		Treatment of Anxiety
	Pathomechanisms Involved in Anxiety
		Role of the Amygdala and Prefrontal Cortex in Anxiety
		Serotonin in Anxiety
		Noradrenergic System Involvement in Anxiety
		GABA Involvement in Anxiety
		Immune Dysfunction and Inflammation in Anxiety
			Inflammation and Anxiety
			Oxidative Stress
		Neurogenesis and the Hippocampus
			Adult Hippocampal Neurons and the Stress Response
			Neuritogenesis and Anxiety
	The Endocannabinoid System in Anxiety
		HPA Axis in Anxiety
		Endocannabinoids, Cannabinoid Receptors and Anxiety
			Enzymes of the ECS
			TRPV1
	Scientific Evidence: CBD in the Treatment of Anxiety
		Mechanisms of Action of CBD in Anxiety
			CBD and the Serotonergic System
			CBD and the HPA
			CBD, Neurogenesis and Neuritogenesis
			CBD and Endocannabinoid Degradation
			CBD, Inflammation and Immune Function
			CBD, Sleep and Anxiety
		Animal Research: Efficacy of CBD in Anxiety
			Animal Models of Anxiety: Elevated Plus Maze
			Anxiety Studies in Rodents
			Animal Studies of Chronic CBD Administration
			Pure CBD Isolate and the Bell-Shaped Dose-Response Curve in Animal Studies
			Animal Study of Pure CBD Versus Whole Plant CBD
			Animal Research of CBDA in Anxiety
		Human Research: Efficacy of CBD in Anxiety
			Surveys
			Regional Cerebral Brain Flow Studies: Anxiety and CBD
			Observational Study: CBD and Anxiety
			Case Studies and Case Series
			Randomised Controlled Trials: CBD for Treatment of Anxiety
			Systematic Reviews: CBD and Anxiety Treatment
	Scientific Evidence: THC in the Treatment of Anxiety
		Preclinical Research: Effects of THC on Anxiety
			Anti-inflammatory Effects
		Human Research: Effects of Cannabis and THC on Anxiety
			Brain Imaging Studies
			Survey of Whole Plant Cannabis: Are Some Strains Better in Alleviating Anxiety?
			Observational Studies
			Randomised Controlled Trials
			Systematic Reviews
		Does Adding CBD to THC Lower Its Anxiogenic Effect?
			Preclinical Research
			Clinical Research
			Systematic Review: The Jury Is Still Out
			What Do We Conclude?
		Whole Plant Medicines and Entourage Effects in Anxiety
			Other Phytocannabinoids with Potential Anxiolytic and Antidepressant Effects
			Terpenes with Anxiolytic Effects
		N-Palmitoylethanolamine (PEA) and Anxiety
		Diet, ECS and Anxiety
	Is Cannabis Use Associated with Anxiety?
		What Is the Evidence?
			Associations Between Cannabis Use, Cannabis Dependence and Anxiety
			Cannabis Use in Adolescence and Anxiety
		Theories to Explain Association Between Cannabis Use and Anxiety
	Guidelines for Treating Anxiety with CBD
		When to Use Medicinal Cannabis
		Type of Product (Blends)
		What Form of Product Should You Use?
		Dosing Guidelines
		Titration and Follow-Up
		Other Tips to Enhance Therapeutic Action
		Drug-Cannabis Interactions
	Case Studies from Dr. Blair’s Practice
		Case 1 Chronic Anxiety
			Treatment Recommendation
			Clinical Course
		Case 2 Posttraumatic Stress Disorder with Prominent Anxiety
			Treatment Recommendations
			Comments
	Conclusion
	References
6: Depression
	Introduction
	What Is Depression?
