What is CBG?
POTENTIAL THERAPEUTIC BENEFITS OF CBG
CBG is synthesized in plants via the decarboxylation of cannabigerolic acid (CBGA). CBGA also serves as the precursor to Δ9-tetrahydrocannabinolic acid (Δ9-THCA), cannabidiolic acid (CBDA), and cannabichromenic acid (CBCA), and thereby the more commonly known, nonacidic forms of Δ9-tetrahydrocannabinol (Δ9-THC), cannabidiol (CBD), and cannabichromene (CBC).
Due to this rapid conversion, there are low concentrations (~10% cannabinoid content) of CBG naturally occurring in the plant, except in the case of rare chemotypes (> 0.3%) with mutations that alter cannabinoid conversion. The relative costs and difficulties of obtaining CBG and the scientific focus on other cannabinoids such as Δ9-THC and CBD have likely contributed to the current gap in the volume and scope of CBG research, particularly regarding human exposure and CBG bioavailability.
However, published literature does indicate that CBG interacts at several different receptor sites within the human body. Cannabinoids in general primarily interact with the endocannabinoid system, which works as a large signaling system to help to regulate biological processes involved in metabolism, inflammation, appetite, pain perception, neuroprotection, and mood.
This system is characterized by two main endocannabinoids, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), which regulate the release of neurotransmitters and the subset of G-protein-coupled receptors they interact with: cannabinoid receptor type 1 (CB1), cannabinoid receptor type 2 (CB2), and the potential nonhomologous “CB3 receptor” GPR55. Furthermore, CB1 and CB2 receptors may also form heteromers called CB1-CB2 heteroreceptors that interact differently than either receptor on its own.
Of the dozens of different cannabinoids identified in the Cannabis sativa plant, interest in cannabigerol (CBG) has greatly increased in recent years. First described by Raphael Mechoulam in 1964, CBG has remained largely in the shadows of public discourse with the spotlight on the more well-known cannabinoids, CBD and THC.
However, progress in cannabinoid legality and access has generated new investigations into this fundamental phytocannabinoid and its potential benefits.
CBG has been shown to have low affinity for CB1 and CB2 receptors, with studies indicating it is a weak or partial agonist for both. Additionally, CBG is an inhibitor for: anandamide (AEA) cellular uptake; monoacyl glycerol lipase (MAGL), the hydrolytic enzyme for 2-arachidonoylglycerol (2-AG); N-acylethanolamine acid amidase (NAAA); COX-1 with full inhibition and approximately 70% of COX-2.
CBG is a very potent α-2 adrenoceptor agonist, displaying nanomolar to sub-nanomolar affinity. At 5HT1A receptors, CBG has been shown to be a potent antagonist (50nM range), reducing 5HT1A autoreceptor activity and thereby increasing synaptic serotonin availability. At PPARγ sites, which regulate adipocyte differentiation, insulin sensitivity, and inflammatory states, CBG demonstrates partial agonism with affinity stronger than CBD and Δ9-THC.
Finally, CBG interacts with certain transient receptor potential cation channels in a similar manner to CBD with generally minor differences in affinity. CBG stimulates and then desensitizes TRPV1 and TRPV2, and has been shown to stimulate TRPV3 and TRPV4 channels. It is also a relatively potent antagonist for TRPM8 receptors and may regulate TRPA1 activity (EC50 in micromolar range).
CBG RECEPTOR ACTIVITY
Given its various interactions within the body, it is no surprise that CBG is under investigation as a therapeutic agent for several disease states. The anti-inflammatory and neuroprotective properties of CBG are a primary area of focus. CBG inhibited PGE2 release in rheumatoid synovial cells stimulated with proinflammatory substances and has demonstrated inflammatory related analgesic effects, likely due to its action as an α-2 agonist.
