Category Archives: Endocannabinoid System

Cannabinoids and Chronic Liver Diseases

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“Nonalcoholic fatty liver disease (NAFLD), alcohol-induced liver disease (ALD), and viral hepatitis are the main causes of morbidity and mortality related to chronic liver diseases (CLDs) worldwide. New therapeutic approaches to prevent or reverse these liver disorders are thus emerging.

Although their etiologies differ, these CLDs all have in common a significant dysregulation of liver metabolism that is closely linked to the perturbation of the hepatic endocannabinoid system (eCBS) and inflammatory pathways. Therefore, targeting the hepatic eCBS might have promising therapeutic potential to overcome CLDs.

Experimental models of CLDs and observational studies in humans suggest that cannabis and its derivatives may exert hepatoprotective effects against CLDs through diverse pathways. However, these promising therapeutic benefits are not yet fully validated, as the few completed clinical trials on phytocannabinoids, which are thought to hold the most promising therapeutic potential (cannabidiol or tetrahydrocannabivarin), remained inconclusive. Therefore, expanding research on less studied phytocannabinoids and their derivatives, with a focus on their mode of action on liver metabolism, might provide promising advances in the development of new and original therapeutics for the management of CLDs, such as NAFLD, ALD, or even hepatitis C-induced liver disorders.”

https://pubmed.ncbi.nlm.nih.gov/36012687/

“Given the significant contribution of the hepatic eCBS and its downstream pathways in the regulation of liver metabolism and the setting of liver abnormalities, pharmacologically targeting peripheral CBRs may have promising potential therapeutic benefits for the treatment of CLDs. Besides this, the use of cannabis by people at risk of developing chronic liver disorders has also suggested hepatoprotective effects by reducing the frequency of NAFLD, ALD, or HCV-induced liver disorders, which would suggest that cannabinoid-based medicine may be effective in treating CLDs.”

https://www.mdpi.com/1422-0067/23/16/9423/htm

Cannabinoids and PPAR Ligands: The Future in Treatment of Polycystic Ovary Syndrome Women with Obesity and Reduced Fertility

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“Cannabinoids (CBs) are used to treat chronic pain, chemotherapy-induced nausea and vomiting, and multiple sclerosis spasticity. Recently, the medicinal use of CBs has attracted increasing interest as a new therapeutic in many diseases.

Data indicate a correlation between CBs and PPARs via diverse mechanisms. Both the endocannabinoid system (ECS) and peroxisome proliferator-activated receptors (PPARs) may play a significant role in PCOS and PCOS related disorders, especially in disturbances of glucose-lipid metabolism as well as in obesity and fertility. Taking into consideration the ubiquity of PCOS in the human population, it seems indispensable to search for new potential therapeutic targets for this condition.

The aim of this review is to examine the relationship between metabolic disturbances and obesity in PCOS pathology. We discuss current and future therapeutic interventions for PCOS and related disorders, with emphasis on the metabolic pathways related to PCOS pathophysiology. The link between the ECS and PPARs is a promising new target for PCOS, and we examine this relationship in depth.”

https://pubmed.ncbi.nlm.nih.gov/36010645/

“There is a great potential to use CBs and their metabolites and non-cannabinoid dual CBRs/PPAR agonists as novel interventions for PCOS and related disorders. PCOS pathophysiology is complex and poorly understood. We demonstrate that the ECS and PPARs play an important role in the pathogenesis of PCOS (including mtCB1R). The complexity of the ECS and the PPARs will allow the development of diverse therapeutic modalities targeting these interrelated systems. Further, these interventions can be used to develop personalized approaches to treatment based on individual patient characteristics.”

https://www.mdpi.com/2073-4409/11/16/2569/htm

The Antimicrobial Properties of Cannabis and Cannabis-Derived Compounds and Relevance to CB2-Targeted Neurodegenerative Therapeutics

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“Cannabinoid receptor 2 (CB2) is of interest as a much-needed target for the treatment or prevention of several neurogenerative diseases. However, CB2 agonists, particularly phytocannabinoids, have been ascribed antimicrobial properties and are associated with the induction of microbiome compositional fluxes. When developing novel CB2 therapeutics, CB2 engagement and antimicrobial functions should both be considered. This review summarizes those cannabinoids and cannabis-informed molecules and preparations (CIMPs) that show promise as microbicidal agents, with a particular focus on the most recent developments. CIMP-microbe interactions and anti-microbial mechanisms are discussed, while the major knowledge gaps and barriers to translation are presented. Further research into CIMPs may proffer novel direct or adjunctive strategies to augment the currently available antimicrobial armory. The clinical promise of CIMPs as antimicrobials, however, remains unrealized. Nevertheless, the microbicidal effects ascribed to several CB2 receptor-agonists should be considered when designing therapeutic approaches for neurocognitive and other disorders, particularly in cases where such regimens are to be long-term. To this end, the potential development of CB2 agonists lacking antimicrobial properties is also discussed.”