		Comorbidities of Depression
		Pharmacological Treatment of Depression
	Pathophysiology of Depression
		Neuromorphometric Changes in Depression
		Monoamine Theory of Depression
		Immune System Function, Inflammation, and Depression
			Evidence for Involvement of Immune System and Inflammation in Depression
			Possible Link Between Immune System Activity and Depression Pathogenesis
			CNS Inflammation
		Malfunction of Lymphatic Vessels in the CNS Could Be Involved in Depression
		HPA Axis Dysfunction and Depression
		Exaggerated and Blunted Autonomic and Neuroendocrine Stress Responses
		Genetic Abnormalities in Depression and a Link with Inflammation
		Neuroplasticity in Depression
			Altered Synaptic Plasticity in the Hippocampus
			Changes in Synaptic Plasticity in the Prefrontal Cortex and Amygdala
			Bidirectional Relationship Between Depression and Altered Neural Plasticity
			Reduced Brain-Derived Neurotrophic Factor Levels and Depression
		Neurogenic Theory of Depression
		The Glutaminergic System, N-Methyl D-Aspartate (NDMA), and Depression
		Disturbances of Serotonin in Depression
			Serotonin-Kynurenine Hypothesis of Depression and the Link to Inflammation
		Multi-receptor Involvement
	The Endocannabinoid System in Depression
		Anatomical Basis
			Interconnection of the ECS and Brain Regions in Mood Regulation
		Evidence from Animal Studies Manipulating Cannabinoid Receptors
			Evidence of CB1 Receptor Involvement in Regulation of Emotions and Depression
			Evidence of Role of Adipocyte CB1 Receptors in Depression
			CB2 Receptors in Emotion Processing and Depression
		Evidence of ECS Imbalance in Depression
			Preclinical (Animal) Studies Implicating ECS Dysregulation in Depression
			Human Studies: Changes in the ECS in Depression
		Genetic Variations and Depression
		Antidepressant Drugs Affect the ECS
		Cross-Talk Between the Immune System and ECS in Depression
		Endocannabinoid System and the Neurogenesis Model of Depression
		Research Linking ECS Activity and Underlying Pathomechanisms Occurring in Depression
		Summary
	Scientific Evidence: CBD in the Treatment of Depression
		Preclinical Research into CBD for Treatment of Depression
			CBD Effects on the Serotonergic System
			CBD Reduces IDO-Mediated Degradation of Tryptophan
			CBD May or May Not Reduce Depressive Symptoms Through Hippocampal Neurogenesis
			CBD May Increase BDNF and Synaptic Plasticity
			CBD Reduces Neuroinflammation
			Other Targets of CBD
			CBD in the Treatment of Depression Comorbid with Diabetes
			CBDA in Animal Models of Depression
		Human Research: CBD in the Treatment of Depression
			Case Studies
	Cannabis and THC: Evidence of Antidepressant Effects
		Preclinical Studies
			THC Effect on Dopaminergic System
			THC Effect on Serotonergic System
			THC Use in Adolescent Animals Induced Depression
		Human Studies: Cannabis, THC, and Depression
			Surveys of Cannabis Users
			Prospective Cohort Study
			Prospective Study: Cannabis Flowers
			Case Reports of Cannabis Use in Depression
			Randomized Controlled Trials of Cannabis and THC for Depression
			RCTs Assessing Depression as Secondary Outcome Variables
		Palmitoylethanolamide (PEA) Supplementation for Depression
			RCT: PEA Supplementation in Major Depressive Disorder
	Can Cannabis Cause Depression?
		Studies of Associations Between Cannabis Use and Depression
		Cannabis Use in Adolescence and Young Adulthood
		Legalization of Medicinal Cannabis Access and Suicide Reduction
		What Is the Nature of the Association Between Cannabis Use and Depression?
	Dosing Guidelines for Treating Depression with Medicinal Cannabis
		When to Use Medicinal Cannabis
		Type of Product (Blends)
		What Form of Product Should You Use?
