The endocannabinoid system, ECS, is a neuromodulatory system spread throughout the body and plays an important role in developing the central nervous system, CNS, the plasticity of Synaptics, and various responses to endogenous and environmental reception, particularly pain. The ECS comprises cannabinoid receptors, endogenous cannabinoids (endocannabinoids), and enzymes responsible for synthesizing and degrading endocannabinoids. CBD is a phytocannabinoid compound produced by cannabis-related plants, i.e., marijuana and hemp. Cannabidiol has gained popularity in recent days due to its potential benefits in promoting human health. Particularly, CBD has potential benefits in combating effects related to anxiety disorders such as post-traumatic disorders.
The ECS comprises endogenous cannabinoids, commonly referred to as endocannabinoids, cannabinoid receptors, and the enzymes used to synthesize and degrade endocannabinoids. Below is a discussion of each of the components:
Endocannabinoids are endogenous lipids that interact with cannabinoid receptors, altering their behavior to at least partially mimic the effects of cannabis's psychoactive components, most notably THC tetrahydrocannabinol. Anandamide (arachidonoyl ethanolamide) and 2-arachidonoyl glycerol, 2-AG, were the first endocannabinoids discovered. An important feature of these endocannabinoids is their precursors in lipid membranes. Endocannabinoids are released into the extracellular space in one or two rapid enzymatic steps when activated, typically by activation of specific G protein-coupled receptors or by depolarization. The efficacy of the endocannabinoids varies—for example, 2-AG is a high efficacy agonist for both CB1 and CB2 receptors. In contrast, anandamide is a low efficacy agonist for CB1 receptors and a very low efficacy agonist for CB2 receptors.
Endocannabinoids' effects are primarily mediated by the CB1 and CB2 cannabinoid receptors, with other receptors such as PPARs and Transient Receptor Potential (TRP)) channels are also mediating some endocannabinoid actions, particularly those of the acylethanolamides. CB1 and CB2 cannabinoid receptors are G protein-coupled receptors (GPCRs) that primarily couple to Gi and Go G proteins. Thus, activation of CB1 or CB2 receptors affects cellular physiology, including synaptic function, gene transcription, and cell motility. CB1 receptors are abundant in the CNS, particularly in the cortex, basal ganglia, hippocampus, and cerebellum. CB1 receptors are mostly found on axon terminals and pre-terminal axon segments. CB2 receptors are expressed at much lower levels in the CNS than CB1 receptors. This receptor is found mostly in microglia and vascular elements. CB2 does appear to be expressed by some neurons, particularly in pathological conditions such as nerve injury.
Although anandamide and 2-AG contain arachidonic acid, their in vivo synthesis and degradation pathways are nearly identical and are mediated by different enzymes. Anandamide appears to be synthesized from N-arachidonoyl phosphatidyl ethanol (NAPE), whereas 2-AG appears to be synthesized from 2-arachidonoyl-containing phospholipids, primarily arachidonoyl-containing phosphatidyl inositol bis-phosphate (PIP2). An important factor to consider in 2-AG biology is that, in addition to acting as an endogenous ligand for cannabinoid receptors, 2-AG is a key metabolic intermediate in lipid synthesis and a major source of arachidonic acid in prostaglandin synthesis (40). Thus, manipulating 2-AG production and degradation can have far-reaching consequences unrelated to ECS.
CBD is a powerful treatment for CECD or Clinical Endocannabinoid Deficiency. CECD is important in various physiological conditions, including PTSD, inflammation, psoriasis, depression, pain, chronic anxiety, and Parkinson's disease. Although uncertain, medical experts believe that CBD inhibits the enzyme Fatty Acid Amide Hydrolase (FAAH), responsible for breaking down and recycling endocannabinoids. However, this is not the only way CBD benefits the body. CBD also has the following therapeutic effects:
Tetrahydrocannabinol, like anandamide and 2-arachidonoylglycerol, can activate CB1 and CB2 receptors. THC is similar to anandamide in terms of CB1 affinity, acting as a partial agonist at CB1 receptors, albeit with less efficacy than anandamide, and exhibiting even lower efficacy at CB2 receptors than at CB1 receptors. THC appears to produce various in vivo in healthy animals by activating neuronal CB1 receptors. These include a 'tetrad' of effects, such as locomotor activity suppression, hypothermia, immobility in the ring test, and antinociception. THC administration in vivo causes CB1-mediated increases in acetylcholine release in the hippocampus and the release of acetylcholine, glutamate, and dopamine in the prefrontal cortex. These increases are most likely caused by this cannabinoid inhibiting the release of an inhibitory transmitter onto acetylcholine-, glutamate-, or dopamine-releasing neurons, either directly or indirectly. THC's mixed stimulatory–inhibitory effect on central neurotransmitter release when administered in vivo may explain why this cannabinoid has been reported to have both excitant and depressant effects; for example, it has been found to have anticonvulsant activity in some in vivo models of epilepsy but proconvulsant activity in others. Although this modulation appears to be protective most of the time, there is evidence that it can occasionally produce harmful effects, such as obesity or contributing to the rewarding effects of drugs of dependence.
The ECS assists the CNS in regulating various homeostatic functions in the body, such as temperature, memory recognition, balancing body energy, and pain reception regulation. The ECS comprises endocannabinoids, cannabinoid receptors, and endocannabinoid enzymes that all work together. CBD primarily interacts with the ECS via the TRPV1, D2, and PPAR-gamma receptors to promote ECS functions. THC, on the other hand, THC interacts with the ECS primarily through CB1 and CB2 receptors, as it has an anandamide-like affinity for these receptors. THC works by inhibiting or activating these receptors to produce drug dependence and a sense of 'highness.'