The effects of cannabinoids on the endocrine system.

“Cannabinoids are the derivatives of the cannabis plant, the most potent bioactive component of which is tetrahydrocannabinol (THC). The most commonly used drugs containing cannabinoids are marijuana, hashish, and hashish oil.

These compounds exert their effects via interaction with the cannabinoid receptors CB1 and CB2. Type 1 receptors (CB1) are localised mostly in the central nervous system and in the adipose tissue and many visceral organs, including most endocrine organs. Type 2 cannabinoid receptors (CB2) are positioned in the peripheral nervous system (peripheral nerve endings) and on the surface of the immune system cells.

Recently, more and more attention has been paid to the role that endogenous ligands play for these receptors, as well as to the role of the receptors themselves. So far, endogenous cannabinoids have been confirmed to participate in the regulation of food intake and energy homeostasis of the body, and have a significant impact on the endocrine system, including the activity of the pituitary gland, adrenal cortex, thyroid gland, pancreas, and gonads.

Interrelations between the endocannabinoid system and the activity of the endocrine system may be a therapeutic target for a number of drugs that have been proved effective in the treatment of infertility, obesity, diabetes, and even prevention of diseases associated with the cardiovascular system.”

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Associations between cannabis use and cardiometabolic risk factors: A longitudinal study of men.

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“This study tested longitudinal associations between cannabis use and cardiometabolic risk factors that underlie the development of cardiovascular diseases.

RESULTS:

Greater cannabis exposure was associated with relatively lower BMI (β=-0.31, p<.001), smaller WHR (β=-0.23, p=.002), better HDL (β=0.14, p=.036) and LDL cholesterol (β=-0.15, p=.026), lower triglycerides (β=-0.17, p=.009), lower fasting glucose (β=-0.15, p<.001) and HOMA-IR (β=-0.21, p=.003), lower systolic (β=-0.22, p<.001) and diastolic blood pressure (β=-0.15, p=.028), and fewer metabolic syndrome criteria (β=-0.27, p<.001). With exception of BMI, cannabis users’ mean levels on cardiometabolic risk factors were generally below clinical cutoffs for high risk. Most associations between cannabis use and cardiometabolic risk factors remained after adjusting for tobacco use, childhood SES, and childhood health. However, after adjusting for adult BMI, these associations were no longer apparent, and mediation tests suggested that cannabis users’ relatively lower BMI might explain their lower levels of risk on other cardiometabolic risk factors.

CONCLUSIONS:

Cannabis use is associated with lower BMI, and lower BMI is related to lower levels of risk on other cardiometabolic risk factors.”

https://www.ncbi.nlm.nih.gov/pubmed/30589665

https://insights.ovid.com/crossref?an=00006842-900000000-98666

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Selective Activation of Cannabinoid Receptor 2 Attenuates Myocardial Infarction via Suppressing NLRP3 Inflammasome.

“The administration of cannabinoid receptor 2 (CB2R) agonist has been reported to produce a cardioprotective effect against the pathogenesis and progression of myocardial infarction (MI).

Here in this study, we investigated the specific mechanism related to inflammatory suppression. JWH-133 was used for the activation of CB2R.

Taken together, we demonstrated for the first time the cardioprotective effect of CB2R agonist and its NLRP3 inflammasome-related mechanism in MI.”

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The endocannabinoid system: Overview of an emerging multi-faceted therapeutic target.

Prostaglandins, Leukotrienes and Essential Fatty Acids Home

“The endocannabinoids anandamide (AEA) and 2-arachidonoylglyerol (2-AG) are endogenous lipid mediators that exert protective roles in pathophysiological conditions, including cardiovascular diseases. In this brief review, we provide a conceptual framework linking endocannabinoid signaling to the control of the cellular and molecular hallmarks, and categorize the key components of endocannabinoid signaling that may serve as targets for novel therapeutics. The emerging picture not only reinforces endocannabinoids as potent regulators of cellular metabolism but also reveals that endocannabinoid signaling is mechanistically more complex and diverse than originally thought.”

https://www.ncbi.nlm.nih.gov/pubmed/30553404

https://www.plefa.com/article/S0952-3278(18)30176-5/fulltext

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Cannabinoids for Treating Cardiovascular Disorders: Putting Together a Complex Puzzle.

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“Cannabinoids have been increasingly gaining attention for their therapeutic potential in treating various cardiovascular disorders. These disorders include myocardial infarction, hypertension, atherosclerosis, arrhythmias, and metabolic disorders.

The aim of this review is to cover the main actions of cannabinoids on the cardiovascular system by examining the most recent advances in this field and major literature reviews.

It is well recognized that the actions of cannabinoids are mediated by either cannabinoid 1 or cannabinoid 2 receptors (CB2Rs). Endocannabinoids produce a triphasic response on blood pressure, while synthetic cannabinoids show a tissue-specific and species-specific response.

