CBD Literature Review
The Role of Hemp-derived Phytocannabinoids in the Treatment of Inflammatory Conditions and Selected Psychiatric Disorders.
Philip Watkins Bsc.(Naturopathy)
Cannabis sativa L. Has been an important source of food, fibre and medicine for thousands of years in the old world. Its achenes (“seeds”) as well as other pant parts have been recorded in Chinese medical texts for nearly 2000 years. References to cannabis are found throughout classical Chinese literature, including many famous works of philosophy, poetry, agriculture, and medicine .
In Europe, medications based on cannabis were used at the end of the 19th century to treat pain, spasms, asthma, sleep disorders, depression and loss of appetite.
Currently, three general types of cannabinoids have been identified: phytocannabinoids present uniquely in the cannabis plant, endogenous cannabinoids produced in humans and animals, and synthetic cannabinoids generated in a laboratory . There are over 550 chemical compounds and over 100 plant cannabinoids or phytocannabinoids isolated from Cannabis sativa, including Δ9 - tetraydrocannabinol (THC) and cannabidiol (CBD) .
The Endocannabinoid System and its relevance to the modern day
Cannabinoid receptors are distributed in the central nervous system and many peripheral tissues, including the immune system, reproductive and gastrointestinal tracts, sympathetic ganglia, endocrine glands, arteries, lung and heart.
The CB1 an CB2 cannabinoid receptors are members of the G protein-coupled receptor (GPCR) family that were identified over 20 years ago. Around this time, the endocannabinoid system was defined as the ensemble of 1) two 7-transmembrane-domain and G-protein-coupled receptors (GPCRs) for THC - cannabinoid receptor type-1 (CB1R) and cannabinoid receptor type-2 (CB2R); 2) their 2most studied endogenous ligands, the “endocannabinoids” N-arachidonoylethanolamine (anandamide) and 2-arachidonolyglycerol (2-AG); and 3) the 5 enzymes considered, at the time, to be uniquely responsible for endocannabinoid biosynthesis (Refer Table 2).
Marzo, Vincenzo Di and Fabiana Piscitelli. “The Endocannabinoid System and its Modulation by Phytocannabinoids.” Neurotherapeutics 12 (2015): 692-698.
There is a broad variety of interactions with the CB1 receptor system and many different neurotransmitters and neuromodulators in the central and peripheral nervous system. For example, activation of the CB1 receptors leads to retrograde inhibition of the neuronal release of acetylcholine, dopamine, GABA, histamine, serotonin, glutamate, cholecystokinin, D-aspartate, glycine, and noradrenaline. Besides their involvement in controlling excitotoxicity and inflammation, compelling evidence shows that CB1 receptors in the CNS play an important role in neuroprotection.
CB2 receptors are identified peripherally in the circulating immune cells, the spleen , and on macrophage-derived cells including osteocytes, osteoclasts, and hepatic Kupffer cells CB2 receptors can also be found in the enteric nervous system and colonic epithelium, where the endogenous ligands of CB receptors, anandamide and 2-AG, play an important role in the regulation of GI motility, secretion, proliferation, and immune function. The CB2 receptor has been shown to have potential as a therapeutic target in models of diseases, such as neuropathic pain and neurogenerative conditions such as Alzheimer’s disease, where activation of the microglia and neuroinflammation are present.
Presently, endocannabinoids have an influence in the pathology of many disorders, serving a “protective role” in many medical conditions. Several diseases like enesis, pain, inflammation, multiple sclerosis, anorexia, epilepsy, glaucoma, schizophrenia, cardiovascular disorders, cancer, obesity, metabolic syndrome related diseases, Parkinson’s disease, Huntington’s disease, Alzheimer’s disease and Tourette’s syndrome could possibly be treated by drugs modulating the endocannabinoid system.
How do the actions of THC and CBD compare?
One of the more common misconceptions lies in the difference between the major endocannabinoids. THC is a major constituent of Cannabis and serves as an agonist of the CB1 and CB2 receptors. Cannabidiol (CBD), the second major constituent of Cannabis, is virtually inactive at the CB1 receptor and because of this negligible activity lacks the psychoactive effects that accompany the use of THC.
In addition, CBD has been demonstrated to antagonise some undesirable effects of THC, including intoxication, sedation, and tachycardia, while sharing protective, anti-oxidative, anti-emetic, and anti-carcinogenic properties.
