Introduction & CBD
The first report of the existence of the brain cannabinoid receptor, termed the cannabinoid receptor type 1 (CB1R), was reported by Howlett’s group in the late 1980s. See, Hapsula and Clark, Int J Mol Sci. 2020 Oct; 21(20): 7693. The cloning and description of the CB1 and CB2 cannabinoid receptors in the central system and the subsequent isolation of the endocannabinoids in the early 1990s renewed the interest in the investigation of cannabinoid compounds, including, but not limited to Cannabidiol (CBD), Cannabinol (CBN), and Cannabigerol (CBG). See, Pertwee, Br. J. Pharmacol. 2008 Jan; 153(2): 199–215. Cannabinoids exhibit their action by a modulation of the signaling pathways crucial in the control of cell proliferation and survival. See, Śledziński et al., Cancer Med. 2018 Mar; 7(3): 765–775. Many in vitro and in vivo experiments have shown that cannabinoids inhibit proliferation of cancer cells, stimulate autophagy and apoptosis, and have also a potential to inhibit angiogenesis and metastasis.
In this introductory article of our Understanding Cannabinoids series, we provide you a summary of scientific literature related to the study of cannabinoids, especially, CBD, CBN, and CBG for their potential therapeutic effects.
Cannabidiol (CBD) is one of over 100 compounds found in hemp and marijuana. It is the second most prevalent compound (second only to THC) in cannabis. CBD belongs to a class of molecules called phyto-cannabinoids and is non-psychoactive. See, Boggs et al., Neuropsychopharmacology. 2018 Jan; 43(1): 142–154. Preclinical and clinical research studies demonstrate that CBD has strong anti-convulsing, anti-inflammatory, anti-oxidant, anti-depressant, anti-tumor, anti-psychotic, and neuroprotective properties. See, Fernández-Ruiz et al., Br. J. Clin. Pharmacol. 2013 Feb; 75(2): 323–333.
Many CBD proponents claim that it can effectively treat conditions such as anxiety, chronic pain, rheumatoid arthritis, cancer, PTSD, MS, and cardiovascular disease. As a matter of fact, studies to determine when CBD helps improve sleep and/or anxiety in a clinical population showed promising results and concluded that CBD may hold benefit for anxiety-related disorders. See, Shannon et al., Perm. J. 2019; 23: 18-041. Research is ongoing in the U.S., and other parts of the world to ascertain the effect of CBD on these and other ailments.
Mechanism of Action:
Cannabinoids, or phytocannabinoids (phyto = plant in Greek), interact with the human body and the brain through the endocannabinoid system (ECS). The ECS plays an important role in a plethora of functions within the body. See, Pacher et al., Pharmacol. Rev. 2006 Sep; 58(3): 389–462 and Donvito et al., Neuropsychopharmacology. 2018 Jan; 43(1): 52–79. At its most basic, the endocannabinoid system is a huge network of cannabinoid receptors which are spread through the body. The human endocannabinoid system releases cannabinoids that interact with the cannabinoid receptors found in the body.
The role of the ECS is to bring balance to our tissues, including the heart, digestive, endocrine, immune, nervous, and reproductive systems, by maintaining homeostasis. See, Kunos et al., J. Biol. Chem. 2008 Nov 28; 283(48): 33021–33025 and Chen, Neural Regen. Res. 2015 May; 10(5): 691–692. Homeostasis is when your body maintains a stable internal environment (i.e. body temperature, pH balance, glucose levels, etc.) despite any changes that may be happening in our external environment (i.e. air quality, toxins, sun exposure, food we eat, etc.).
The ECS itself is made up of three parts:
Receptors in the nervous system and around your body that endocannabinoids and cannabinoids bind with, and
Enzymes that help break down endocannabinoids and cannabinoids.
The human body produces cannabinoids known as endogenous cannabinoids or endocannabinoids. Examples of endocannabinoid include n-arachidonoyl dopamine (NADA), 2-arachidonoylglycerol (2-AG), anandamide, and virodhamine (OAE).
Endocannabinoids operate differently when compared to other neurotransmitters like serotonin or dopamine. Endocannabinoids are not synthesized in advance and stored. Rather, they are produced on demand as needed. See, Alger and Kim, Trends Neurosci. 2011 Jun; 34(6): 304–315; and Zou and Kumar, Int. J. Mol. Sci. 2018 Mar; 19(3): 833. Endocannabinoids are also hydrophobic, and hence are localized since they can’t travel very far. See, Medeiros et al., Sci. Rep. 2017; 7: 41362. Once manufactured, endocannabinoids attach to cannabinoid receptors. It was initially believed that endocannabinoid receptors only existed in the brain and nerves, but receptors have since been discovered throughout the entire human body, including the skin. See, Tóth et al., Molecules. 2019 Mar; 24(5): 918.
