Endocannabinoid System

The unique role of fatty acid amide hydrolase (FAAH) in terminating endocannabinoid (EC) signaling supports its relevance as a therapeutic target. Inhibition of EC metabolizing enzymes elicits indirect agonism of cannabinoid receptors (CBRs) and therapeutic efficacy devoid of psychotropic effects. Based on our previous ligands, and aiming at the discovery of new selective FAAH inhibitors, we developed a series of 12 new compounds characterized by functionalized tricyclic scaffolds. All the developed compounds display negligible activity on monoacylglycerol lipase (MAGL) and CBRs. The most potent FAAH inhibitors of the newly developed series, 6-oxo-5,6-dihydro-4H-benzo[f]pyrrolo[1,2-a][1,4]diazepin-9-yl-6-phenylhexylcarbamate (5 h) and 4-oxo-5,6-dihydro-4H-benzo[f]pyrrolo[1,2-a][1,4]diazepin-9-yl-(6-phenylhexyl)carbamate (5 i) (nanomolar FAAH inhibitors, the latter of which also shows micromolar affinity at the CB R), were selected for further studies. Results of cell-based studies o...

Objective: To research the biological impact on the endocannabinoid system (ECS) from dietary sources of β-caryophyllene (BCP). This will encompass pre-clinical and clinical research for BCP. The bioavailability of BCP will be explored, focusing on bioavailability improvement. This research will establish if there is justification to warrant the development of a medical food for supporting the ECS through dietetic supplementation of BCP.

Methods: Research and review papers were identified through the search engines Google Scholar, PubMed, and ScienceDirect. Main keywords included β-caryophyllene, endocannabinoid system, dietary cannabinoids, cannabinoid type-2 receptor, and bioavailability.

Results: The human body is limited in the digestion of BCP from food. This is because BCP is poorly absorbed in the gut. Everyone has different underlying endocannabinoid efficiency and most people do not have the full potential of supporting their ECS through diet.

Conclusion: A medical food can be developed to use BCP with a delivery system, so that the bioactive food cannabinoid is readily absorbed. This will deliver dietary support to the ECS, that otherwise would be available from food. This review provides insight into the efficacy of using BCP in medical foods as dietary support for the ECS. Supporting the ECS can assist in maintaining homeostasis, regulating immune function, pain intensity, inflammatory markers, sleep patterns, mood, appetite, and stress sus- ceptibility.

The understanding that hyper-excitability and hyper-synchronism in epilepsy are indissociably bound by a cause-consequence relation has only recently been challenged. Thus, therapeutic strategies for seizure suppression have often aimed at inhibiting excitatory circuits and/or activating inhibitory ones. However, new approaches that aim to desynchronize networks or compromise abnormal coupling between adjacent neural circuitry have been proven effective, even at the cost of enhancing local neuronal activation. Although most of these novel perspectives targeting circuitry desynchronization and network coupling have been implemented by non-pharmacological devices, we argue that there may be endogenous neurochemical systems that act primarily in the desynchronization component of network behavior rather than dampening excitability of individual neurons. This review explores the endocannabinoid system as one such possible pharmacological landmark for mimicking a form of "on-demand" desynchronization analogous to those proposed by deep brain stimulation in the treatment of epilepsy. This essay discusses the evidence supporting the role of the endocannabinoid system in modulating the synchronization and/or coupling of distinct local neural circuitry; which presents obvious implications on the physiological setting of proper sensory-motor integration. Accordingly, the process of ictogenesis involves pathological circuit coupling that could be avoided, or at least have its spread throughout the containment of other areas, if such endogenous mechanisms of control could be activated or potentiated by pharmacological intervention. In addition, we will discuss evidence that supports not only a weaker role played on neuronal excitability but the potential of the endocannabinoid system strengthening its modulatory effect, only when circuitry coupling surpasses a level of activation.