Table 1 summarises some of these differences
Broad spectrum phytocannabinoids and their potential in pain management
Chronic pain represents an emerging public health issue of extreme proportions, particularly as a result of raging populations in industrialised countries. Associated facts and figures are unsettling: In Europe, chronic musculoskeletal pain of a disabling nature affects over one in four people , while figures in Hong Kong suggest that chronic pain is a significant health problem in the adult population, with pain sufferers studied not being satisfied with the treatment they are receiving.
Particular difficulties face the clinician managing intractable patients afflicted with with cancer-associated pain, neuropathic pain, and central pain states (eg, pain associated with multiple sclerosis) that are often inadequately treated with available opiates, antidepressants and anticonvulsant drugs. Physicians are seeking new approaches to treatment of these conditions but remain concerned about increasing government scrutiny of their prescribing practices or prescription drug abuse.
The approach for pharmacological treatment for the relief of chronic pain is based primarily on pain intensity. This approach determines that mild pain should be treated with “simple” analgesics, whereas moderate to severe pain should be treated with opioids.
Interestingly, responses to an ABC news poll in the USA indicated that of the roughly 38 million people with chronic pain, 6% or an estimated 12 million people have utilised cannabis in attempts to treat it.
The Irish physician William Brooke O’Shaughnessy first introduced the analgesic effect of cannabis to the western world in a pioneer study in 1839. Any advancements in the development of the cannabis has been impeded in the 20th century by prohibition in the majority of countries due to cannabis’ psychoactivity and potential for dependance. The psychotropic side effects (e.g. euphoria, anxiety, paranoia) or other central nervous system (CNS)-related undesired side effects have also seemingly produced limitations for extended medicinal use.
Pharmacodynamics: Phytocannabinoids act on multiple pain targets
Originally, it was thought that the CB1 receptors, found predominantly in the CNS, and CB2 receptors found predominantly in cells involved with immune function However, recently this has become much more complicated, as it has been recognised that cannabinoids, both plant-derived and endogenous, act simultaneously on multiple pain targets within the peripheral and CNS.
Beside acting on cannabinoid CB1/CB2 receptors they may reduce pain through interaction with the putative non CB1/CB2 cannabinoid G protein-coupled receptor (GPCR) 55 (GPR55) or GPCR 18 (GPR18), also known as the N-arachidonoyl glycine (NAGly) receptor and other well-known GPCRs such as opioid or serotonin (5-HT) receptors.
Cannabidiol (CBD) also regulates the perception of pain by affecting the activity of a significant number of other targets, including non-cannabinoid GPCRs (e.g. 5-HT1A), ion channels (TRPV1, TRPA1 and TPRM8, GlyR), PPARs, while also inhibiting uptake of AEA and weakly inhibiting its hydrolysis by the enzyme fatty acid amide hydrolase (FAAH).
Several lines of evidence indicate that cannabinoids may contribute to pain relief through an anti-inflammatory action In addition, non-cannabinoid constituents of the cannabis plant that belong to miscellaneous groups of natural products (terpenoids and flavonoids) may contribute to the analgesic, as well as the anti-inflammatory effect of cannabis.
Further animal and genetic modals suggest that the mechanisms of the analgesic effect of cannabinoids include inhibition of the release of neurotransmitters and neuropeptides from presynaptic nerve endings, modulation of postsynaptic neutron excitability, activation of descending inhibitory pain pathways, and reduction of neuronal inflammation.
Anti-Inflammatory effects and Pain management with Phytocannabinoids and CBD
Although CBD is still be evaluated clinically as a mono therapy for pain, its anti-inflammatory and anti-spasmodic benefits and good safety profile suggest that it could be an effective and safe analgesic. At this point there is moderate-quality evidence support the use of cannabinoids for the treatment of chronic pain and spasticity.
As human studies continue to develop our knowledge relating to the contribution of phytocannabinoids, the attenuation of central sensitisation by the activation of CB2 receptors in osteoarthritis sees a therapeutic potential for the use of CBD and other phytocannabinoids for the treatment of osteoarthritis.
Central sensitisation plays a pivotal role in the switch from acute to chronic pain mechanisms and the manifestation of altered sensory responses, such as touch-evoked pain (mechanical allodynia), in models of chronic pain. The discovery of a contribution of central sensitisation to osteoarthritic pain supports the investigation of novel molecular targets within the central nervous system and the peripheral for the treatment of osteoarthritic pain. The analgesic effects produced by activation of the cannabinoid receptor system are well documented and mediated by multiple sites of action.