		Dosing
		Titration and Follow-Up
		Other Tips to Enhance Therapeutic Action
		Drug-Cannabis Interactions
	Case Studies from Dr. Blair’s Practice
		Case 1 Professional Male with Depression
			Treatment
		Case 2 Young Adult with Depression
			Treatment
	Conclusion
	References
7: Post-Traumatic Stress Disorder
	Introduction
	What Is PTSD?
		PTSD as an Anxiety Disorder and a Paradoxical Disorder of Memory
		DSM-5 Definition
		Predisposing Factors and Epigenetics
		Comorbidities of PTSD
			Risk of Suicide
			Sleep Problems
			Increased Risk of Diseases
		Prevalence of PTSD
			General Population
			Armed Forces
			Domestic Violence and Sexual Assault
	Orthodox Treatment of PTSD
		Psychological Treatments
		Pharmaceutical Interventions
	Pathophysiology of PTSD
		PTSD as a Disorder of Memory
			The Necessity of Sleep for Memory Processes
			Maladaptive Memory Processing in PTSD
		Brain Morphological and Neurophysiological Functioning Changes in PTSD
			Changes in Brain Morphology and Function in PTSD
		Dysregulation of the Stress Response, HPA-Axis Dysfunction, and Inflammation
			Sympathetic Nervous System Reactivity
			HPA-Axis Dysregulation
		Synaptic Plasticity in PTSD
		Dysregulation of Neurotransmitters in PTSD: GABA and Glutamate
		Other Receptor-Ligand Systems Involved in PTSD
		Association Between PTSD and Inflammation
			Inflammation as Both a Pre-existing Risk Factor and a Result of PTSD
			Relationship Between IL-6 and Noradrenergic Activity in PTSD
		Genetic (and Epigenetic) Factors
	The Endocannabinoid System and PTSD
		The Endocannabinoid System Modulation of Stress Response
			Chronic Mild Stress Alters Endocannabinoid-Mediated Neurotransmission
		CB1 Signaling and the Amygdala Involved in Short- and Long-Term Fear Extinction
		CB1 Receptor mRNA Downregulation in Amygdaloid Complex and Frontal Cortex in PTSD
		Levels of Endocannabinoids Altered in PTSD
			Age When Traumatic Event Occurred Affects ECS Changes
			Evidence of Altered Endocannabinoid Levels in Animal Models of PTSD
			Evidence of Altered Endocannabinoid Levels from Human Research
		Levels of CB1 Receptors Altered in PTSD
			Evidence of Altered CB1 Receptors in Animal Models of PTSD
			Evidence of Altered CB1 Receptor Levels from Human Research
	Medicinal Cannabis and Cannabinoids for the Treatment of PTSD
		Research into Synthetic Cannabinoids in PTSD
			Animal Models of PTSD: Studies in Synthetic Cannabinoid Agonists
			Cannabinoid Agonists Can Alter Neuroplastic Changes in Amygdala and Hippocampus
			Cannabinoid Agonists Prevent BDNF Decreases in Brain Fear Circuits
			Cannabinoid Agonist Reverses Anxiety-Like Behavior and Reduces Inflammation in PTSD
			Synthetic Cannabinoids Promote Neurogenesis
			Cannabinoid Effects on Consolidation of Traumatic Experiences
			Cannabinoid Agonists Impair Memory Retrieval
			Problems with Synthetic Cannabinoid Agonists and Antagonists
		Epidemiological Studies of Cannabis Use in Humans with PTSD
		Potential Mechanisms of Action of Medicinal Cannabis in Alleviating PTSD Symptoms
		CBD: Mechanisms of Action and Evidence of Efficacy from Animal Studies
			CBD Disrupts the Acquisition of Fear Learning and Formation of Fear Memories
			CBD Attenuates Fear Memory Reconsolidation
			CBD Enhances Extinction Learning and Retention
			CBD Can Reduce Predator Anxiety
		THC: Mechanisms of Action and Evidence of Efficacy from Animal Studies
		Clinical Evidence of Efficacy of Treatment of PTSD with Medicinal Cannabis
			Case Study of Cannabis in PTSD Treatment
			Retrospective Study of Cannabis Use in PTSD
			Qualitative Research in PTSD and Cannabis Use
			RCTs and Systematic Reviews
			New Studies Examining Short-Term and Long-Term Effects of Cannabis with Different Ratios of THC/CBD
		Clinical Studies of Efficacy of THC and Synthetic THC
		Clinical Studies of Efficacy of CBD
			Case Studies
			Clinical Study
			Open-Label Pilot Study
	Safety Aspects of Use of Medicinal Cannabis in PTSD
		Heavy Cannabis Use and Impaired Fear Extinction
		THC May Distort Memories
		Medicinal Use Is Not Equivalent to Recreational Use
	Guidelines for Treating PTSD with Medicinal Cannabis
		When to Use Medicinal Cannabis
		Type of Product (Blends)
		What Form of Product Should You Use?
