## 3 Results and Discussion
### Integrated Centrality and Essential Protein Targets  
Biological networks are heterogeneous by nature, where the connecting nodes play very different roles in structure and function, and the importance of nodes can be described by network centrality [26].However, a single centrality measure (such as degree centrality, betweenness centrality, closeness centrality, and eigenvector centrality, etc.) would not be sufficient to predict the essential nodes in biological networks; therefore, integrating various centrality measures is a preferred way to predict the essential nodes in the biological systems [46]. In this work, IC values were determined using Equation (2) (see Section 2.4) (Table S6) and the IC values > 0.5 were used to predict the essential protein targets in each functional module [33]. Table 2 listed eighteen essential protein targets of cannabinoids, including 16 targets selected by IC values and two targets (i.e., CNR1 and CNR2) supported by text mining of biomedical literature [39,47,48], and 8 cannabinoid ligands that bind to these targets. Figure 7: The contribution scores (CS) of each module to various diseases. These 18 essential protein targets of cannabinoids include seven from Module 1 (i.e., CAT, COMT, CYP17A1, GSTA2, GSTM3, GSTP1, and HMOX1), five from Module 2 (i.e., AKT1, CASP9, PLCG1, PRKCA, and PRKCB), two from Module 3 (i.e., CYCS and TNF), and four from Module 4 (i.e., CNR1, CNR2, CREB1, and CRIN2B). The health benefits or medical harms of cannabinoids on humans may come from the combined modulation which perturbs the functional modules of various diseases upon the binding of multiple cannabinoid ligands to the multiple essential protein targets to achieve restoration of homeostasis or induction of diseases due to the agonist or antagonist activities of the cannabinoids [49]. Many of these essential protein targets have been reported to interact with cannabinoids and are associated with Groups I and II diseases. For example, Both CNR1 and CNR2 are members of the GPCR family and are largely involved in various activities and disorders of the central nervous system, including learning and memory, appetite, anxiety, depression, stroke, schizophrenia, multiple sclerosis, neurodegenerative diseases, epilepsy, pain, and addiction [50; 51; 52]. Several variations of CNR1 have been reported to be associated with _Cannabis_ dependence [53; 54; 55]. THC suppresses soluble macrophage tumoricidal activity and partially inhibits TNF signals [56], CBD prevents ischemic injury by partially inhibiting TNF [57], and CBD and its analogs had an inhibitory effect on TNF production by lipopolysaccharide-stimulated macrophages [58]. THCA has been known to suppress the expression of TNF in vitro, suggesting a mechanism for immune modulation [59]. AKT1, the serine-threonine protein kinase commonly referred to as protein kinase B (PKB), is a critical mediator of growth factor-induced neuronal survival and critical for transmitting growth-promoting signals. Gene polymorphisms in AKT1 have been shown to play a mediating role between _Cannabis_ exposure and the development of psychosis, indicating the AKT1 pathway is a possible target for the prevention and treatment of _Cannabis_-related psychosis [60]. GRIN2B encoding two essential \(N\)-methyl-d-aspartate (NMDA) subunits have been shown to have a combined effect on the pathogenesis of Schizophrenia and are involved in regulating cortical excitability and plasticity [61]. Moreover, GRIN2B gene products play a fundamental role in many brain functions. A growing number of studies