The joint pain, often originating from central sensitisation, can often be characterised by increases in the activity of metalloproteases MMP-2 and MMP-9 in the spinal cord. CB2 agonists exert their analgesic effects in these osteoarthritis models by attenuating the activity of these enzymes.
In mouse models, CBD and THC decrease the production and release of pro inflammatory cytokines, including interleukin 1B, interleukin-6, and interferon (IFN)B, from LPS-activated microglial cells. In addition, CBD, not THC, reduces the activity of the NF-KB pathway, a primary pathway regulating the expression of pro inflammatory genes.
Other promising conditions utilising the use of phytocannabinoids include neuropathic pain and cancer-related pain. Cannabis - based medicinal extracts used in different populations of chronic nonmalignant neuropathic pain patients may provide effective analgesia in conditions that are refractory to other treatments.
Cannabinoids are also approved in many countries as an adjunctive analgesic in those with progressed cancer and malignant diseases where standard opioid treatment is ineffective. A systematic review of literature indicates cannabinoid therapy reduces pain intensity by >30% in those with malignant diseases.
Phytocannabinoids and the treatment of neurodegenerative disorders
Microglial activation and neuroinflammation appear to be the upstream mechanism underlying the pathogenesis of neurodegenerative diseases - including neuropathic pain, Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, amyotrophic lateral sclerosis, AIDS and Huntington’s disease.
CBD is a well-known antioxidant, exerting neuroprotective actions that might be relevant to the treatment of neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s Disease (PD) and Huntington’s Disease (HD).
CBD exerts a combination of neuroprotective, anti-oxidative and anti-apoptotic effects against the neuronal damage induced by the B-amyloid peptide (AB). It inhibits AB-induced neurotoxicity in PC12 cells and this effect is mediated by the WNT-B-catenin pathway, an important finding in light of the observation that disruption of the Wnt pathway by AB represents a pivotal event in the neuronal apoptosis occurring in Alzheimer’s disease. CBD may also prove beneficial in preventing apoptotic signalling in neutrons via restoration of Ca+2 homeostasis.
Several clinical studies have shown CBD as an effective treatment modality for reducing psychotic symptoms, improving dystonic symptoms, diminishing events related to REM sleep behaviour disorder, and improving quality of life in movement disorders such as Parkinson’s disease.
Phytocannabinoids and CBD in Anxiety-Based Conditions
Existing preclinical evidence strongly supports CBD as a treatment for generalised anxiety disorder, panic disorder, social anxiety disorder, obsessive-compulsive disorder, and post-traumatic stress disorder when administered acutely.
Interestingly, a single dose of CBD not only significantly decreased subjective anxiety symptoms, but also reduced cognitive impairment, speech performance discomfort and alert in anticipatory speech during a Simulation Public Speaking Test, in comparison to the placebo group.
It is believed that the acute anxiolytic effect of the CBD in individuals with generalised social anxiety disorder comes from it’s modification of cerebral blood flow in limbic and paralimbic areas and as a 5-HT1A receptor agonist in animal models.
The 5-HT1A receptor (5-HT1AR) is an established anxiolytic target. Buspirone and other 5-HT1AR agonist are approved for the treatment of generalised anxiety disorder with fair response rates. In preclinical studies, 5-HT1AR agonists are anxiolytic in animal models of general anxiety, prevent the adverse effects of stress, and enhance fear extinction. This leads the way for CBD to be further developed as a natural alternative for those wishing to follow that route.
This same activation of the 5-HT1A receptor has CBD improving several symptoms associated with post-traumatic stress disorder, including reducing acute heart rate and blood pressure, delaying (24 hours) antigenic effects of stress, reducing arousal and avoidance, and enhancing the extinction and blocking the reconsolidating of persistent fear memories.
Preclinical and animal models studies in the endocannabinoid system have found numerous ways which phytocannabinoids can expand on therapeutic options for conditions either in combination or independently of modern pharmaceutical applications via their influence on multiple molecular targets.
As more human clinical studies are completed, the potential of phytocannabinoids and their use in pain, mental health and other classically inflammatory conditions is clear and exciting.
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