Cannabinoid receptors are found throughout the human body rooted in the cell membranes that are responsible for regulating multiple pathways leading to our daily experiences including mood, appetite, memory and pain sensation. See, Pacher et al., Pharmacol. Rev. 2006 Sep; 58(3): 389–462 and Donvito et al., Neuropsychopharmacology. 2018 Jan; 43(1): 52–79. The ESC is activated by naturally occurring endocannabinoids, CBD, or by the plant, cannabinoids present in hemp.
Both receptors can be activated by naturally occurring endocannabinoids, as well as by phytocannabinoids found in hemp and cannabis. There are two major cannabinoid receptors – CB1 and CB2. See, Howlett and Abood, Adv. Pharmacol. 2017; 80: 169–206.
CB1 receptors are highly concentrated within the brain and nervous system. In fact, there are more endocannabinoid receptors in a human brain than any other neurotransmitter receptor! Because of their high concentration in the brain, CB1 receptors are responsible for regulating mood, emotions, movement, appetite, memories, and more. CB1 receptors are also present in connective tissue, glands, some organs, and gonads. Also, CB1 receptors have been noticed in the T lymphocytes and it is proposed that their activation may be connected with the cytokine biasing induced by cannabinoids.
CB2 receptors are found mostly within the immune system (which is spread throughout the body). CB2 receptors are also found in several major organs, including the heart, liver, and kidneys, in addition to blood vessels, bones, lymph nodes, and reproductive organs. CB2 receptors are responsible for regulating a variety of pathways, but pain and inflammation are two of the biggest. The highest level of CB2 expression has been observed in B cells, followed by NK cells, monocytes, polymorphonuclear neutrophils, and T cells. It has been shown that the expression level of CB2 correlates with the cell activation state and with the presence of immune modulators.
Exogenous cannabinoids, such as tetrahydrocannabinol, produce their biological effects through their interactions with cannabinoid receptors. See, Lu and Mackie, Biol. Psychiatry. 2016 Apr 1; 79(7): 516–525. 2-arachidonoyl glycerol (2-AG) and arachidonoyl ethanolamide (anandamide) are the best-studied endogenous cannabinoids. Despite similarities in chemical structure, 2-AG and anandamide are synthesized and degraded by distinct enzymatic pathways, which impart fundamentally different physiological and pathophysiological roles to these two endocannabinoids.
CBD has been shown to inhibit fatty acid amide hydrolase (FAAH), which breaks down anandamide, and lead to an increased concentration of anandamide. See, Marzo and Pisticelli, Neurotherapeutics. 2015 Oct; 12(4): 692–698. Anandamide is considered the “bliss molecule” and plays an important role in the generation of pleasure and motivation. The increased concentration of anandamide can have a positive effect on the endocannabinoid system.
CBD also affects the fatty acid binding protein (FABP). FABP proteins bind to anandamide and transport the enzyme outside the synapse to broken down and metabolized by the FAAH. See, Ramer et al., Front Pharmacol. 2019; 10: 430. CBD affects the transportation process of FABP so that less anandamide is metabolized, again resulting in a higher concentration of anandamide.
Finally, CBD binds itself to the G-protein receptors known as TRPV-1. See, Petrocellis et al., Br. J. Pharmacol. 2011 Aug; 163(7): 1479–1494. TRVP-1 receptors are involved in regulating pain, body temperature, and inflammation. It is through this bind that scientists believe CBD helps with inflammation and pain relief.
Benefits of CBD
“Among Cannabis compounds, cannabidiol (CBD), which lacks any unwanted psychotropic effect, may represent a very promising agent with the highest prospect for therapeutic use.” See, Iuvone et al., CNS Neurosci. Ther. 2009 Spring; 15(1): 65–75. CBD is being used as a specific therapy for a number of diverse medical conditions—particularly pain and inflammatory disorders, in addition to anxiety, depression, and sleep disorders.
