The research on the anti-palliative effects of cannabinoids, namely THC, has produced pharmaceutical options like Marinol that have been on the market since the mid-80s and remain available to patients with intractable chemo-related nausea and vomiting. However, recent research suggests that cannabinoids may do more than treat the symptoms associated with conventional cancer therapies; some cannabinoids may kill cancer cells altogether and with a low risk of side effects or damage to healthy cells.
Recent pre-clinical studies have found that one such phytochemical component, cannabigerol (CBG), may be exceptionally efficacious against a number of cancer cell lines, and without the risk of intoxication.
CBG is the precursor to all other cannabinoids, including THC, CBD and CBC. CBG in its raw form, cannabigerolic acid (CBGA), develops within the plant’s cells when two organic compounds produced by the plant, olivetolic acid (OA) and geranyl pyrophosphate (GPP), combine. CBGA then is secreted into trichomes before it converts into the three major cannabinoid lines: THCA, CBDA, and CBCA, otherwise known in their more studied, “activated” forms as THC, CBD and CBC.
Unlike THC, CBG doesn’t have any great affinity for activating CB1 receptors, thus it doesn’t create a classic cannabis high in consumers—though its psychoactive efficacy may help treat certain mood disorders, including anxiety and depression. However, much like other cannabinoids, CBG does engage with the endogenous cannabinoid system both directly and indirectly, as well as through a number of peripheral pathways in the body.
Deactivation, or antagonism, of the ion channel TRPM8 (Transient Receptor Potential Cation Channel subfamily Melastatin member 8), otherwise known as the “cold and menthol receptor”, is one such mechanism of action for CBG. Irregular expression of this receptor is implicated in the initiation and progression of tumors, including prostate, melanoma, breast adenocarcinoma, bladder and colorectal cancers. Currently, the strongest evidence for CBG anti-tumor therapy via the TRPM8 channel is supported by research into colon cancer cell lines.
CBG Studies on Colorectal Cancer
A number of studies have pointed to CBG’s efficacy against colorectal cancer via TRPM8 antagonism including a 2014 paper published in Carcinogenesis which described potent in vivo action that promoted apoptosis (programmed cell death), improved oxidative stress responses, and reduced cell growth in colorectal cancer cells. The study found that these results were independent of CBG’s engagement with other TRP receptor channels and were improved by CB2 receptor deactivation, the endocannabinoid receptor predominately associated with immune system response. Inversely, activation of CB2 receptors has been linked to colon cancer progression which suggests that cannabinoids whose primary mechanisms of action lie outside of canonical cannabinoid receptors, like CBG, may prove most effective, according to the study’s authors.
CBG isn’t alone in its cytotoxic effects on colorectal cancer; its raw form has also demonstrated promising early results. A 2018 paper published in Cannabis and Cannabinoid Research observed CBGA-rich cannabis extractions were also involved in cytotoxic activity on in vitro colon cancer cells, indicating the presence of additive effects with combined cannabinoid ratios in the presence of minute amounts of other cannabis compounds like terpenes, specifically in relation to preparations rich in both CBGA and THCA. The THCA-rich fraction was found to be moderately effective, but efficacy improved significantly with the addition of CBGA. Furthermore, both neutral (THC and CBG) and acidic forms of these cannabinoids displayed cytotoxicity, but the acidic forms were less active on normal colon cell lines thereby elucidating their potential for chemopreventative activity against noncancerous colorectal growths associated with a greater risk of developing cancer, according to the study. These results on mixed ratio applications strengthen previous research that demonstrated CBG botanical extracts to be more active at TRPM8 than pure CBG.
The therapeutic potential of cannabinoid synergy, known as the Entourage or Ensemble Effect, was also discussed in a 2018 study that examined activity against breast cancer cell lines. Referencing extensive preclinical data that demonstrated cannabinoids can trigger antitumor responses in various forms of cancer, the authors found that botanical drug preparations rich in CBG, THCA, and THC were more effective than THC alone in cell culture and animal models.