https://pubmed.ncbi.nlm.nih.gov/36009504/

https://www.mdpi.com/2227-9059/10/8/1959/htm

Interacting binding insights and conformational consequences of the differential activity of cannabidiol with two endocannabinoid-activated G-protein-coupled receptors

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“Cannabidiol (CBD), the major non-psychoactive phytocannabinoid present in the plant Cannabis sativa, has displayed beneficial pharmacological effects in the treatment of several neurological disorders including, epilepsy, Parkinson’s disease, and Alzheimer’s disease. In particular, CBD is able to modulate different receptors in the endocannabinoid system, some of which belong to the family of G-protein-coupled receptors (GPCRs). Notably, while CBD is able to antagonize some GPCRs in the endocannabinoid system, it also seems to activate others. The details of this dual contrasting functional feature of CBD, that is, displaying antagonistic and (possible) agonistic ligand properties in related receptors, remain unknown. Here, using computational methods, we investigate the interacting determinants of CBD in two closely related endocannabinoid-activated GPCRs, the G-protein-coupled receptor 55 (GPR55) and the cannabinoid type 1 receptor (CB1). While in the former, CBD has been demonstrated to function as an antagonist, the way by which CBD modulates the CB1 receptor remains unclear. Namely, CBD has been suggested to directly trigger receptor’s activation, stabilize CB1 inactive conformations or function as an allosteric modulator. From microsecond-length unbiased molecular dynamics simulations, we found that the presence of the CBD ligand in the GPR55 receptor elicit conformational changes associated with antagonist-bound GPCRs. In contrast, when the GPR55 receptor is simulated in complex with the selective agonist ML186, agonist-like conformations are sampled. These results are in agreement with the proposed modulatory function of each ligand, showing that the computational techniques utilized to characterize the GPR55 complexes correctly differentiate the agonist-bound and antagonist-bound systems. Prompted by these results, we investigated the role of the CBD compound on the CB1 receptor using similar computational approaches. The all-atom MD simulations reveal that CBD induces conformational changes linked with agonist-bound GPCRs. To contextualize the results we looked into the CB1 receptor in complex with a well-established antagonist. In contrast to the CBD/CB1 complex, when the CB1 receptor is simulated in complex with the ligand antagonist AM251, inactive conformations are explored, showing that the computational techniques utilized to characterize the CB1 complexes correctly differentiate the agonist-bound and antagonist-bound systems. In addition, our results suggest a previously unknown sodium-binding site located in the extracellular domain of the CB1 receptor. From our detailed characterization, we found particular interacting loci in the binding sites of the GPR55 and the CB1 receptors that seem to be responsible for the differential functional features of CBD. Our work will pave the way for understanding the CBD pharmacology at a molecular level and aid in harnessing its potential therapeutic use.”

https://pubmed.ncbi.nlm.nih.gov/36016551/

https://www.frontiersin.org/articles/10.3389/fphar.2022.945935/full

The effects of acute alcohol administration on circulating endocannabinoid levels in humans

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“Several lines of evidence suggest that endocannabinoid signalling may influence alcohol consumption. Preclinical studies have found that pharmacological blockade of cannabinoid receptor 1 leads to reductions in alcohol intake. Furthermore, variations in endocannabinoid metabolism between individuals may be associated with the presence and severity of alcohol use disorder. However, little is known about the acute effects of alcohol on the endocannabinoid system in humans. In this study, we evaluated the effect of acute alcohol administration on circulating endocannabinoid levels by analysing data from two highly-controlled alcohol administration experiments. In the first within-subjects experiment, 47 healthy participants were randomized to receive alcohol and placebo in a counterbalanced order. Alcohol was administered using an intravenous clamping procedure such that each participant attained a nearly identical breath alcohol concentration of 0.05%, maintained over 3 h. In the second experiment, 23 healthy participants self-administered alcohol intravenously; participants had control over their exposure throughout the paradigm. In both experiments, circulating concentrations of two endocannabinoids, N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG), were measured at baseline and following alcohol exposure. During the intravenous clamping procedure, acute alcohol administration reduced circulating AEA but not 2-AG levels when compared to placebo. This finding was confirmed in the self-administration paradigm, where alcohol reduced AEA levels in an exposure-dependent manner. Future studies should seek to determine whether alcohol administration has similar effects on brain endocannabinoid signalling. An improved understanding of the bidirectional relationship between endocannabinoid signalling and alcohol intake may deepen our understanding of the aetiology and repercussions of alcohol use disorder.”