A large percentage of respondents indicate that CBD treats their condition(s) effectively in the absence of conventional medicine and with non-serious adverse effects. See, Corroon and Phillips, Cannabis Cannabinoid Res. 2018; 3(1): 152–161. Of note, the increasing amount of human studies evaluating the role of CBD in the alleviating anxiety and anxiety-related disorders are showing potential therapeutic success, specifically when CBD is administered with acute dosing. However, fewer studies exist that evaluate the safety and efficacy of long-term use of CBD in human populations.
There is a growing body of research that suggests CBD helps people with sleep disorders. See, Babson et al., Curr. Psychiatry Rep (2017) 19: 23. For its sedation effects, CBD activates the GABA receptors and the serotonin receptors in the endocannabinoid system of the brain. These receptors play an important role in modulating mood and anxiety, which are vital for sleep. GABA inhibit excess activity in the brain, thereby promoting relaxation. In a study to determine whether CBD helps improve sleep and/or anxiety in a clinical population, it was determined that "CBD appears to be better tolerated than routine psychiatric medications. "Furthermore, CBD displays promise as a tool for reducing anxiety in clinical populations." See, Shannon et al., Perm J. 2019; 23: 18-041. However, more randomized and controlled trials are needed to provide definitive clinical guidance."
Overall, current evidence indicates CBD has considerable potential as a treatment for multiple anxiety disorders. See, Blessing et al., Neurotherapeutics. 2015 Oct; 12(4): 825–836. The researchers found that existing preclinical evidence strongly supports CBD as a treatment for generalized anxiety disorder, panic disorder, social anxiety disorder, obsessive–compulsive disorder, and post-traumatic stress disorder when administered acutely. Researchers conducted a systematic review was to evaluate the current evidence on the safety and efficacy of CBD in the management of anxiety and anxiety-related disorders. See, Skelley et al., Cannabis Review, Volume 60, Issue 1, P253-261, JANUARY 01, 2020.
"[I]t is seen that CBD has demonstrated a developing role as an alternative therapy in the indications of anxiety disorders, specifically GAD, SAD, and anxiety related to PTSD." The researchers found that in the studies reviewed, "CBD regularly showed improved clinical outcomes in GAD, SAD, and anxiety related to PTSD, with minimal adverse effects, which differs from other therapeutic agents that are currently used for these indications. These results indicate that CBD could provide a unique therapeutic opportunity to augment or replace existing pharmacotherapy in patients with inadequate relief while causing fewer adverse effects."
CBD is a nonpsychotomimetic substance, and it is considered one of the most promising candidates for the treatment of psychiatric disorders. See, Calapai et al., Evid. Based Complement. Alternat. Med. 2019; 2019: 2509129. Researchers found that “CBD is effective in animal models of predictive of antidepressant effect. CBD promotes both a rapid and a sustained antidepressant effect in animal models. This effect seems to be due to its ability to interact with multiple neurotransmitter systems involved in depression, including the serotonergic, glutamatergic, and endocannabinoid systems.” CBD’s positive interaction with serotonin receptors in the brain is considered by many to be a crucial element of therapy for managing depression.
Studies show that CBD exhibits anxiolytic, antipsychotic, and neuroprotective properties. See, Crippa et al., Front Immunol. 2018; 9: 2009. "In addition, basic and clinical investigations on the effects of CBD have been carried out in the context of many other health conditions, including its potential use in epilepsy, substance abuse and dependence, schizophrenia, social phobia, post-traumatic stress, depression, bipolar disorder, sleep disorders, and Parkinson."
Evidence strongly supports that prolonged treatment (i.e. > 7 days) with CBD alleviates chronic pain caused by chronic constriction injury of the sciatic nerve. See, Argueta et al., Front Pharmacol. 2020; 11: 561. Rising prevalence of the non-psychoactive cannabinoid CBD presents an opportunity for the treatment of intractable chronic pain for which primary treatments are insufficient or not possible. CBD has been shown to be effective in alleviating pain due to its anti-inflammatory properties. It reduces inflammation and promotes sleep by interacting with other receptors in the endocannabinoid system.
Most of the scientific evidence that supports this claim is in animal-based research. Currently, very little evidence exists from human studies apart from testimonial claims. Further, some studies concluded that "[t]he phytocannabinoids have efficacy in the treatment of various chronic pain conditions with greatest promise as a therapeutic adjunct in treating peripheral and central neuropathic pain and inflammation-mediated chronic pain. See, Fine and Rosenfeld, Rambam Maimonides Med J. 2013 Oct; 4(4): e0022.
