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Part 1 is also online
Part 2 is also online
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This is the third and final installment of a series of articles discussing cannabinoid-rich hemp oil and a new certification program for dietary supplement manufacturers and healthcare practitioners offered by the International Center for Cannabis Therapy (ICCT). As Chief Medical Officer–USA of the ICCT, a Czech Republic-based partnership of qualified doctors and scientists who specialize in the medical application of cannabis, Dr. Meletis is an expert on the clinical applications and research supporting the use of cannabinoid-rich hemp oil and its effects on the endocannabinoid system. Last month, we discussed the endocannabinoid system, its role in health, and how the endocannabinoid system interacts with the adrenals, sex hormones, and gut. We also shared pre-clinical and clinical research and Dr. Meletis' observations about the use of cannabinoid-rich hemp oil in clinical practice, with an emphasis on the management of pain and inflammation and how to balance the endocannabinoid system without overwhelming its receptors. In this article, we'll address the use of cannabinoid-rich hemp oil in applications such as Alzheimer's disease, depression, anxiety, irritable bowel syndrome, stroke, schizophrenia, autoimmunity, and epilepsy, among other uses. We'll also discuss the role of cannabinoids in the gut-brain axis.
Healthcare practitioners who want to delve deeper into the benefits of cannabinoid-rich hemp oil, understand the legal ramifications of prescribing it, and become certified as a respected hemp oil expert who understands proper dosing and other nuances of hemp oil use, can sign up for the ICCT online medical certification program at www.icctcertification.com.
 Townsend Letter provides a platform for those examining and reporting on functional and integrative medicine. Please support these independent voices. |
A Brief Review of the Endocannabinoid System
Endogenous endocannabinoids that are produced within the body including anandamide (arachi-donylethanolamide) and 2-arachidonylglycerol (2-AG) are able to activate receptors in the endocannabinoid system. Phytocannabinoids such as Δ 9-tetrahydrocannabinol (THC), the psychoactive component of Cannabis sativa, and cannabidiol (CBD), a non-psychoactive component, are also able to activate endocannabinoid receptors. Two of the main receptors in the endocannabinoid system are CB1 and CB2. CB1 is the primary receptor in the nervous system. It is also found in the adrenal gland, adipose tissue, heart, liver, lungs, prostate, uterus, ovary, testis, bone marrow, thymus, and tonsils. CB2 is primarily expressed in the immune system. Endocannabinoids and phytocannabinoids also act upon other receptors to achieve some of their beneficial effects. When the endocannabinoid system is stressed, there is a loss of homeostasis; and a number of diseases can result. For more detail about endocannabinoids and their receptors as well as supporting references, we recommend you read part two of this article.
 The Endocannabinoid System and Neurological Diseases
An impaired endocannabinoid system may play a role in neurodegenera-tive disorders including Alzheimer's, Parkinson's, and Huntington's disease. Endogenous cannabinoid signaling performs many functions in the central nervous system (CNS), such as modulating neuroinflammation and neurogenesis, as well as regulating synaptic plasticity, and the response to stress.1,2 Furthermore, upregulation of type-2 cannabinoid (CB2) receptors is associated with many neurodegenerative disorders. Consequently, influencing CB2 receptor signaling may be neuroprotective.2
Endocannabinoids possess a broad-spectrum of activity,2 which is advantageous in neurodegenerative diseases where neural dysfunction is caused by a combination of different factors including protein misfolding, neuroinflammation, excitotoxicity, oxidative stress, and mitochondrial dysfunction.2 The endocannabinoid signaling system is thought to regulate each of these factors.2 The endocannabinoid system also modulates brain tissue homeostasis during aging and/or neuroinflammation.2
CB2 receptors exert neuroprotective properties through their ability to suppress inflammation.3 Activation of CB2 receptors regulates the production of cytokines, proteins that play a significant role in immune function and inflammatory responses.4 Conversely, rather than inhibiting neurodegenerative diseases via an immunological pathway, the CB1 receptor suppresses cell death through protecting against excitotoxicity, overstimulation of excitatory receptors and simultaneous calcium release.2
In the neurons of healthy brains, there is a lower expression of CB2 receptors. However, a significant increase in expression of these receptors is noted in reactive microglia and activated astrocytes during neuroinflammation.5,6 Microglia are cells in the brain and spinal cord. When they become reactive, it is associated with neurodegenerative diseases. Activated microglia modulate inflammatory responses to pathogens and injury by signaling the synthesis of pro-inflammatory cytokines. Similarly, diseases that impact the central nervous system activate astrocytes. The fact that CB2 receptors are highly expressed when both these types of cells are activated may indicate they are needed to combat inflammation. This led researchers to conclude, "Therefore, the CB2 receptors have the potential to restrain the inflammatory processes that contribute to the declines in neural function occurring in a number of neurodegenerative disorders."2
The involvement of CB2 receptors in Alzheimer's disease was demonstrated in a number of human studies. Inspections of postmortem brains from individuals with Alzheimer's disease showed that CB2 receptors are upregulated in cells that are linked to amyloid beta (Aβ)-enriched neuritic plaques.7-10 The deposition of amyloid beta plaques in the brain are involved in Alzheimer's disease pathology. Other researchers found markedly higher CB2 receptor levels in individuals with severe Alzheimer's disease compared with age-matched controls or people with moderate Alzheimer's.11 Activation of the CB2 receptor has resulted in beneficial effects in Alzheimer's disease, including the inhibition of microglial activation in mice.12
Further support for the role of the endocannabinoid system in Alzheimer's is provided by preclinical studies showing that cannabidiol, the non-psychoactive component of Cannabis sativa, may be beneficial in Alzheimer's. In one of these studies, mice inoculated with Aβ then injected with CBD (2.5 or 10 mg/kg) for seven days had anti-inflammatory and neuroprotective effects as evidenced by its ability to suppress a marker of activated astrocytes.13 A rat model of Alzheimer's-related neuroinflammation further elucidated the role CBD may play in Alzheimer's. In this study, adult male rats were inoculated with human Aβ42 in the hippocampus.14 Then, for 15 days, they were given 10 mg/kg CBD either with or without a PPAR-γ or PPAR-α receptor antagonist. CBD counteracted many of the pathogenic mechanisms of Aβ, and its effects involved the regulation of PPAR-γ. This makes sense since PPAR-γ receptors are increased in people with Alzheimer's disease.
