3.2.3. Cannabigerol (CBG)

CBG is another non-psychoactive *Cannabis* component that is produced at elevated levels in some industrial hemps [204–206]. It binds to both CB1 and CB2 receptors and modulates the signaling through these receptors, as well as the CB1-CB2 receptor heteromer, at concentrations as low as 0.1–1 μM [207]. CBG competes with the binding of [3H]-WIN-55,212-2 to CB2, but not to CB1 [207]. Further studies sugges<sup>t</sup> that CBG is a partial agonist of CB1 and CB2 [207–209]. CBG activates TRPV1, TRPV2, TRPV3, TRPV4, TRPA1, 5-HT1a receptor, α2-adrenergic receptor, and PPARγ, while being a TRPM8 antagonist [210–215]. CBG has anti-inflammatory, anti-oxidative, and anti-nociceptive activities [117,209,213,216]. The anti-inflammatory property is thought to be achieved by modulating the CB2 receptor, TRP channels, and PPARγ, and by inhibiting cyclooxygenase 1 and 2 (COX-1/2) [210,211,217], while the analgesic effect of CBG is thought to be mediated through the α2-adrenergic receptor [211]. CBG has been shown to have potential beneficial effects in treating inflammatory bowel disease and neurological disorders, such as Huntington's disease, Parkinson's disease, and multiple sclerosis [213,215,216,218,219].

## 3.2.4. Cannabichromene (CBC)

CBC is a non-psychoactive phytocannabinoid that activates the CB1 and CB2 receptors, resulting in decreased intracellular levels of cAMP [209]. CBC also activates the TRPA1, TRPV3, and TRPV4 channels [210]. CBC has anti-inflammatory, anti-nociceptive, and neuroprotective activities [220–225]. CBC reduces the activity of both the ON and OFF

neurons in the rostral ventromedial medulla (RVM) and elevates the endocannabinoid levels in the ventrolateral periaqueductal gray matter [221]. The anti-nociceptive activity of CBC is mediated by the adenosine A1 and TRPA1 receptors [221]. CBC increases the viability of neural stem progenitor cells through activation of the adenosine A1 receptor [224]. Moreover, it has been shown to suppress reactive astrocytes, thus offering a protective effect against neuro-inflammation and Alzheimer's disease [225]. CBC had anti-convulsant properties in a mouse model of Dravet syndrome [226], and it exhibited cytotoxic activity against some carcinoma cells [227,228].

#### 3.2.5. Cannabidiolic Acid (CBDA)

CBDA has low affinity for both CB1 and CB2 receptors, with moderate inhibition of adenylyl cyclase activity [209,229], and functions as an allosteric regulator on the 5-HT1A receptor, resulting in anti-emetic effects [230–233]. In addition, it activates PPARα and PPARγ [212]. CBDA shows anti-nociceptive and anti-inflammatory effects that are in part mediated by COX-2 inhibition and activation of the TRPV1 channel [217,234,235]. CBDA has anxiolytic and anti-convulsant effects in animal models [236–238].

#### 3.2.6. Cannabigerolic Acid (CBGA)

CBGA displays low affinity for both CB1 and CB2 receptors but causes a similar decrease in intracellular cAMP levels as Δ9-THC [229]. Since CBGA can activate PPARs [212], it is expected to affect lipid metabolism [117]. A *Cannabis sativa* cultivar containing high levels of CBG and CBGA inhibited the activity of the aldose reductase enzyme, which catalyzes the reduction of glucose to sorbitol [239]. Since the aldose reductase level is increased at high glucose levels and has been implicated in the development of neuropathy, nephropathy, retinopathy, and cataract in diabetes, CBGA has been suggested as a potential drug in preventing diabetic complications [239]. In the Scn1a+/− mouse model of Dravet syndrome, CBGA was found to have an anti-convulsant effect that was mediated by its interaction with the GPR55, TRPV1, and GABAA receptors [240].