EPILEPSY SEIZURE DISORDER
Epidiolex, a plant-based CBD product, was recently approved by the FDA to treat seizures in people two-years and older with Lennox-Gastaut syndrome (LGS) and Dravet syndrome.
NEUROPROTECTIVE & NEURODEGENERATIVE DISEASES
CBD “may represent a lead compound for the development of therapeutics that are able to exert neuroprotection as well as to operate against neuroinflammatory component of neurodegenerative disorders.” See, Iuvone et al., CNS Neurosci. Ther. 2009 Spring; 15(1): 65–75. Effects of CBD on immune cells include the modulation of tumour necrosis factor (TNF)‐α, interleukin (IL)‐1, and interferon (IFN)‐γ by mononuclear cells [57, 58] and the suppression of chemokine production by human B cells. The antiinflammatory effects of CBD have not been restricted to the control of the peripheral inflammatory process since interesting results have also been observed in the prevention of the neuroinflammation, an effect that may justify the emerging role, described for CBD, as a potential neuroprotective agent.
“CBD, in fact, resulted in being able to protect neuronal and nonneural cells against several detrimental insults, such as β‐amyloid or 6‐hydroxydopamine and glutamate, which are considered to be the basis of disorders such as AD and PD.” According to NCBI, in the article cited above, inflammation is responsible for the loss of neurons in the nervous system. This, in turn, is responsible for the decline in motor and cognitive function, thereby causing the cascade of neurodegenerative symptoms.
"Experimental evidences show that cannabinoid system activity is neuroprotective regulating critical homeostatic processes and that cannabinoid signalling is possibly decreasing in ageing. Thus, elevation of cannabinoid receptor activity either by pharmacological blockade of the degradation of cannabinoids or by receptor agonists could be a promising strategy for slowing down the progression of brain ageing and for alleviating the symptoms of neurodegenerative disorders." See, Gorzo, Philos Trans R Soc Lond B Biol Sci. 2012 Dec 5; 367(1607): 3326–3341.
Gene profiling showed that the CBD treatment suppresses the transcription of a large number of proinflammatory genes in activated TMOG. See, Kozela, J. Neuroinflammation. 3, 136 (2016). These include cytokines (Xcl1, Il3, Il12a, Il1b), cytokine receptors (Cxcr1, Ifngr1), transcription factors (Ier3, Atf3, Nr4a3, Crem), and TNF superfamily signaling molecules (Tnfsf11, Tnfsf14, Tnfrsf9, Tnfrsf18). “IL-17 differentiation” and “IL-6 and IL-10-signaling” were identified among the top processes affected by CBD.
In a study conducted by Kozela and colleagues, highlighted in the above cited article, CBD was shown to increase a number of IFN-dependent transcripts (Rgs16, Mx2, Rsad2, Irf4, Ifit2, Ephx1, Ets2) which are known to execute anti-proliferative activities in T cells. Interestingly, certain MOG35-55 up-regulated transcripts were maintained at high levels in the presence of CBD, including transcription factors (Egr2, Egr1, Tbx21), cytokines (Csf2, Tnf, Ifng), and chemokines (Ccl3, Ccl4, Cxcl10) suggesting that CBD may promote exhaustion of memory TMOG cells. In addition, CBD enhanced the transcription of T cell co-inhibitory molecules (Btla, Lag3, Trat1, and CD69) known to interfere with T/APC interactions. Furthermore, CBD enhanced the transcription of oxidative stress modulators with potent anti-inflammatory activity that are controlled by Nfe2l2/Nrf2 (Mt1, Mt2a, Slc30a1, Hmox1).
Using microarray-based gene expression profiling, Kazela and colleagues, in the above study, demonstrated that CBD exerts its immunoregulatory effects in activated memory TMOG cells via (i) suppressing proinflammatory Th17-related transcription, (ii) by promoting T cell exhaustion/tolerance, (iii) enhancing IFN-dependent anti-proliferative program, (iv) hampering antigen presentation, and (v) inducing antioxidant milieu resolving inflammation. These findings put forward mechanism by which CBD exerts its anti-inflammatory effects as well as explain the beneficial role of CBD in pathological memory T cells and in autoimmune diseases.
Research has shown that one of the main physiological function of the cutaneous ECS is to constitutively control the proper and well-balanced proliferation, differentiation and survival, as well as immune competence and/or tolerance, of skin cells. See, Biro et al., Trends in Pharmacological Sciences 30(8):411-20. The disruption of this delicate balance might facilitate the development of multiple pathological conditions and diseases of the skin (e.g. acne, seborrhea allergic dermatitis, itch and pain, psoriasis, hair growth disorders, systemic sclerosis and cancer). The research studies conclude that targeted manipulation of the ECS (aiming to normalize the unwanted skin cell growth, sebum production and skin inflammation) might be beneficial in a multitude of skin diseases.
