Introduction Cannabigerol (CBG), a non-psychoactive cannabinoid found in the Cannabis sativa plant, is gaining attention in the scientific community for its potential therapeutic benefits. Unlike its more famous counterparts, THC and CBD, CBG is often referred to as the "mother of all cannabinoids" due to a common misconception about its role as a precursor from which other cannabinoids are synthesized (these cannabinoids are synthesized from CBGA, the acidic form of CBG, from which CBG is itself synthesized). This article delves into the effects, benefits, and legal status of CBG, with a particular focus on its interaction with various receptor sites in the human body.
The Endocannabinoid System and CBG The endocannabinoid system (ECS) is a complex cell-signaling system that plays a key role in regulating a wide range of functions and processes, including sleep, mood, appetite, memory, and reproduction. It is composed of endocannabinoids, receptors, and enzymes. CBG, like other cannabinoids, interacts with this system, but it does so in a unique way.
CBG has a low affinity for CB1 and CB2 receptors, the primary receptors in the ECS. However, it acts as an antagonist of the CB1–CB2 heteromer, a complex that forms when CB1 and CB2 receptors come into close proximity. This interaction may have implications for the modulation of the ECS and the potential therapeutic applications of CBG. In addition to its known affects with the endocannabinoid system, CBG also interacts in a few key ways with other receptor sites in the body:
5-HT1A Receptor
The 5-HT1A receptor is a subtype of the serotonin receptor, which is widely distributed throughout the brain and plays a key role in the regulation of mood and cognition. CBG has been shown to have a high affinity for this receptor, suggesting potential antidepressant and anti-anxiety effects. A study found that CBG exhibits a strong affinity for the 5HT1A receptor, acting as a partial agonist. This interaction leads to a cascade of immediate physiological effects, including modulation of neurotransmission, regulation of mood, and control of stress responses. These effects are primarily due to the role of the 5HT1A receptor in the serotonergic system, which is crucial for maintaining mental health.
The interaction between CBG and the 5HT1A receptor also opens up potential medicinal uses. For instance, a study in 2020 suggested that CBG could be used in the treatment of anxiety and depression due to its ability to modulate serotonin levels. Additionally, a review by Russo and Marcu (2017) highlighted the potential of CBG in alleviating symptoms of conditions such as Parkinson's disease and migraines, where the 5HT1A receptor is known to play a significant role.
α-2 Adrenoceptor
α-2 adrenoceptors play a crucial role in regulating neurotransmitter release in the central and peripheral nervous system. CBG's interaction with this receptor could potentially influence a variety of physiological processes, including pain perception, mood regulation, and immune response. CBG is a very potent α-2 adrenoceptor agonist, displaying nanomolar to sub-nanomolar affinity. However, data on CBG selectivity for receptor subtypes is currently lacking.
The anti-inflammatory and neuroprotective properties of CBG are another 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.
α-2 adrenoceptor agonists can decrease sympathetic outflow, leading to a reduction in the fight-or-flight response. This could result in a decrease in heart rate, blood pressure, and blood glucose levels. α-2 adrenoceptor agonists are also known to decrease blood pressure. They do this by inhibiting the release of norepinephrine, a neurotransmitter that normally increases heart rate and blood pressure. Therefore, CBG might also have hypotensive effects.
PPARγ
Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor that plays a crucial role in regulating lipid metabolism, inflammation, and glucose homeostasis. CBG has been shown to activate PPARγ, suggesting potential benefits in the treatment of metabolic disorders. According to a study by Granja et al., CBG acts as a potent PPARγ agonist, with an EC50 value of 0.47 μM, which is comparable to the strength of the synthetic PPARγ agonist rosiglitazone.
The interaction between CBG and PPARγ has implied physiological effects, including the modulation of lipid metabolism and the reduction of inflammation. This is particularly relevant in the context of neuroinflammation, where CBG has been shown to reduce the expression of pro-inflammatory markers such as iNOS and IL-1β, likely through its activation of PPARγ. Furthermore, CBG's interaction with PPARγ may also have implications for metabolic disorders, as PPARγ is a key regulator of adipocyte differentiation and insulin sensitivity.
In terms of potential medicinal uses, CBG's interaction with PPARγ could be harnessed for the treatment of conditions such as neuroinflammatory diseases, metabolic disorders, and potentially even cancer. For instance, a study by De Petrocellis et al. found that CBG exhibited anti-proliferative effects on human colorectal cancer cells, potentially through its activation of PPARγ. However, more research is needed to fully elucidate the therapeutic potential of CBG in relation to PPARγ.
GPR55
GPR55 is a G protein-coupled receptor that is involved in various physiological processes, including pain perception and bone development. One of the key interactions of CBG is with the G-protein coupled receptor 55 (GPR55), a receptor that is recently beginning to be considered part of the endocannabinoid system.
