Legends
Fig. 1. The complexity of the endocannabinoid system. Diagram showing the components of the expanded endocannabinoid system including the biosynthesis and degradation of endocannabinoids in the CNS. In response to demand, AEA and 2-AG are produced, which can cross the synaptic cleft and activate presynaptic CB1 receptors resulting in neurotransmitter inhibition. Biosynthesis and inactivation of AEA endocannabinoids in postsynaptic neurons is done by FAAH and NAPE-PLD. O 2-AG is hydrolyzed in presynaptic neurons by MAGL, also by enzymes DAGLα and DAGLβ. Note the complexity of the endocannabinoid system that interacts with several neuromediators, receptors and new molecular targets. 2-AcGs; 2-acylglycerols; 2-AG, 2-arachidonoyl-glycerol; 5-HT1A, serotoninergic receptors of the 5-HT1A type; AA, arachidonic acid; Abh4, alpha-betahydrolase-4; AEA, anandamide; CB1, cannabinoid receptor 1; CB2, cannabinoid receptor 2; COX-2, cyclooxygenase-2; DAGL, sn-1-diacylglycerol lipase; ETA, ethanolamide;  FAAH, fatty acid amide hydrolase; GLY, glycerol; GPRs, G protein-coupled receptors; Lyso PLC, lysoPI-specific PLC; LOX, lipoxygenase; MAGL, monoacylglycerol lipase; NAES; N-acylethanolamines; NAPE-PLD, N-acyl-phosphatidyl ethanolamine-specific phospholipase D; PLA1, phospholipase A1; PPARγ, peroxisome proliferator-actived receptor γ; PTPN22, protein tyrosine phosphatase nonreceptor type 22; TRPV1, transient receptor potential vanilloid 1. (Created with BioRender.com).
Fig. 2 . Diagram of interactions and therapeutic effects of CBD in epilepsy.
2-AG, 2-arachidonoyl-glycerol; 5-HT1A, serotoninergic receptors of the 5-HT1A type; AEA, anandamide; CB1, cannabinoid receptor 1; CBD, cannabidiol; GPR55, G protein-coupled receptor 55; TRPV1, transient receptor potential vanilloid 1. (Created with BioRender.com).
Fig. 3. Diagram of interactions and therapeutic effects of THC:CBD in multiple sclerosis. A perivascular and parenchymal infiltrate of macrophages, B lymphocytes and T lymphocytes is observed in MS, which cross the blood-brain barrier and destroy the myelin sheath, followed by partial remyelination by oligodendrocytes (acute inflammatory phase) than by infiltration of T lymphocytes, oligodendrocyte destruction and axonal injury will progress to the progressive phase of the disease. Combined THC:CBD therapy has demonstrated pharmacological activation of the CB2 receptor strongly associated with suppression of neuroinflammation and induction of remyelination processes and neuronal survival. Furthermore, the decrease in astrocyte activity leading to inhibition of the neuroinflammatory process was also notable. CBD, cannabidiol; CB1, cannabinoid receptor 1; MS; multiple sclerosis; THC, Δ9-tetrahidrocanabinol. (Created with BioRender.com).
Fig. 4. Diagram of interactions and therapeutic potential of phytocannabinoids in Parkinson’s disease. PD is characterized by dopaminergic damage to the nigrostriatal pathway, dopamine depletion, excitocicity, accumulation of α-synuclein and Lewy bodies, reduced trophic support and oxidative stress in the brain region. Cannabis-derived products have been used for the treatment of PD, such as: THC and THCV which have shown neuroprotective effects. In the case of THC, possibly mediated by the CB1 receptor, being also associated with PPARγ, in the negative regulation of the CB1 receptor and the restoration of mitochondrial content. THCV is mediated by the CB1 receptor. CBD has been linked to CB2 and TRPV receptors showing neuroprotective, anti-apoptotic, neuroinflammatory and antioxidant effects. CB2 receptor-mediated anti-inflammatory and antioxidant effects have been demonstrated by BCP. 2-AG, 2-arachidonoyl-glycerol; AEA, anandamide; BCP, β-caryophyllene; CB1, cannabinoid receptor 1; CB2, cannabinoid receptor 2; CBD, cannabidiol; FAAH, fatty acid amide hydrolase; NAPE-PLD, N-acyl-phosphatidyl ethanolamine-specific phospholipase D; PD, Parkinson’s disease; PPARγ, peroxisome proliferator-actived receptor γ; THC, Δ9-tetrahidrocanabinol;  THCV, Δ9-tetrahydrocannabivarin; TRPV1, transient receptor potential vanilloid 1. (Created with BioRender.com).