# _Cannabis sativa_ L. as a Natural Drug Meeting the Criteria of a Multitarget Approach to Treatment
## 2 Endocannabinoid System  
The endocannabinoid system is responsible for the regulation of numerous vital functions, including learning, memory, mood, anxiety, drug addiction, nutritional behavior, pain perception, modulation, and the functions of the cardiovascular system. It consists of cannabinoid receptors, endogenous ligands, secondary messengers, and endocannabinoid degradation pathways [32; 33]. This system is still under investigation, but so far, three receptors have been discovered and described: CB\({}_{1}\), cannabinoid type 2 (CB\({}_{2}\)), and G protein-coupled receptor 55 (GPR\({}_{55}\)). They are located extracellularly and intracellularly in the mitochondria, Golgi apparatus, and the nucleus [32]. The receptors that are located on cell membranes are coupled with the G protein. The endocannabinoid system is regulated by endocannabinoids, which are produced in response to neural network activity [34]. These are endogenous ligands produced by the human body. The two main ones are anandamide (AEA) and 2-arachnoidylglycerol (2-AG) [32]. Their formulas are shown in Figure 1. They are derivatives of arachidonic acid, a precursor of numerous endogenous particles, such as prostaglandandins, prostacyclins, thromboxanes, and leukotrienes. These endocannabinoids are produced on demand from membrane precursors and phospholipids and are not stored in vesicles like other neurotransmitters but released immediately. Once made, they return to the presynaptic neurons to attach to receptors there. After their activation, the influx of potassium ions into the cell increases, leading to membrane hyperpolarization. As a result, the likelihood of neurotransmitters being released from presynaptic neurons is reduced. It makes it impossible to connect with other neurotransmitters, such as \(\gamma\)-aminobutyric acid (GABA), glutamate, or acetylcholine, affecting the central nervous system's various functions. The stimulation of cannabinoid receptors may lead to a weakening of their responses, depending on the type of neurons they act on. After inducing a biological response, their reuptake by endocannabinoid membrane transporters takes place, followed by enzymatic degradation [33; 34; 35; 36; 37]. CB\({}_{1}\) receptors mediate pain modulation, memory processing, motor function, and psychoactivity. They are located mainly in the brain. They achieve the highest density in such structures as the hippocampus, cerebellum, basal ganglia, cerebral cortex, hypothalamus, dorsal vagus nerve complex, and spinal cord. Moreover, several receptors are located in the structures responsible for the control of respiratory functions. The CB\({}_{1}\) receptor predominates in the GABA inhibitory interneurons in the spinal cord's posterior horn over excitatory neurons, with AEA being its major ligand. These presynaptic receptors influence the release of neuropeptides and neurotransmitters and inhibit synaptic conduction. Their activation stimulates potassium channels, which inhibit the presynaptic  
Figure 1: Endocannabinoid structures: (**A**) anandamide and (**B**) 2-arachnoidglycerol. stimulation of neurons and block potentially dependent calcium channels, which reduce the release of neurotransmitters. CB2 receptors are mainly associated with the immune system and are mostly found in the spleen, digestive system, peripheral nervous system, and testes. Although several of them are located in the brain, their function in this organ is unclear. Knowing the receptors' exact locations allows an understanding of how the system works and _Cannabis_'s effects on the body. The stimulation of this receptor does not have a psychoactive effect, nor does it affect the circulation. Its main endogenous ligand is 2-AG. The stimulation of these receptors reduces the release of chemokines and neutrophils and the migration of macrophages, and what is more, it has the effect of reducing chronic inflammatory processes and chronic pain. Both CB1 and CB2 found on mast cells are involved in the anti-inflammatory activity of cannabinoids.