While THC displayed some efficacy by elevating immune and antioxidant responses through activation of CB2 receptors, the authors described the importance of non-cannabinoid receptor pathways in the improvement of botanical drug preparations activity against cancer cells, especially in cancer types that inherently express low to undetectable levels of cannabinoid receptors. For these types, a 2005 study published in The Journal of Immunology described how THC and other cannabinoids whose primary mechanism of anti-tumor action appears to rely on canonical cannabinoid receptor engagement may not be as effective as cannabinoids that engage through peripheral pathways, like CBG.
Stomach, Bone, and Gastrointestinal Cancers
Cannabics Pharmaceuticals, a U.S. company with research facilities in Israel, specifically focuses on the development of cannabinoid therapies for cancer treatment and its conventional therapy side effects. In recent headlines, the company announced preliminary findings that further elucidate the anti-tumor potential of CBG and the potential for cannabinoid synergy in cancer treatments.
In pre-clinical work that looked at human stomach and bone cancer cell lines in vitro, CBG was found to be more effective than its acidic form, CBGA, against diseased cells. Additionally, investigators demonstrated the potency of both CBG and CBC (cannabichromene) against gastrointestinal cancer cells. Here, both cannabinoids were shown to induce significantly higher rates of cancer cell death compared to other cannabinoids and suggest the need for further investigation into synergistic efficacy.
Other Areas Worthy of Investigation
The potential of CBG to regulate inflammatory and oxidative mechanisms across numerous receptor sites bodes well for its use against a plethora of pathologies. In fact, in a GW Pharmaceuticals patent application, the company provided a large list of diseases and conditions where they felt CBG research was warranted:
This long list is no surprise when considering the primary role of the endocannabinoid system as a regulator of balance within bodily systems for optimal health and wellness.
Other promising cancer-related research for CBG includes a 1996 investigation that demonstrated the cannabinoid’s “significant antitumor activity” against mouse melanoma cells and that same team’s 1998 discovery of the cytotoxic effects of CBG at high doses against human oral epithelial carcinoma cells. As seen in colorectal cancer cell lines, TRPM8 receptors may also play a role in epithelial carcinogenesis as these menthol receptors have also been found in human epithelial cells. The implication of TRPM8 in the growth and progression of pancreatic cancer should not be discounted and its potential as a molecular target for prostate cancer has already been suggested by scientists.
The deactivation of overactive TRPM8 receptors by CBG is not the only mechanism of action to consider when it comes to cannabinoid-based cancer therapies. Another attractive molecular target for CBG’s anti-inflammatory and antioxidant benefits is through potent activation of the peroxisome proliferator-activated receptor gamma, or PPARγ. These nuclear hormone receptors play an important role in regulating inflammation, glucose metabolism and cancer. In a 2017 review of PPAR receptors as potential drug targets for cancer therapy, investigators noted that PPARγ activation inhibits tumor progression and increases tumor suppression. Research from 2013 published in Cell Death and Disease demonstrated the efficacy of THC, another PPARγ agonist, against in vitro and in vivo liver cancer cell lines. With THC’s risk of unwanted intoxication, CBG and mixed-cannabinoid preparations should be further studied for their efficacy against liver cancer development and progression.
While human trials have not yet been published on the potential efficacy of CBG against various forms of cancers and there is a great deal more to understand before therapeutic pharmaceutical treatments are developed, scientists are chomping at the empirical evidence bit. More importantly, understanding cannabinoid potential, even in its investigational infancy, can help consumers better navigate the products currently available on the market to fit their needs. By actively engaging with receptors in the body implicated in the development and progression of a number of cancer cell lines, as well as playing a vital role in regulating the body’s own natural defense systems without fear of intoxication, research suggests that CBG holds enormous therapeutic promise moving forward.