Cannabinoids are regarded with growing interest as eligible compounds in the treatment of skin inflammatory conditions, with potential anticancer effects, and the readiness in monitoring of effects and the facility of topical application may contribute to the growing support of the use of these substances. See, Scheau et al., Molecules. 2020 Feb; 25(3): 652. "Cannabinoids have proven effective as protective agents in neuroinflammatory disorders, and their anti-inflammatory and immunomodulating effects have also proven beneficial in inflammatory skin disorders." The current literature describes numerous, exciting potential applications of cannabinoids in the treatment of various skin disorders. See, Eagleston et al., Deratology Online Journal, Vol. 24, No. 6, June 2018. However, the mechanisms, safety, and efficacy of cannabinoids in the treatment of dermatologic diseases remain to be defined.
CBD showed promise in alleviating negative withdrawal effects and reducing motivation to self-administer or reinstatement of drug use in animals. See, Chye et al., Front Psychiatry. 2019; 10: 63. Although further studies are necessary to evaluate the role of CBD in preventing substance abuse. Some preclinical studies suggest that CBD may have some therapeutic properties in treating opioid-, cocaine-, and psychostimulant-use disorders. Some preliminary data suggest that it could be advantageous in treating cannabis and tobacco-use disorder in humans. See, Hurd et al., Neurotherapeutics. 2015 Oct; 12(4): 807–815 and Prud'homme et al., Subst. Abuse. 2015; 9: 33–38.
Although they do have major differences, CBD and Cannabinol (CBN) are quite similar in the health benefits they produce. CBN is also a potent sedative that can potentially offer an alternative to traditional pharmaceutical for certain conditions. Some of the health benefits of CBN include:
Pain relief: Research has shown that cannabinol can help with pain relief as it alters the pain signals that are sent to the brain by the neurons.
Antibacterial: CBN has shown promise at fighting MRSA bacteria, an infection particularly resistant to antibiotics.
Anti-convulsive: As a by-product of THC, CBN has potent anti-convulsive properties.
CBN may be the the most potent sedative of all the cannabinoids. This sedation makes it a robust sleep aid and treatment for poor sleep. CBN has been found to initiate sleep onset and prolong sleep times, in addition to reducing drowsiness and promoting wakefulness during the day. It has been shown to lull patients to sleep and recover sustained sleep. Cannabinol may hold the key to feeling refreshed in the morning. This 'refresh' remains energized throughout the day when using CBN. However, more research on the exact processes it aids sleep and wakefulness is needed.
While Cannabigerol (CBG) is yet to match the appeal of CBD, it may soon play a pivotal role in everyday consumer products as it quietly demonstrates a wide array of intriguing medicinal benefits. “The pharmacological effects of CBG described in the scientific literature include: anti-fungal, anti-insect and anti-inflammatory activity; neuroprotective activity; stimulation of appetite, and enhancement of the death process of cancer cell,” Dr. Itzhak Kurek, CEO and co-founder of Cannformatics, a Northern California biotech company that uses bioinformatics to improve medical cannabis.
Cannabigerolic acid (CBGA) is the chemical precursor to tetrahydrocannabinolic acid (THCA; precursor of THC) and cannabidiolic acid (CBDA; precursor of CBD), playing a key role in the biochemistry of the cannabis plant. CBG interacts with both the CB1 and CB2 receptors, potentially inhibiting the intoxicating effects of THC. See, Navarro et al., Front Pharmacol. 2018; 9: 632. CBG has also demonstrated an ability to increase anandamide, commonly referred to as the “bliss molecule,” an endogenous cannabinoid that helps regulate a wide range of bodily functions, including appetite, sleep, mood, and the immune system.
We will cover more about CBN and CBG in our upcoming articles, along with other relevant topics. Stay tuned!!!
The Federal Food, Drug, and Cosmetic Act require that we inform you that the efficacy of any cannabinoid, including, but not limited to, CBD or CBN, products has not been confirmed by FDA-approved research as a treatment for any medical condition. The information in this document is not intended to diagnose, treat, cure or prevent any disease.
Originally posted by FP Botanicals LLC on October 30, 2020. Last updated on November 2, 2020.