Cannabigerol (CBG): A Comprehensive Review of Its Molecular Mechanisms and Therapeutic Potential

Abstract

Cannabigerol (CBG), a non-psychoactive cannabinoid found in cannabis, has emerged as a promising therapeutic agent with a diverse range of potential applications. Unlike its well-known counterpart tetrahydrocannabinol (THC), CBG does not induce intoxication, making it an attractive option in the clinic. Recent research has shed light on CBG's intriguing molecular mechanisms, highlighting its potential to modulate multiple physiological processes. This review delves into the current understanding of CBG's molecular interactions and explores its therapeutic power to alleviate various conditions, including cancer, metabolic, pain, and inflammatory disorders, amongst others. We discuss how CBG interacts with the endocannabinoid system and other key signaling pathways, such as CB1, CB2, TPR channels, and α2-adrenoceptor, potentially influencing inflammation, pain, neurodegeneration, and other ailments. Additionally, we highlight the ongoing research efforts aimed at elucidating the full spectrum of CBG's therapeutic potential and its safety profile in clinical settings. Through this comprehensive analysis, we aim to provide a deeper understanding of CBG's role in promoting human health and pave the way for future research endeavors.

Keywords: Cannabigerol (CBG); cannabinoid receptor; endocannabinoid system; molecular mechanism.

Figure 1

Chemical structures and biosynthesis pathways of the primary cannabinoids. Cannabinoid biosynthesis is initiated with the synthesis of CBGA from Geranyl pyrophosphate and Olivetolic acid. Geranyl pyrophosphate and Olivetolic acid served as substrates for 2-O-geranyl olivetolic acid, 5-geranyl olivetolic acid, and 4-O-geranyl olivetolic acid. CBGA is the primary precursor for most of the cannabinoids. CBDA synthase directs the conversion of CBGA to CBDA [23]. Decarboxylation of CBDA yields cannabidiol (CBD) [24]. Similarly, THCA synthase facilitates the formation of tetrahydrocannabinolic acid (THCA) from CBGA [25], with subsequent decarboxylation generating tetrahydrocannabinol (THC). Interestingly, THCA can also be oxidized to cannabinolic acid (CBNA), the precursor to cannabinol (CBN). Finally, CBCA synthase and decarboxylation lead to the formation of cannabichromene (CBC) through cannabichromenic acid (CBCA), in a similar fashion as CBD and THC [26].

Figure 2

CBG-related receptors and potential therapeutical benefit. CBG acts as the agonist of the receptors of the TRPV family, PPARγ, and 5-HT_1A, and as an antagonist of the receptor TRPVM8. CBG weakly agonizes the action of CB1 and partially acts as an agonist on CB2 receptor agonists. CBG also inhibits FAAH, which results in increased anandamide levels. Current studies revealed that CBG has potential therapeutic effects on neuroprotection, inflammation, antibacterials, metabolic syndrome, pain management, and cancer treatment. CB1, cannabinoid receptor type 1; CB2, cannabinoid receptor type 2; TRPM8, transient receptor potential cation channel 8; 5-HT_1A, serotonin receptor 1A; FAAH, fatty acid amide hydrolase; TRPV, transient receptor potential vanilloid; PPARγ, peroxisome proliferator-activated receptor gamma.

Figure 3

The neuroprotective effects of CBG. CBG treatment improved motor function and reduced a marker of oxidative stress in the hypothalamus. In combination with CBC and CBN, CBG significantly mitigated the toxic effects of Aβ protein in PC12 cells. Furthermore, CBG decreased cytokine and nitric oxide production associated with MS.

Figure 4

The mechanism of CBG anti-inflammatory effects. The figure depicts the main mechanisms by which CBG affects inflammation and antioxidant activity. CBG reduces the activity of inducible nitric oxide synthase (iNOS) and modulates the expression of superoxide dismutase-1 (SOD-1). Furthermore, CBG inhibits diacylglycerol lipase (DAGL) and decreases the activity of cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) enzymes.

Figure 5

The primary pathways of CBG’s anti-tumor effects. The figure illustrates the principal signaling pathways. The combined use of CBG/CBD, curcumin, and piperine leads to a reduction in YAP expression levels, thereby regulating the Hippo pathway. CBD/CBG also inactivates GPR55 signaling, resulting in decreased GBM proliferation and promoting cell differentiation. In addition, CBD/CBG desensitized TRPV1, inducing a pro-apoptotic response via Ca²⁺ depletion and triggering ER stress. Moreover, CBG reduced CSF-1 secretion by melanoma cells [81].