Traumatic brain injury (TBI) is the leading cause of morbidity and mortality worldwide. The initial injury is followed by a series of secondary processes that can further harm the injured brain and worsen the outcome. The endocannabinoid system (ECS) consists of ligands, such as anandamide and 2-arachidonoyl-glycerol (2-AG), receptors (e.g., Cannabinoid receptor type 1 and Cannabinoid receptor type 2), as well as transporters, and enzymes. Dexanabinol (HU-211) is a synthetic cannabinoid with cerebroprotective effects devoid of cannabimimetic effects, which exhibits the pharmacological properties of N-Methyl-D-aspartate receptor antagonist. The increase in the brain levels of
endocannabinoids in the pathogenic events of brain injury suggests that this system plays a role in compensatory repair mechanisms. In recent years, the therapeutic effects of cannabinoid manipulative drugs have been numerously studied through the manipulation of the ECS in TBI. Therefore, the literature review was performed to assess the therapeutic
effects of ECS manipulation, cannabinoid-derived drugs, and HU-211 in traumatic brain injury pathology. The ECS possesses promising effects in the treatment of diverse TBI pathologies through releasing endogenous ligands and changes in cannabinoid receptors activity or both. Preclinical studies suggest that the ECS has many targets for
therapeutic agents that might help decrease TBI pathologic effects and should be considered for developing novel drugs. Furthermore, more clinical trials with larger populations and more extended follow-up periods should be performed for a better understanding of the effects of ECS manipulative drugs.

The purpose of this compilation of texts, ideas and opinions from emails and Facebook
conversations is to present the current status quo of knowledge regarding the use of
cannabis oils/extracts in medicine. All information is presented for educational
purposes only, and it is not presented with the intention of promoting the use of
dangerous addictive drugs whatsoever, on the contrary. We bear no responsibility
for any misuse of the information included in this book. We bear no responsibility
for anything that will or might occur in connection with the use of the oil or
information found in this book. Treatment results may vary.

Electroacupuncture (EA) and cannabinoids have been reported to have anti-inflammatory and antinociceptive effects in animal models of arthritis. Male Wistar rats were injected with saline or zymosan (2 mg) into the temporomandibular joint (TMJ). EA (10 Hz, 30 min) was performed 2 h after or 1 h before zymosan administration. AM251 or AM630 (3 mg/kg, i.p.)were administered before EA treatment. Mechanical hypernociception was accessed after zymosan administration. Rats were sacrificed 6 h after zymosan administration and the joint was removed for histopathological analysis. The gene expression of CB₁ and CB₂ receptors was assessed after sacrifice of the TMJ arthritic animals. EA inhibited zymosan-induced hypernociception (p < 0.05). AM251 reversed significantly the antinociceptive effect of EA, suggesting that the CB₁ receptor is involved in this effect. AM630 reversed the anti-inflammatory effect of EA. CB₁ and CB₂ receptor gene expression was upregulated 6 h after zymosan-induced arthritis in the EA-treated group. We observed downregulation of CB₂ receptor gene expression in the EA group at the 24th hour compared with the 6th hour. Higher CB₁ receptor gene expression was also found compared with the 6th hour. EA produced antinociceptive and anti-inflammatory effects, and these effects appeared to be mediated through CB₁ and CB₂ receptor activation.

Molecular engineers are studying FAAH as a target for pharmaceuticals as controlling levels of FAAH may produce some of the same health effects that excite clinicians about the potential for phytocannabinoid-based medicines. Synthetic cannabinoids work by flooding the system with molecules structurally similar to THC and other phytocannabinoids. Medicines that inhibit the body's production of FAAH are theorized to have a similar effect by maximizing the concentration of deficient endocannabinoids in the nervous system. Technological limitations coupled with a suppression of research of biologic cannabinoids at many major research universities have limited our understanding of the endocannabinoid system. Questions still need to be answered to provide a comprehensive comparison of biologic with synthetic FAAH inhibitors. Advancement and research aimed at understanding of endogenous and exogenous cannabinoids, and particularly the medicinal properties of the Trans-Δ⁹-Tetrahydrocannabinol (THC) molecule and its endocannabinoid equivalent anandamide are hindered by prohibitive restrictions resulting from the Food and Drug Administration (FDA), Drug Enforcement Administration (DEA), National Institute of Health (NIH), and the National Institute on Drug Abuse (NIDA). The mission statements of each of these entities effectively integrate to ensure research and utilization of the medicinal properties of THC will be nearly impossible to attain