Regarding Inflammatory Bowel Disease (IBD), CBG’s action on TRP channels (which play a role in gastrointestinal inflammation) has been shown to restore antioxidant protection to intestinal epithelial cells as well as counteract inflammatory increases in colonic interleukin-1β, increase in interferon-γ, and decrease in interleukin-10. Furthermore, CBG was found to increase the rate of colonic tissue recovery and ratio of colon weight to length while also demonstrating anti-inflammatory effects on murine colitis and preventing colitis-related damage.
Taken together, the scientific literature indicates that there is immense potential for CBG as a therapeutic agent. However, there are still several key gaps in knowledge that prevent recommendations for widespread use, chief among which is the lack of in vivo human studies. Without these studies to identify effects and outcomes in living human subjects, there are concerns regarding CBG’s mechanisms of action and how they will interact with other body systems and medications.
For example, the inhibition of 5-HT1A may affect the speed and efficacy of selective serotonin reuptake inhibitors (SSRIs), leading to unpredictable potentiating effects on concurrently administered psychiatric medications and serotonin-modulating substances. Additionally, its potency as an α-2 agonist may unpredictably change blood pressure, induce sedation, and interact with other cardiovascular medications, leading to hypotension, bradycardia, or xerostomia.
Another knowledge gap exists concerning the “entourage effect,” or the synergistic action of the phytocannabinoids, terpenes, and flavonoids found in Cannabis sativa. Botanical drug substances (BDS) that contain CBG in combination with these compounds has been found to be more effective than CBG alone.
However, the majority of CBG studies published have utilized isolated CBG as opposed to CBG-BDS containing other naturally occurring substances. This is further exacerbated by low CBG concentrations found in most Cannabis strains, making it potentially more difficult and costly to prepare CBG-BDS at effective doses compared to other phytocannabinoids like CBD and Δ9-THC.
Finally, there are urgent concerns around the vast increase in visibility, marketing, and access to unregulated CBG products. While many companies are now publicizing CBG as the “mother of all cannabinoids,” given the Cannabis plant’s ability to convert CBG and CBGA into other molecules, these companies neglect to mention that the human body lacks the necessary conversion pathways for cannabinoids.
CBG’s raised public profile and potential drug-drug interactions combined with the lack of data on the effects of human consumption highlight a vital and urgent need for in vivo human research and consumption monitored and controlled by trained healthcare professionals.
GAPS IN KNOWLEDGE
Other areas of therapeutic focus for CBG include potential treatments for cancer, metabolic disorders, and bacterial infection. It has shown antiproliferative effects in multiple cancer lines, such as breast, prostate, colorectal carcinoma, and gastric adenocarcinoma, likely due to its action at TRP channels. In metabolic disorders, CBG has been shown to significantly inhibit aldose reductase and increase insulin sensitivity via PPARγ agonism with comparative effects to rosiglitazone. Additionally, it demonstrates the ability to stimulate appetite and opposes the antiemetic effects of CBD, indicating potential for CBG in treating weight loss and loss of appetite in cancer anorexia-cachexia syndrome.
Finally, CBG demonstrates strong antibacterial properties, superior to that of other major cannabinoids, towards gram-positive bacteria, mycobacteria, and fungi. This is particularly true in the case of methicillin-resistant Staphylococcus aureus (MRSA), where CBG has been found to have a lower inhibitory concentration in five of six MRSA strains compared to norfloxacin and reduced colony forming units at equivalent efficacy to vancomycin.
The neuroprotective properties of CBG, on the other hand, appear to be related to its action at 5HT1A and PPARγ receptors. CBG was able to protect against oxidation-related neuronal death linked to 5HT1A receptor activity. Researchers found that action at CB1 and CB2 did not seem to be related to neuroprotective potential and CBG demonstrated differences in neuroprotective action depending on the damage signaling pathway involved. The cannabinoid has also demonstrated neuroprotective affects mediated through PPARγ receptors, improving motor function and restoring locomotor activity to normal, which has the potential to reduce the severity of neurological illnesses like Huntington’s disease, Parkinson’s disease, and multiple sclerosis.