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A 2014 study entitled "Care and Feeding of the Endocannabinoid System: A Systematic Review of Potential Clinical Interventions that Upregulate the Endocannabinoid System" that was published in the journal PLOS ONE explored methods by which the human endocannabinoid system (ECS) might be improved, or upregulated.
The study reported that the ECS includes the cannabinoid receptors CB1 and CB2 and the endocannabinoids 2-AG and anandamide, including the metabolic enzymes that produce them. "An emerging literature documents [an endocannabinoid system] deficiency syndrome" that may lead to a variety of conditions, including "migraine, fibromyalgia, irritable bowel syndrome, and psychological disorders [such as anxiety and depression]."
The design of this study was that of a literature review in which the scientists performed an analysis of 322 prior studies (all of which met predefined selection criteria), with a focus on "clinical interventions that enhance the ECS." The survey revealed that most of these were in the form of preclinical research, not clinical trials involving humans.
The research reported that the CB1 receptor of the ECS "is the most abundant G protein-coupled receptor expressed in the brain" and noted "particularly dense expression" in several sections of the brain.
ECS Receptors
The research reported that the CB1 receptor of the ECS "is the most abundant G protein-coupled receptor expressed in the brain" and noted "particularly dense expression" in several sections of the brain, including the hippocampus, cerebral cortex, cerebellum, and amygdala. The scientists noted that CB1 receptors are also expressed in non-neuronal cells such as musculoskeletal tissues.
As reported by other investigations of the ECS, this study reported that CB2 receptors are "principally associated with cells governing immune function," but noted that they also appear in the central nervous system (although in lower densities than their CB1 siblings).
ECS Deficiency Syndrome
The study reported that suboptimal functioning of the ECS may result in a range of diseases and conditions. One previous study reviewed "speculated that a dysfunctional ECS in infants contributes to 'failure to thrive' syndrome."
THC molecular structure
Another prior study proposed that "deficient ECS signaling could be involved in the pathogenesis of depressive illnesses." The study's authors reported that ECS deficiencies have also been implicated in multiple sclerosis, Huntington's disease, Parkinson's disease, anorexia, and even chronic motion sickness.
The study's authors reported that ECS deficiencies have also been implicated in multiple sclerosis, Huntington's disease, Parkinson's disease, anorexia, and even chronic motion sickness.
The study examined how a number of compounds and environmental influences may affect the functionality of the ECS and characteristics such as receptor density, binding affinity for particular endo- and phytocannabinoids, and overall activity. These included alcohol, nicotine, cannabis, caffeine, opiates, exercise, herbal remedies, and a wide range of pharmaceutical drugs.
Complex Polypharmaceutical
"Cannabis and cannabis products are complex polypharmaceuticals consisting of THC, cannabidiol (CBD), [and] dozens of minor cannabinoids, as well as terpenoids, flavonoids, and other compounds," reported the study.
The study reported that "THC mimics anandamide and 2-AG by acting as an agonist at CB1 and CB2" receptors. "But rather than simply substituting for anandamide and 2-AG, cannabis and its many constituents work, in part, by 'kick-starting' the ECS," noted the report.
In rodent studies, "acute administration of THC increased CB1 density." The study also reported that acute THC "increased the sensitivity of CB1 [receptors] to cannabinoids" in rat brains and that THC also stimulated the production of the endocannabinoid anandamide.
The study confirmed what thousands of anecdotal testimonies have indicated: "Chronic, high dosing of THC causes a predictable desensitization and downregulation of CB1 and CB2 [receptors], accompanied by drug tolerance."
Complex Mechanisms
Interestingly, the study reported that "the potential synergy between THC and the ECS" is analogous to "the potential synergy between [the endocannabinoids] anandamide and 2-AG."
The study stressed that "cannabis is more than THC" and stated that "adding CBD to THC in mice enhanced CB1 expression" in the hippocampus and hypothalamus regions of the brain.
The study reported that previous rodent investigations have revealed that "anandamide and 2-AG may activate CB1 receptors in different parts of the central nervous system," with each endocannabinoid causing "unique behavioral effects." The scientists also revealed that both cannabinoids working together may cause "new effects [to] emerge."
The study stressed that "cannabis is more than THC" and stated that "adding CBD to THC in mice enhanced CB1 expression" in the hippocampus and hypothalamus regions of the brain. It reported that many cannabinoids beyond THC "interact with enzymes of the ECS," including cannabidivarin (CBDV), cannabidiolic acid (CBDA), cannabigerol (CBG), and cannabichromene (CBC).