		Dosage Guidelines
		Titration and Follow-Up
		Other Tips to Enhance Therapeutic Action
		Interactions with Other Drugs
	Case Studies from Dr. Blair’s Practice
		Case 1: Air Force Veteran with PTSD
			Initial Formulation and Dose
			Follow-Up
			Case Comment
		Case 2: Army Medic with PTSD
			Initial Dosing
			Follow-Up
			Case Comment
		Case 3 War Photographer
			Case Comment
	Conclusion
	Additional Reading
		Studies Evidencing Elevated Cytokines in Association with PTSD
	References
8: Insomnia
	Introduction
	Sleep and Sleep Health
		Why Do We Need Sleep?
			Sleep and the Immune and Endocrine Systems
			Sleep and Emotional Well-Being
			Sleep and Memory Formation
			Synaptogenesis
		Sleep Needs Over Our Life Cycle
			Teenagers
			As We Age
	The Mechanism of Sleep
		Architecture of Sleep
			NREM Sleep
			REM Sleep
		Our Internal Biological Mechanisms Regulating Sleep
			Sleep-Wake Homeostasis
			Circadian Rhythms
			Regulation of the Sleep-Wake State
	Types of Sleep Disorders
	What Is Insomnia?
		Subtypes of Insomnia
		Prevalence of Insomnia
		Insomnia Can Be Persistent
		Insomnia in the Aging Population
		Risk Factors for Short Sleep
		Comorbidities of Insomnia
			Insomnia and Cardiovascular Disease
			Sleep and Obesity and Diabetes
			Insomnia and Anxiety, Depression, and Pain
			Insomnia and PTSD
			Insomnia and Cognition
			Insomnia and Cancer
		Inflammation, Immune Function, and Sleep
		Treatment of Insomnia
			Cognitive Behavioral Therapy
			Pharmaceutical Approaches
	Pathophysiology of Insomnia
		Hyperarousal Theory of Insomnia
		Other Models of Insomnia
		Genetics and Insomnia
		Neuroanatomical and Functional Brain Changes in Insomnia
		Neurotransmitter and Hormone Involvement in Insomnia
	The Endocannabinoid System and Regulation of Sleep
		Cannabinoid Receptors and Sleep
			Diurnal Fluctuations of CB1 Receptors
			CB1 Receptors and Orexins/Hypocretins and Melanin-Concentrating Hormone Neurons
		Endocannabinoids and Sleep
			Endocannabinoids Fluctuate and Follow Circadian Rhythmicity
		How Do Changes in the Endocannabinoid System and Age Contribute to Sleep Disorders in the Elderly?