https://pubmed.ncbi.nlm.nih.gov/36001429/

https://onlinelibrary.wiley.com/doi/10.1111/adb.13197

Plasma endocannabinoids and cannabimimetic fatty acid derivatives are altered in gastroparesis: A sex- and subtype-dependent observation

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“Background: Gastroparesis (GP) is a motility disorder of the stomach presenting with upper gastrointestinal symptoms in the setting of delayed gastric emptying. Endocannabinoids are involved in the regulation of GI function including motility. However, their role in the pathophysiology of GP has not been sufficiently investigated. Our goal was to compare the circulating levels of endocannabinoids and cannabimimetic fatty acid derivatives in GP versus control subjects.

Methods: The study compared plasma concentrations of endocannabinoids and their lipoamine and 2-acyl glycerol congeners, measured by high-pressure liquid chromatography/tandem mass spectrometry (HPLC-MS-MS), in adult patients with diabetic gastroparesis (DM-GP; n = 24; n = 16 female), idiopathic gastroparesis (ID-GP; n = 19; n = 11 female), diabetic patients without GP (DM; n = 19; n = 10 female), and healthy controls (HC; n = 18; n = 10 female). Data, presented as mean ± SEM, were analyzed with ANOVA (Sidak post hoc).

Key results: Endocannabinoids anandamide (AEA: 0.5 ± 0.1 nMol/L) and 2-arachidonoyl glycerol (2-AG: 2.6 ± 0.7 nMol/L) were significantly lower in female DM-GP patients vs. DM females (AEA: 2.5 ± 0.7 nMol/L and 2-AG: 9.4 ± 3.3 nMol/L). Other monoacylglycerols including 2-palmitoyl glycerol and 2-oleoyl glycerol were also lower in female DM-GP patients compared to DM females. No changes were observed in men.

Conclusions & inferences: Endocannabinoids and other fatty acid derivatives with cannabimimetic properties are reduced in female DM-GP patients. Since GP, particularly with diabetic etiology, is more prevalent among women and since cannabinoids are antiemetic, this decrease in levels may contribute to symptom development in these subjects. Targeting the endocannabinoid system may be a future therapeutic option in DM-GP patients.”

https://pubmed.ncbi.nlm.nih.gov/32779297/

“Targeting the endocannabinoid system may be a future therapeutic option in DM-GP patients.”

https://onlinelibrary.wiley.com/doi/full/10.1111/nmo.13961

Pentadecanoylcarnitine is a newly discovered endocannabinoid with pleiotropic activities relevant to supporting physical and mental health

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“As an emerging dietary essential fatty acid, pentadecanoic acid (C15:0) is expected to have bioactive metabolites with broad health benefits. Here, we evaluated pentadecanoylcarnitine, an endogenous C15:0 metabolite, for dose dependent cell-based activities, including measurement of its effects on 148 clinically relevant biomarkers across twelve primary human cell systems mimicking various disease states.

Mechanisms of action for pentadecanoylcarnitine were also assessed across 78 cell-based target assays. Pentadecanoylcarnitine had dose-dependent anti-inflammatory activities, including lower IL-1α, ITAC, MCP-1, and IP-10, across five cell systems relevant to treating cardiovascular, immune, neoplastic, pulmonary, and skin diseases.

Targeted assays showed pentadecanoylcarnitine as a full-acting cannabinoid 1 and 2 receptor agonist (EC50 3.7 and 3.2 µM, 111% and 106% maximum activity compared to the positive control, respectively). Pentadecanoylcarnitine also had 5-HT1A and 5-HT1B receptor agonist and histamine H1 and H2 receptor antagonist activities.