Blocking cannabinoid 1 receptors have been shown to be effective against cardiometabolic disorders, although this should be done peripherally. Blocking CB2Rs may be a useful way to treat atherosclerosis by affecting immune cells. The activation of CB2Rs was reported to be useful in animal studies of myocardial infarction and cardiac arrhythmia.

Although cannabinoids show promising effects in animal models, this does not always translate into human studies, and therefore, extensive clinical studies are needed to truly establish their utility in treating cardiovascular disease.”

https://www.ncbi.nlm.nih.gov/pubmed/30464888

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Activating Cannabinoid Receptor 2 Protects Against Diabetic Cardiomyopathy Through Autophagy Induction.

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“Cannabinoid receptor 2 (CB2) has been reported to produce a cardio-protective effect in cardiovascular diseases such as myocardial infarction. Here in this study, we investigated the role of CB2 in diabetic cardiomyopathy (DCM) and its underlying mechanisms.

In conclusion, we initially demonstrated that activating CB2 produced a cardio-protective effect in DCM as well as cardiomyocytes under HG challenge through inducing the AMPK-mTOR-p70S6K signaling-mediated autophagy.”

https://www.ncbi.nlm.nih.gov/pubmed/30459625

“Taken together, in this study, we initially showed that activating CB2 produced a cardio-protective effect in DCM as well as cardiomyocytes under HG challenge through the induction of the AMPK-mTOR-p70S6K signaling-mediated autophagy process. We believe that the findings of this study might enhance our knowledge on the understanding of the pathogenesis and progression of DCM and provide a novel insight in the development of therapeutic strategies against DCM.”

https://www.frontiersin.org/articles/10.3389/fphar.2018.01292/full

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Beta-caryophyllene alleviates diet-induced neurobehavioral changes in rats: The role of CB2 and PPAR-γ receptors.

Biomedicine & Pharmacotherapy

“Insulin resistance (IR) and obesity predispose diseases such as diabetes, cardiovascular and neurodegenerative disorders.

Beta-caryophyllene (BCP), a natural sesquiterpene, exerts neuroprotective, anxiolytic and antidepressant effects via its selective agonism to cannabinoid receptor 2 (CB2R). BCP was shown to have an anti-diabetic effect, however, the implication of CB2R is yet to be elucidated. A link between CB2R agonism and PPAR-γ activation has been discussed, but the exact mechanism is not well-defined.

This study was designed to examine the role of BCP in improving diet-induced metabolic (insulin resistance), neurobehavioral (anxiety, depression and memory deficit), and neurochemical (oxidative, inflammatory and neurotrophic factor) alterations in the prefrontal cortex of obese rats’ brain. The involvement of CB2R and/or PPAR-γ dependent activity was also investigated.

KEY RESULTS:

Beta-caryophyllene alleviated HFFD-induced IR, oxidative-stress, neuroinflammation and behavioral changes. The anxiolytic, anti-oxidant and anti-inflammatory effects of BCP were mediated by both PPAR-γ and CB2R. The effects of BCP on glycemic parameters seem to be CB2R-dependent with the non-significant role of PPAR-γ. Furthermore, BCP-evoked antidepressant and memory improvement are likely mediated only via CB2R, mainly by upregulation of PGC-1α and BDNF.

CONCLUSION:

This study suggests the potential effect of BCP in treating HFFD-induced metabolic and neurobehavioral alterations. BCP seems to activate PPAR-γ in a ligand-independent manner, via upregulation and activation of PGC-1α. The BCP activation of PPAR–γ seems to be CB2R-dependent.”

https://www.ncbi.nlm.nih.gov/pubmed/30469079

https://www.sciencedirect.com/science/article/pii/S0753332218370033?via%3Dihub

“β-caryophyllene (BCP) is a common constitute of the essential oils of numerous spice, food plants and major component in Cannabis.”   http://www.ncbi.nlm.nih.gov/pubmed/23138934

“Beta-caryophyllene is a dietary cannabinoid.”  https://www.ncbi.nlm.nih.gov/pubmed/18574142

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New insights on atherosclerosis: A cross-talk between endocannabinoid systems with gut microbiota.

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“The incidence of atherosclerosis is increasing rapidly all over the world. Inflammatory processes have outstanding role in coronary artery disease (CAD) etiology and other atherosclerosis manifestations. Recently attentions have been increased about gut microbiota in many fields of medicine especially in inflammatory diseases like atherosclerosis. Ineffectiveness in gut barrier functions and subsequent metabolic endotoxemia (caused by rise in plasma lipopolysaccharide levels) is associated with low-grade chronic inflammation i.e. a recognized feature of atherosclerosis. Furthermore, the role of trimethylamine-N-oxide (TMAO), a gut bacterial metabolite has been suggested in atherosclerosis development. On the other hand, the effectiveness of gut microbiota modulation that results in TMAO reduction has been investigated. Moreover, considerable evidence supports a role for the endocannabinoid system (ECS) in atherosclerosis pathology which affects gut microbiota, but their effects on atherosclerosis are controversial. Therefore, we presented some evidence about the relationship between gut microbiota and ECS in atherosclerosis. We also presented evidences that gut microbiota modulation by pre/probiotics can have significant influence on the ECS.