	The Involvement of the ECS in Insomnia
		Animal Studies
		Human Studies
	Cannabis in the Treatment of Insomnia
		Historical Use
		Epidemiological Studies
			Positive Effects of Cannabis Use on Sleep
			Surveys Indicating Preference for CBD-Dominant Products
			Cannabis Use and Expectations of Better Sleep
		Observational Study in Insomniacs
		RCTs and Systematic Reviews
		Some Negative Results: Cannabis Use and Disturbances to Sleep
			Adolescents and Children at Risk
			Cofounding Factors in Research
		Chronic Use and Tolerance
		Sleep Disruption in Cannabis Withdrawal
	Evidence of Efficacy of CBD for Sleep Disorders
		Preclinical Studies: CBD and Sleep
			Effect of Chronic CBD Use in Adolescent Rats on Adult Rat Sleep Patterns
			Cell Research: Effect of CBD on Circadian Clock Genes
		Human Studies: CBD and Sleep
			Sedating or Alerting: Which Is It?
			CBD and Parasomnias
			Restless Legs Syndrome
	Efficacy of THC in Sleep Disorders
		Animal Studies: THC and Sleep
		Human Studies: THC and Sleep
			Cannabis, THC, and Sleep as a Secondary Outcome Measure
			Nabiximols and Insomnia
			Studies of THC in Treatment of Sleep Disorders Associated with PTSD
	Other Phytocannabinoids and Terpenes in the Treatment of Insomnia
		Cannabinol (CBN)
		Terpenes
	Nutritional Factors Impacting Sleep Quality
	Obstructive Sleep Apnea
		Cannabinoids in the Treatment of Obstructive Sleep Apnea (OSA)
			Animal Research
			Human Research
	Guidelines for Treating Insomnia with Medicinal Cannabis
		When to Use Medicinal Cannabis
			Comprehensive Treatment Plan
		Type of Product (Blends)
		What Form of Product Should You Use?
		Dosing Guidelines
		Titration and Follow-Up
		Other Tips to Enhance Therapeutic Action
	Case Studies from Dr. Blair’s Practice
		Case 1
		Case 2: Insomnia Secondary to Restless Legs Syndrome
	Conclusion
	References
9: Dementia: Alzheimer’s Disease
	Introduction
	About Dementia
		Prevalence of Dementia
		Types of Dementia
		Risk Factors for Dementia
		Common Neuropsychiatric Symptoms of Dementia
		Treatment of Dementia
		Impact of Dementia on Caregivers
		Financial Impacts of Dementia
	Alzheimer’s Disease
		Two Types of Alzheimer’s Disease
		Risk Factors for Alzheimer’s Disease
		Prevalence of Neuropsychiatric Symptoms in Alzheimer’s Disease
	Overview of Pathophysiology of Alzheimer’s Disease
		Triad of Changes
		Aggregated Aβ Peptide and Alzheimer’s Disease
			Amyloid Cascade Hypothesis
		Neuroinflammation
			Pathways of Neuroinflammation
			Oxidative Stress
		Autophagy and mTOR
			Two Key Systems Regulating Autophagy
			Associations Between Autophagy Regulation and AD
			Changes in the mTOR Pathway Linked to Cognitive Decline and AD
		Tau Hyperphosphorylation
		Changes Occurring Prior to Signs and Symptoms of AD
		Scientific Debate: Is Aβ the Key Toxic Entity After All?
		Cholinergic Involvement in Alzheimer’s Disease
			Cholinergic Hypothesis of AD
			Acetylcholinesterase Activity Is Reduced in AD
		Glutaminergic Involvement in Alzheimer’s Disease
		Glucose, Brain Metabolism, and Vascular Impairments
			Is AD the New Type 3 Diabetes?
			Diabetes Treatment and AD
			Genes and Glucose Utilization
		Genes and Familial Alzheimer’s Disease
		Poor Sleep, Aβ Plaques, and Tau Tangles in the Pathophysiology of Alzheimer’s Disease
		Is Age a Risk Factor for Alzheimer’s Disease?