Parkinson's Disease
The progressive loss of dopaminergic neurons primarily in the substantia nigra (SN) is the distinguishing characteristic of Parkinson's disease. This dopaminergic neuron loss impairs the basal ganglia leading to bradykinesia (slowness of movement), rigidity, and tremors. Inflammation is a prominent player in Parkinson's disease pathogenesis. Post-mortem evaluations of Parkinson's disease patients observed microglia activation in the SN.15 Structural brain imaging studies have also shown that activated microglia and an increase of proinflammatory cytokines occur in the nigrostriatal system of Parkinson's disease patients.16,17A post-mortem study indicated that individuals with Parkinson's disease have increased expression of CB2 receptors in microglial cells of the SN.18 This and other evidence suggests that targeting the CB2 receptor may serve as an anti-inflammatory approach in Parkinson's.2
In support of the idea that modulating the endocannabinoid system is beneficial in Parkinson's disease are a number of small studies investigating the use of cannabidiol in this group of patients. In a double-blind, placebo-controlled study of 21 Parkinson's patients without dementia or comorbid psychiatric conditions, 300 mg/day cannabidiol enhanced well-being and quality of life.19 In an open-label pilot study, six Parkinson's disease outpatients (four men and two women) who suffered from psychosis for at least three months received CBD starting with an oral dose of 150 mg/day for four weeks combined with their usual therapy.20 CBD intervention resulted in a marked decline in psychotic symptoms as measured by the Brief Psychiatric Rating Scale and the Parkinson Psychosis Questionnaire. CBD also lowered the total scores of the Unified Parkinson's Disease Rating Scale. Furthermore, cannabidiol significantly reduced the frequency of sleep behavior disorder (RBD) in four patients with Parkinson's disease.21
Anxiety and Post-Traumatic Stress Disorder
The endocannabinoid system regulates stress and anxiety, and modulation of the endocannabinoid system has been found to reduce anxiety. Repeated injections of cannabidiol to mice exposed to chronic unpredictable stress reduced anxiety in the animals.22 This effect was mediated by CB1, CB2, and serotonin (5HT1A) receptors. In a double-blind randomized trial investigating subjects with generalized social anxiety disorder not receiving medication, 600 mg of cannabidiol reduced anxiety and cognitive impairment caused by simulated public speaking and improved the participants' comfort level in their speech performance.23 Another study of 10 individuals with generalized social anxiety disorder observed that 400 mg of cannabidiol was associated with markedly reduced subjective anxiety.24 Furthermore, advanced imaging studies indicate that the endocannabinoid system is underactive in post-traumatic stress disorder.25 Preliminary studies in humans have observed that cannabinoids may improve PTSD symptoms such as sleep quality and hyperarousal.26 Nabilone, a synthetic cannabinoid, reduced PTSD-related nightmares in a small group of Canadian military personnel.27 In an animal model, cannabinoids given shortly after experiencing a traumatic event blocked the development of a PTSD-like phenotype.26
For more information about the interaction between the endocannabinoid system and anxiety, we recommend you enroll in the ICCT medical certification program at www.icctcertification.com. This is a vast topic that cannot be addressed in one article alone.
Depression
Dysregulation of the endocannabinoid system may be involved in the development of depression. Suppressing the CB1 receptor results in a phenotypic state that is comparable to melancholic depression, with identical symptoms such as decreased appetite, increased anxiety, arousal, and wakefulness, an inability to release aversive memories, and increased sensitivity to stress.28 Furthermore, some antidepressant medications enhance endocannabinoid activity.28
One mechanism by which CBD reduces depression may be via its ability to protect against the effects of stress. Stress can lead to anxiety and depression. In animal models, CBD lowers autonomic indices of stress and behavioral effects of depression and anxiety and improves the delayed emotional consequences of stress via mechanisms that involve serotonin receptors.29,30 CBD is also thought to reduce depressive symptoms by enhancing hippocampal neurogenesis. Ongoing administration of CBD in mice undergoing chronic unpredictable stress improved depressive- and anxiety-like behaviors and triggered hippocampal progenitor proliferation and neurogenesis.31
CBD is thought to stimulate neurogenesis by elevating hippocampal levels of the endocannabinoid anandamide (AEA). A clinical study found that higher serum concentrations of AEA were associated with reduced anxiety in patients with major depression, although in this group of patients AEA levels were not associated with major depressive symptoms.32 Conversely, in people with minor depression, AEA concentrations were elevated compared to controls, suggesting that these levels might be raised as the body's way to compensate for the depression and that they may have a neuroprotective role in patients with less severe depressive symptoms.
The role of cannabinoids in depression is a vast topic, and we recommend that you enroll in the ICCT medical certification program to understand how phytocannabinoids can be safely used in depression.
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