## 4 Molecular Effects of _Cannabis sativa_ L.  
Several molecular processes are strictly related to cancer initiation and development including inflammation, oxidative stress, and proliferation. Cannabinoids exert a number of beneficial pharmacological effects, including anti-inflammatory and antioxidant properties [42]. Several studies indicate that cannabinoid receptors and endogenous ligands are overexpressed in tumor tissues [43]. Moreover, increased expression of enzymes involved in endocannabinoid metabolism is often associated with the aggressiveness of cancer. [44; 45]. Cannabinoids target the tumor affecting signaling and cellular pathways such as tumor cell proliferation, angiogenesis, tumor invasion, and apoptosis both in in vitro and in vivo experiments [46]. In particular, different evidence suggests that these compounds exert inhibition of initiation, progression, and metastatic capacity of several cancer types [17; 43; 47; 48]. Both THC and non-psychoactive cannabinoids have been reported to possess peripheral anti-inflammatory properties in a plethora of in vitro and in vivo models [49; 50; 51]. In human peripheral blood cells, CB1 is expressed by B cells, NK cells, neutrophils, CD8\({}^{+}\) T cells, monocytes, and CD4+ T cells, whereas CB2 mRNA is expressed by human B cells, NK cells, monocytes, neutrophils, and T cells [52]. Typically, CB2 inhibits the production of proinflammatory cytokines, such as tumor necrosis factor alpha (TNF-\(\alpha\)), interleukin (IL)-2, IL-6, IL-8, and IFN-\(\gamma\) by immune cells [51]. CBD decreases peripheral inflammation through reduction of prostaglandin E2 (PGE2), nitric oxide (NO), and malondialdehydedehyde production [53; 54; 55; 56; 57]. In addition, CBD, in combination with minor phytocannabinoids of _Cannabis sativa_ L. extracts, can induce a greater pharmacological anti-inflammatory activity [52; 58]. Indeed, a standardized cannabis extract enriched with CBD exerts a more powerful anti-inflammatory activity than CBD alone [59]. Besides CBD, THC also possesses potent anti-inflammatory properties both in vivo and in vitro [60; 61]. Recently, in a mouse model of acute respiratory distress syndrome, THC leads to the suppression of the cytokine storm [62]. The molecular mechanisms at the basis of THC down-regulation of the inflammatory processes are various and tissue-dependent [61]. Indeed, regarding gastrointestinal and systemic inflammatory reactions, THC suppresses both lymphocytes and neutrophils activity [63; 64]; in epithelial and skin cells, THC inhibits the release of inflammatory mediators through impairment of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) pathway [65]. It is of note that there is clear evidence of the synergistic action of THC and CBD in terms of down-regulation of the inflammatory processes [66; 67]. Regarding other combination extracts, [PERSON] et al. demonstrated that _Cannabis sativa_ L. oil extract markedly suppresses the release of TNF-\(\alpha\) in LPS-stimulated rat monocytes with inhibition of LPS-induced COX-2 and i-NOS protein expression and blockage of MAPKs phosphorylation [68]. Additionally, the presence of phenols, terpenes, or other phytocannabinoids enhance the therapeutic activity of CBD, defined as 'entourage effects' [69; 70; 71]. In addition, cannabis extract inhibits the production of IL-8, matrix metalloproteinases (MMP)-9, and vascular endothelial growth factor (VEGF), an effect not detected with CBD alone, in skin cells [65]. Other non-psychoactive cannabinoids, including CBC and CBN, also showed substantial in vivo anti-inflammatory responses. On the other hand, monoterpenes such as \(\alpha\)- and \(\beta\)-pinene, myrcene, and limonene have been also reported to possess substantial anti-inflammatory properties [72; 73; 74]. Regarding neuroinflammation, both CBD and THC have protective effects [75; 76; 77] through the activation of NF-\(\kappa\)B as well as the inhibition of Toll like receptor (TLR4) [78; 79].