	Deficits in Current Treatments for AD
	The Endocannabinoid System in Alzheimer’s Disease
		Overview of Changes in the Endocannabinoid System in Alzheimer’s Disease
		Preclinical Research: The Endocannabinoid System and Alzheimer’s Disease
			Protective Role of Endocannabinoids
			Cannabinoid Receptor Involvement in Pathology
			Evidence of ECS Involvement in AD: Experiments with Cannabinoid Receptor Agonists
		Human Studies: Evidence of ECS Involvement in Alzheimer’s Disease
			Positron-Emission Tomography Studies in Humans
	Medicinal Cannabis for Treatment of Alzheimer’s Disease
		Synthetic Cannabinoid Agonists in Treatment of Alzheimer’s Disease
		Cannabis Constituents and Target Symptom Treatment
		Mechanisms of Action of CBD in Alzheimer’s Disease
			CBD Is Protective Against Neuroinflammation and Oxidative Stress
			CBD, Regulation of Proteostasis, and Induction of Autophagy
			CBD Prevents Tau Hyperphosphorylation
			CBD Prevents Neurite Degeneration Induced by Aβ
		Mechanisms of Action of THC in Alzheimer’s Disease
		Preclinical Evidence of Efficacy of Cannabinoids in Treating AD
			Cannabidiol
			Efficacy of CBD and THC Combinations in Treating Alzheimer’s Disease
		Clinical Evidence of Efficacy of Cannabinoids in Treatment of Alzheimer’s Disease
			Cannabidiol for Treatment of AD
			Tetrahydrocannabinol for Treatment of Dementia Including AD
			Combinations of Cannabidiol and Tetrahydrocannabinol for Treatment of AD
			Systematic Reviews
			Take-Home Points
		Terpenes and Dementia
			Beta-Caryophyllene
		PEA and Dementia
			PEA and the Extended Endocannabinoid System
			Preclinical Studies of PEA in AD
			Human Studies of PEA in AD
		Oleamide
		Omega-3 PUFAs and Alzheimer’s Disease
	Guidelines for Treating Dementia with Medicinal Cannabis
		When to Use Medicinal Cannabis
		What Formulation Should You Use? (Blends)
		When Might You Consider Adding THC?
		Dosing
		Titration and Follow-Up
		Other Tips to Enhance Therapeutic Action
		Drug-Cannabis Interactions
	Case Studies from Dr. Blair’s Practice
		Case 1: Down Syndrome and Dementia
			My Thoughts
		Case 2: Vascular Dementia Complicated with Trauma and Infection
			My Thoughts
		Case 3: Vascular Dementia
			My Comments
	Conclusion
	References
10: Autism Spectrum Disorder
	Introduction
	What Is Autism Spectrum Disorder?
		Prevalence
		Associated Comorbidities
		ASD and Reduced Mortality
		Prenatal, Perinatal, and Neonatal Risk Factors for ASD
		Treatment
	Etiology and Pathogenesis of Autism Spectrum Disorder
		Neuroanatomical Findings
		Abnormal Connectivity and Signalling of Neuronal Networks
		Genes
		Sleep Dysregulation and ASD
		Environmental Factors Contributing to ASD
		Neuronal Hyperexcitability Hypothesis
		Immune System Activation and Inflammation
		Microbiota-Gut-Brain Axis
	The Endocannabinoid System in ASD Pathology
		ECS and Regulation of Neurotransmitter Excitation and Inhibition in ASD
		Abnormal Endocannabinoid Signaling in ASD
		ECS and Regulation of Social Behavior
		Genetic Changes, the Endocannabinoid System, and ASD
		ECS, Regulation of the Immune System, and Inflammation and ASD
		Environmental Toxins, the Endocannabinoid System, and ASD
		ECS, the Gut, and Gastrointestinal Conditions in ASD
		Endocannabinoid System and Comorbidities of ASD
	How CBD May Work in Autism Spectrum Disorder
		Actions of CBD on Glutamate and GABA
		Possible Neurogenic Effects of CBD
		Anti-inflammatory Action of CBD
		CBD and Mitochondrial Functioning
		Actions on mTOR Pathway
		Actions of CBD on the Endocannabinoid System
		CBD’s Potential Role in Recovering the Gastrointestinal System
		CBD May Help Treat Other Comorbidities of ASD
		Combining CBD, Oxytocin, and Melatonin
	Scientific Evidence of Efficacy: Medicinal Cannabis in the Treatment of Autism Spectrum Disorder
		Preclinical Research into CBD
			Fragile X Syndrome
		Human Research
			Retrospective Study: CBD-Rich Cannabis Oil as Adjuvant Treatment
			Prospective Study in Children with ASD Treated with CBD-Rich Oil
			Brazilian CBD-Enriched Cannabis sativa Extract Observational Study
			Chilean Study: Whole Plant Cannabis Extract
			Open-Label Study of Children with ASD with 20:1 Ratio CBD:THC Oil
			Case Reports of CBD Treatment in Fragile X Syndrome Patients
			Randomized Controlled Trial of Oral Cannabinoids in ASD
			Systematic Review
	Guidelines for Treating ASD with Medicinal Cannabis
		When to Use Medicinal Cannabis
		Type of Product (Blends)
		What Form of Product Should You Use?
