The endocannabinoid system (ECS) is a biological system composed of endocannabinoids, which are endogenous lipid-based retrograde neurotransmitters that bind to cannabinoid receptors, and cannabinoid receptor proteins that are expressed throughout the mammalian central nervous system (including the brain) and peripheral nervous system. The endocannabinoid system is involved in regulating a variety of physiological and cognitive processes including fertility, pregnancy, during pre- and postnatal development, appetite, pain-sensation, mood, and memory, and in mediating the pharmacological effects of cannabis. The ECS is also involved in mediating some of the physiological and cognitive effects of voluntary physical exercise in humans and other animals, such as contributing to exercise-induced euphoria as well as modulating locomotor activity and motivational salience for rewards. In humans, the plasma concentration of certain endocannabinoids (i.e., anandamide) have been found to rise during physical activity; since endocannabinoids can effectively penetrate the blood–brain barrier, it has been suggested that anandamide, along with other euphoriant neurochemicals, contributes to the development of exercise-induced euphoria in humans, a state colloquially referred to as a runner's high.
CB1 (Ki = 10 nM) and CB2 are the primary cannabinoid receptors responsible for several of the effects of cannabinoids, although other receptors may play a role as well. Both belong to a group of receptors called G protein-coupled receptors (GPCRs). CB1 (Ki = 10 nM) receptors are found in very high levels in the brain and are thought to be responsible for psychoactive effects. CB2 (Ki = 24 nM) receptors are found peripherally throughout the body and are thought to modulate pain and inflammation.
Cannabidiol has very low affinity for the cannabinoid CB1 and CB2 receptors but is said to act as an indirect antagonist of these receptors. At the same time, it may potentiate the effects of THC by increasing CB1 receptor density or through another CB1 receptor-related mechanism.
Cannabidiol has been found to act as an antagonist of GPR55, a G protein-coupled receptor and putative cannabinoid receptor that is expressed in the caudate nucleus and putamen in the brain. It has also been found to act as an inverse agonist of GPR3, GPR6, and GPR12. Although currently classified as orphan receptors, these receptors are most closely related phylogenetically to the cannabinoid receptors. In addition to orphan receptors, CBD has been shown to act as a serotonin 5-HT1A receptor partial agonist, and this action may be involved in its antidepressant,anxiolytic, and neuroprotective effects. It is an allosteric modulator of the μ- and δ-opioid receptors as well. The pharmacological effects of CBD have additionally been attributed to PPARγ agonism and intracellular calcium release.
Research suggests that CBD may exert some of its pharmacological action through its inhibition of fatty acid amide hydrolase (FAAH), which may in turn increase the levels of endocannabinoids, such as anandamide, produced by the body. It has also been speculated that some of the metabolites of CBD have pharmacological effects that contribute to the biological activity of CBD. Cannabidiol is metabolized in the liver, as well as the gut by CYP2C19 and CYP3A4 enzymes, and UGT1A7, UGT1A9, and UGT2B7 isoforms.
Tetrahydrocannabinol is the principal psychoactive constituent of cannabis. With chemical name (−)-trans-Δ⁹-tetrahydrocannabinol, the term THC also refers to cannabinoid isomers. Like most pharmacologically-active secondary metabolites of plants, THC is a lipid found in cannabis, assumed to be involved in the plant's self-defense, putatively against insect predation, ultraviolet light, and environmental stress.
The actions of THC result from its partial agonist activity at the cannabinoid receptor CB1, located mainly in the central nervous system, and the CB2 receptor, mainly expressed in cells of the immune system. The psychoactive effects of THC are primarily mediated by the activation of cannabinoid receptors, which result in a decrease in the concentration of the second messenger molecule cAMP through inhibition of adenylate cyclase.
The presence of these specialized cannabinoid receptors in the brain led researchers to the discovery of endocannabinoids, such as anandamide and 2-arachidonoyl glyceride (2-AG). THC targets receptors in a manner far less selective than endocannabinoid molecules released during retrograde signaling, as the drug has a relatively low cannabinoid receptor efficacy and affinity. In populations of low cannabinoid receptor density, THC may act to antagonize endogenous agonists that possess greater receptor efficacy. THC is a lipophilic moleculeand may bind non-specifically to a variety of entities in the brain and body, such as adipose tissue(fat).
THC, similarly to cannabidiol, albeit less potently, is a positive allosteric modulator of the μ- and δ-opioid receptors. Due to its partial agonistic activity, THC appears to result in greater downregulation of cannabinoid receptors than endocannabinoids, further limiting its efficacy over other cannabinoids. While tolerance may limit the maximal effects of certain drugs, evidence suggests that tolerance develops irregularly for different effects with greater resistance for primary over side-effects, and may actually serve to enhance the drug's therapeutic window.
THC, as well as other cannabinoids that contain a phenol group, possesses mild antioxidant activity sufficient to protect neurons against oxidative stress, such as that produced by glutamate-induced excitotoxicity.
THC is metabolized mainly to 11-OH-THC by the body. This metabolite is still psychoactive and is further oxidized to 11-nor-9-carboxy-THC (THC-COOH). In humans and animals, more than 100 metabolites could be identified, but 11-OH-THC and THC-COOH are the dominating metabolites. Metabolism occurs mainly in the liver by cytochrome P450 enzymes CYP2C9, CYP2C19, and CYP3A4.
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For more information, please see the Wikipedia entries for THC and CBD.