In summary, pentadecanoylcarnitine, a second discovered full-acting endocannabinoid, had broad pleiotropic activities relevant to regulating inflammation, pain, mood, and sleep. This study’s findings further the need to evaluate the potential health impacts of C15:0 nutritional deficiencies caused by population-wide avoidance of all dietary saturated fats, including C15:0.”

https://pubmed.ncbi.nlm.nih.gov/35999445/

“In summary, similar to other essential fatty acids, we have demonstrated that C15:0 itself, and now a C15:0 metabolite, have pleiotropic effects with expected broad health benefits. Specifically, pentadecanoylcarnitine has potent pro-endocannabinoid, serotonin-supporting, and antihistamine activities relevant to promoting both physical and mental health, including its ability to regulate inflammation, pain, mood, sleep, and stress. Due to population-wide decreases in whole fat milk intake, paired with declining circulating C15:0 concentrations4, further studies are needed to evaluate possible links between the global rise in allergies, mental health conditions, and sleep disorders and C15:0 nutritional deficiencies.”

https://www.nature.com/articles/s41598-022-18266-w


Investigation of the Effects of the Endogenous Cannabinoid Anandamide on Luminal A Breast Cancer Cell Line MCF-7

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“The present study was carried out to investigate anti-tumoral effects of Anandamide (AEA) in luminal A breast cancer cell line MCF-7. Cell viability was measured by MTT assay and cell index was measured by xCelligence DP analyzer system. The Feulgen method was used to determine the mitotic index parameter, and the 3H-Thymidine method was used to determine the labeling index parameter. The apoptotic index parameter was determined using a fluorescent dye DAPI. The results of this study showed that 25 µM Anandamide concentration was the optimum concentration for MCF-7 cells. While this concentration decreased the proportion of cells in the mitotic phase and synthesis phase, it increased the proportion of apoptotic cells.”

https://pubmed.ncbi.nlm.nih.gov/35988272/

https://www.cellmolbiol.org/index.php/CMB/article/view/4374

Structural basis for cannabinoid-induced potentiation of alpha1-glycine receptors in lipid nanodiscs

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Nature Communications

“Nociception and motor coordination are critically governed by glycine receptor (GlyR) function at inhibitory synapses. Consequentially, GlyRs are attractive targets in the management of chronic pain and in the treatment of several neurological disorders. High-resolution mechanistic details of GlyR function and its modulation are just emerging.

While it has been known that cannabinoids such as Δ9-tetrahydrocannabinol (THC), the principal psychoactive constituent in marijuana, potentiate GlyR in the therapeutically relevant concentration range, the molecular mechanism underlying this effect is still not understood.

Here, we present Cryo-EM structures of full-length GlyR reconstituted into lipid nanodisc in complex with THC under varying concentrations of glycine. The GlyR-THC complexes are captured in multiple conformational states that reveal the basis for THC-mediated potentiation, manifested as different extents of opening at the level of the channel pore.

Taken together, these structural findings, combined with molecular dynamics simulations and functional analysis, provide insights into the potential THC binding site and the allosteric coupling to the channel pore.”

https://pubmed.ncbi.nlm.nih.gov/35982060/

https://www.nature.com/articles/s41467-022-32594-5

Pharmacophore-based virtual screening from phytocannabinoids as antagonist r-CB1

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SpringerLink

“Search for new pharmacological alternatives for obesity is based on the design and development of compounds that can aid in weight loss so that they can be used safely and effectively over a long period while maintaining their function.

The endocannabinoid system is related to obesity by increasing orexigenic signals and reducing satiety signals.

Cannabis sativa is a medicinal plant of polypharmaceutical potential that has been widely studied for various medicinal purposes.

The in silico evaluation of their natural cannabinoids (also called phytocannabinoids) for anti-obesity purpose stems from the existence of synthetic cannabinoid compounds that have already presented this result, but which did not guarantee patient safety.

In order to find new molecules from C. sativa phytocannabinoids, with the potential to interact peripherally with the pharmacological target cannabinoid receptor 1, a pharmacophore-based virtual screening was performed, including the evaluation of physicochemical, pharmacokinetic, toxicological predictions and molecular docking.

The results obtained from the ZINC12 database pointed to Zinc 69 (ZINC33053402) and Zinc 70 (ZINC19084698) molecules as promising anti-obesity agents. Molecular dynamics (MD) studies disclose that both complexes were stable by analyzing the RMSD (root mean square deviation) values, and the binding free energy values demonstrate that the selected structures can interact and inhibit their catalytic activity.”

https://pubmed.ncbi.nlm.nih.gov/35978141/

https://link.springer.com/article/10.1007/s00894-022-05219-3