The interaction between CBG and GPR55 is intriguing due to the receptor's role in modulating pain perception, inflammation, and energy homeostasis. A study by Laun and Song (2017) demonstrated that CBG has a strong binding affinity for GPR55, which may contribute to its potential anti-inflammatory and analgesic effects. Additionally, research by Anavi-Goffer et al. (2012) showed that CBG can act as a GPR55 antagonist, potentially modulating the receptor's activity and influencing physiological processes.
The potential medicinal uses of CBG related to its interaction with GPR55 are vast. Given the receptor's role in pain perception and inflammation, CBG could potentially be used in the treatment of conditions such as chronic pain and inflammatory diseases. Furthermore, the receptor's involvement in energy homeostasis suggests that CBG could also have applications in metabolic disorders. However, more research is needed to fully understand the implications of the CBG-GPR55 interaction and to validate these potential therapeutic uses.
TRP Channels
Transient receptor potential (TRP) channels are a group of ion channels located on the cell membrane. They are involved in various physiological processes, including temperature sensation, taste, and pain perception6. CBG has been found to interact with several transient receptor potential (TRP) channels, playing a significant role in carcinogenesis. CBG potently blocks TRPM8, activates TRPA1, TRPV1, and TRPV2 channels, and inhibits the reuptake of endocannabinoids. These interactions stimulate reactive oxygen species (ROS) production, promote apoptosis, and inhibit cell growth in colorectal cancer (CRC) cells. The effects of CBG on cell growth are independent of TRPA1, TRPV1, and TRPV2 channels activation, and are further increased by a CB2 receptor antagonist.
In addition to its interactions with TRP channels, CBG has been found to upregulate CHOP mRNA and reduce cell growth in CRC cells. This effect is shared by other TRPM8 antagonists and is reduced in TRPM8 silenced cells. In vivo, CBG has been shown to inhibit the growth of xenograft tumors as well as chemically induced colon carcinogenesis.
In conclusion, CBG's interactions with TRP channels, particularly its antagonistic effect on TRPM8, have significant implications for the treatment of colorectal cancer. Further research is needed to fully understand the mechanisms underlying these interactions and their potential therapeutic applications.
The FDA and Cannabinoids The U.S. Food and Drug Administration (FDA) regulates cannabis-derived compounds as it does any other FDA-regulated products. However, the FDA has also stated that ingredients derived from parts of the cannabis plant that do not contain THC or CBD might be able to be marketed as dietary supplements. For example, the FDA has issued a GRAS (Generally Recognized as Safe) certification for three hemp-related products, including hemp-seed oil, indicating that some parts of the cannabis plant are safe to consume or study without the need for an Investigational New Drug (IND) application or additional legal restrictions.
The FDA's regulations distinguish between parts of the cannabis plant that are generally recognized as safe and may be consumed or studied without the need for an IND (such as hemp seed oil), and those that are drugs by definition and must be treated as such (like isolated CBD). However, the FDA has not provided clear guidance on substances that contain cannabinoids other than THC and CBD, particularly when those substances contain only trace elements of both THC and CBD.
When it comes to CBG, it's important to examine the FDA’s current positioning, the reasoning behind it, and the safety information and research that is presently available. The FDA's primary concern with potential contaminants in hemp seed-derived ingredients is THC and CBD. However, the GRAS approval and previous responses indicate the potential for other cannabinoids in legal hemp seed products. This aligns with research that has found a statistically significant amount of cannabinoids in GRAS hemp seed oils, including CBG.
The FDA is currently evaluating the regulatory frameworks that apply to certain cannabis-derived products that are intended for non-drug uses. While CBG products as a whole appear to remain in a legislative gray area until the FDA is able to collect additional information and issue a determination, it is clear that their guidelines are focused on product safety as well as the concentration, if any, of THC and CBD in the product. They have stated they are committed to setting sound, science-based policy and are seeking evidence, based in clinical science, to make determinations on non-THC, non-CBD cannabis-derived products. It is this determination that Formula30A Cannabigerol, a full-spectrum extract naturally containing zero percent THC from seed to end product and only trace amounts of CBD, was approved by an Independent Review Board for clinical study in healthy humans. This commitment by the FDA is underscored by the launch of the Cannabis Derived Products Data Acceleration Plan, which aims to increase the FDA's ability to gather information on the safety of cannabis-derived products, including emerging cannabinoid markets such as CBG.
Conclusion CBG is a fascinating cannabinoid with a unique profile of activity at various receptor sites. Its potential therapeutic benefits, coupled with its non-psychoactive nature, make it a promising candidate for further research and potential therapeutic applications. As our understanding of the endocannabinoid system and the role of cannabinoids like CBG continues to grow, so too does the potential for new, innovative treatments for a variety of conditions.