*3.4. Cannabinoid Receptors*

CBD has been shown to be a weak agonist of the human, mouse, and rat CB1 receptor [61]. The activation of the CB1 receptor increases ROS production and a pro-inflammatory response, including the downstream synthesis of tumor necrosis factor α (TNFα) [62]. In addition, it was shown that CBD is a negative allosteric modulator of the CB1 receptor [63]. Regardless of the e ffect on the CB1 receptor, CBD is a weak agonist of the CB2 receptor [64], but it has also been suggested that it may demonstrate inverse agonism of the CB2 receptor [65]. Importantly, CB2 activation leads to a decrease in ROS and TNFα levels, which reduces oxidative stress and inflammation [62]. Therefore, it has been suggested that CBD may indirectly improve anti-inflammatory e ffects. Clinical studies have confirmed that CBD reduces the levels of pro-inflammatory cytokines, inhibits T cell proliferation, induces T cell apoptosis and reduces migration and adhesion of immune cells [66]. In addition, CBD anti-inflammatory activity has been shown to be antagonized by both a selective CB2 antagonist and AEA, an endogenous CB2 receptor agonist [67].

CB1 and CB2 are receptors with strong expression in the central nervous system and the immune system primarily, but also occur in other tissues. CBD, acting on the above receptors, inhibits the activity of adenylyl cyclase and voltage gated calcium channels, activates potassium channels and activates mitogen activated protein kinase (MAPK), 3-phosphoinositol kinase (PI3K)/AKT, and the mammalian target of rapamycin (mTOR) signaling pathways [68]. The PI3K/AKT/mTOR pathway is one of the basic pathways necessary for physiological protein synthesis and induction of other intracellular pathways, such as the MAPK pathway, which plays an important role in regulating cell survival, proliferation, and apoptosis [69]. CBD was found to induce apoptosis in leukemia cells by reducing p38-MAPK levels [70]. However, CBD was also shown to inhibit apoptosis in human breast cancer cell lines (T-47D and MDA-MB-231) by inhibiting expression of oncogenic and pro-survival cyclin D1 and mTOR, and by increasing PPARγ receptor expression [71].

**Figure 3.** Indirect antioxidant and anti-inflammatory e ffects of CBD (closed arrows indicate inhibition; opened arrows indicate activation.