Even though there are many questions which have been unanswered, studies demonstrated that mucosal barrier function disruption and subsequent gut microbiota-derived endotoxemia could contribute to cardiometabolic diseases pathogenesis. As well, number of studies revealed that TMAO in systemic circulation can activate macrophages which lead to cholesterol accumulation and subsequent foam cells formation in atherosclerotic lesions. On the other hand, accumulating evidence proposes that ECS involved in many physiological processes that are related to maintenance of gut-barrier function and inflammation regulation. Hence, although present literature review provides beneficial evidence in support of crosstalk between ECS and gut microbiota, additional studies are needed to clarify whether gut microbiota modulation can alter ECS tone and inflammation levels or not.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6203867/

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Acute administration of beta-caryophyllene prevents endocannabinoid system activation during transient common carotid artery occlusion and reperfusion.

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“The transient global cerebral hypoperfusion/reperfusion achieved by induction of Bilateral Common Carotid Artery Occlusion followed by Reperfusion (BCCAO/R) has been shown to stimulate early molecular changes that can be easily traced in brain tissue and plasma, and that are indicative of the tissue physiological response to the reperfusion-induced oxidative stress and inflammation.

The aim of the present study is to probe the possibility to prevent the molecular changes induced by the BCCAO/R with dietary natural compounds known to possess anti-inflammatory activity, such as the phytocannabinoid beta-caryophyllene (BCP).

CONCLUSIONS:

Collectively, the pre-treatment with BCP, likely acting as agonist for CB2 and PPAR-alpha receptors, modulates in a beneficial way the ECS activation and the lipoperoxidation, taken as indicative of oxidative stress. Furthermore, our results support the evidence that BCP may be used as a dietary supplement to control the physiological response to the hypoperfusion/reperfusion-induced oxidative stress.”

“beta-caryophyllene (BCP), a sesquiterpene found as a common constituent of the essential oils of numerous food plants and primary component in Cannabis sativa L., is a dietary phytocannabinoid acting as selective agonist for CB2 receptor and peroxisome-proliferator activating receptor alpha (PPAR-alpha)”
“β-caryophyllene (BCP) is a common constitute of the essential oils of numerous spice, food plants and major component in Cannabis.”   http://www.ncbi.nlm.nih.gov/pubmed/23138934
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Up-regulation of heme oxygenase-1 expression and inhibition of disease-associated features by cannabidiol in vascular smooth muscle cells.

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“Aberrant proliferation and migration of vascular smooth muscle cells (VSMC) have been closely linked to the development and progression of cardiovascular and cancer diseases.

The cytoprotective enzyme heme oxygenase-1 (HO-1) has been shown to mediate anti-proliferative and anti-migratory effects in VSMC. This study investigates the effect of cannabidiol (CBD), a non-psychoactive cannabinoid, on HO-1 expression and disease-associated functions of human umbilical artery smooth muscle cells (HUASMC).

HO-1 protein and mRNA were significantly increased by CBD in a time- and concentration-dependent manner. Although the expression of several cannabinoid-activated receptors (CB1, CB2, G protein-coupled receptor 55, transient receptor potential vanilloid 1) was verified in HUASMC, CBD was shown to induce HO-1 via none of these targets. Instead, the CBD-mediated increase in HO-1 protein was reversed by the glutathione precursor N-acetylcysteine, indicating the participation of reactive oxygen species (ROS) signaling; this was confirmed by flow cytometry-based ROS detection.

CBD-induced HO-1 expression was accompanied by inhibition of growth factor-mediated proliferation and migration of HUASMC. However, neither inhibition of HO-1 activity nor knockdown of HO-1 protein attenuated CBD-mediated anti-proliferative and anti-migratory effects. Indeed, inhibition or depletion of HO-1 resulted in induction of apoptosis and intensified CBD-mediated effects on proliferation and migration.

Collectively, this work provides the first indication of CBD-mediated enhancement of HO-1 in VSMC and potential protective effects against aberrant VSMC proliferation and migration. On the other hand, our data argue against a role of HO-1 in CBD-mediated inhibition of proliferation and migration while substantiating its anti-apoptotic role in oxidative stress-mediated cell fate.”

https://www.ncbi.nlm.nih.gov/pubmed/30349652

http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=26191&path[]=81658

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