		Dosing Guidelines
			Target Dose
			Frequency
			Duration
			Stopping Other Medications
		Titration and Follow-Up
		Other Tips to Enhance Therapeutic Action
		Adverse Effects and Interactions
	Case Studies from Dr. Blair’s Practice
		Case 1, ASD Level 3
		Case 2, ASD Level 2
	Conclusion
	References
11: Routes of Administration, Pharmacokinetics and Safety of Medicinal Cannabis
	Introduction
	Routes of Administration (Delivery Methods)
		Types of Delivery Methods
		Inhalation: Smoking Cannabis
		Inhalation: Vaporising
		Oral Routes
		Topical Route
		Other Delivery Routes
	Pharmacokinetics
		Cannabidiol
		Tetrahydrocannabinol
	Safety of Cannabis
		Adverse Events Associated with Cannabis
		Drug-Cannabis Interactions
		Cannabis Dependence, Abuse and Cannabis Use Disorder
		Pregnancy and Cannabis Use
		Alcohol and Cannabis
		Workplace Injuries and Recreational Cannabis Use
		Cannabis Use, Psychosis and Schizophrenia
	Safety of THC
		Possible Side Effects of THC
		Toxicity of THC
		Cardiovascular Effects of THC
		THC, Alcohol and Driving
		Drug-THC Interactions
		THC in Individuals with Substance Use Disorders
	Safety of CBD
		CBD Adverse Effects
		CBD Is Not Addictive
		CBD Does Not Convert to THC
		What Does the Preclinical Research on CBD Show in Relation to Safety?
		Toxicity of CBD
		CBD-Drug Interactions
		Studies of CBD in Epilepsy: Side Effects
		CBD and Alcohol
		CBD and Blood Pressure
		Whole Spectrum CBD Versus Pure Isolate: Any Difference in Side Effects (and Efficacy)?
		What Doses of CBD Are Considered Safe?
	Drug-Cannabinoid Interactions
		Metabolism and Drug-Drug Interactions
		Main P450 Enzymes Metabolising CBD
		Main CYP Enzymes in the Metabolism of THC
		Effect of Co-administration of Drugs and Cannabinoids: Looking in Both Directions
		CBD Interactions with Liver UGT Enzymes in the Liver
		CBD and Other Enzymes: Breast Cancer Resistance Protein and Bile Salt Export Pump
		Pharmacodynamic Interactions: Use of Sedating Medications and Antidepressants
	Safety of Terpenes
	Conclusion
	References
12: Conclusion
	Philosophical Thoughts
		Mind and Body Are Not Really So Separate
		The Notion of Balance
	The Many Factors that Keep Us Healthy
		Physical Activity
		Nutrition
		Other Factors
	Medicinal Cannabis
	An Herbal Medicine Rediscovered
	References
Index