Potential Mechanisms Influencing the Inverse Relationship Between Cannabis and Nonalcoholic Fatty Liver Disease: A Commentary.

Image result for Nutrition and Metabolic Insights“Nonalcoholic fatty liver disease (NAFLD) develops when the liver is unable to oxidize or export excess free fatty acids generated by adipose tissue lipolysis, de novo lipogenesis, or dietary intake. Although treatment has generally been centered on reversing metabolic risk factors that increase the likelihood of NAFLD by influencing lifestyle modifications, therapeutic modalities are being studied at the cellular and molecular level.

The endocannabinoid system has been of recent focus. The agonism and antagonism of cannabinoid receptors play roles in biochemical mechanisms involved in the development or regression of NAFLD. Exocannabinoids and endocannabinoids, the ligands which bind cannabinoid receptors, have been studied in this regard.

Exocannabinoids found in cannabis (marijuana) may have a therapeutic benefit. Our recent study demonstrated an inverse association between marijuana use and NAFLD among adults in the United States.

This commentary combines knowledge on the role of the endocannabinoid system in the setting of NAFLD with the findings in our article to hypothesize different potential mechanisms that may influence the inverse relationship between cannabis and NAFLD.” https://www.ncbi.nlm.nih.gov/pubmed/31308686

https://journals.sagepub.com/doi/10.1177/1178638819847480

Diet, endocannabinoids, and health.

Nutrition Research“Healthy aging includes freedom from disease, ability to engage in physical activity, and maintenance of cognitive skills for which diet is a major lifestyle factor. Aging, diet, and health are at the forefront of well-being for the growing population of older adults with the caveat of reducing and controlling pain. Obesity and diabetes risk increase in frequency in adults, and exercise is encouraged to control weight, reduce risk of type II diabetes, and maintain muscle mass and mobility.

One area of research that appears to integrate many aspects of healthy aging is focused on understanding the endocannabinoid system (ECS) because of its role in systemic energy metabolism, inflammation, pain, and brain biology. Physical activity is important for maintaining health throughout the life cycle. The benefits of exercise facilitate macronutrient use, promote organ health, and augment the maintenance of metabolic activity and physiological functions. One outcome of routine exercise is a generalized well-being, and perhaps, this is linked to the ECS.

The purpose of this review is to briefly present the current knowledge of key components of the ECS that contribute to appetite and influence systemic energy metabolism, and dietary factors that alter the responses of ligand binding and activation of cannabinoidreceptors and its role in the brain. Herein, the objectives are to (1) explain the role of the ECS in the body, (2) describe the relationship between dietary polyunsaturated fatty acids and macronutrient intake and systemic metabolism, and (3) present areas of promising research where exercise induces endocannabinoid production in the brain to benefit well-being. There are many gaps in the knowledge of how the ECS participates in controlling pain through exercise; however, emerging research will reveal key relationships to understand this system in the brain and body.”

https://www.ncbi.nlm.nih.gov/pubmed/31280882

https://www.sciencedirect.com/science/article/pii/S027153171930572X?via%3Dihub

Distinct Functions of Endogenous Cannabinoid System in Alcohol Abuse Disorders.

British Journal of Pharmacology banner

“Δ9-tetrahydrocannabinol (Δ9 -THC), the principal active component in Cannabis sativa extracts such as marijuana, participates in cell signaling by binding to cell surface receptors. CB1 receptors (CB1 s) are present in both inhibitory and excitatory presynaptic terminals. CB2 receptors (CB2 s) found in neuronal subpopulations in addition to microglial cells and astrocytes and are present in both pre- and postsynaptic terminals.

Subsequent to endocannabinoid (eCB) system discoveries, studies have suggested that alcohol alters the eCB system and that the eCB system plays a major role in the motivation to abuse alcohol.

Preclinical studies have provided evidence that chronic alcohol consumption modulates eCBs and CB1 expression in brain addiction circuits. In addition, studies have further established the distinct function of the eCB system in the development of fetal alcohol spectrum disorders. This review provides a recent and comprehensive assessment of the literature related to the function of the eCB system in alcohol abuse disorders.”

https://www.ncbi.nlm.nih.gov/pubmed/31265740

https://bpspubs.onlinelibrary.wiley.com/doi/abs/10.1111/bph.14780

“Cannabis and Alcohol: From Basic Science to Public Policy.”  https://www.ncbi.nlm.nih.gov/pubmed/31265135

Cannabis sativa L. extract and cannabidiol inhibit in vitro mediators of skin inflammation and wound injury.

Publication cover image“The present study investigates the potential effect of a Cannabis sativa L. ethanolic extract standardized in cannabidiol as antiinflammatory agent in the skin. The extract inhibited the release of mediators of inflammation involved in wound healing and inflammatory processes occurring in the skin. Cannabis extract and cannabidiol showed different effects on the release of interleukin-8 and vascular endothelial growth factor, which are both mediators whose genes are dependent on NF-κB. Our findings provide new insights into the potential effect of Cannabis extracts against inflammation-based skin diseases.” https://www.ncbi.nlm.nih.gov/pubmed/31250491

https://onlinelibrary.wiley.com/doi/abs/10.1002/ptr.6400

“The endocannabinoid system of the skin in health and disease: novel perspectives and therapeutic opportunities” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2757311/

“The endocannabinoid system of the skin. A potential approach for the treatment of skin disorders” https://www.sciencedirect.com/science/article/abs/pii/S0006295218303484

Cannabinoid system in the skin – a possible target for future therapies in dermatology.”   https://www.ncbi.nlm.nih.gov/pubmed/19664006

“Extracts of the hemp plant cannabis are traditionally used as a popular remedy against inflammation.” https://medicalxpress.com/news/2007-06-cannabinoids-human-body-anti-inflammatory-effect.html

Cannabinoid receptor 1 (CB1R) expression in rat dental pulp

Oral Science International“Accumulating evidence supports the role of the cannabinoid system in providing an antinociceptive effect in various painful conditions.

This effect is mediated through the Cannabinoid receptor 1 (CB1R) expressed on nociceptive afferent nerve terminals.

To investigate whether this receptor plays a similar role in dental pain, we studied the presence and distribution of CB1R in rat dental pulp.

CB1R was present on nerve fibers in rat dental pulp and possibly plays a role in dental pain mechanisms.

Interestingly, CB1R has recently been demonstrated in human dental pulp.

This strongly suggests that CB1R could be a therapeutic target for dental pain management.”

https://www.sciencedirect.com/science/article/pii/S1348864312000031

Endocannabinoid system imbalance in the postmortem prefrontal cortex of subjects with schizophrenia.

Image result for Journal of Psychopharmacology“The present findings reveal an imbalance in the expression and function of different elements of the endocannabinoid system in schizophrenia.

This outcome highlights the relevance of the endocannabinoid system in the pathophysiology of schizophrenia and emphasises its elements as potential targets in the search for new therapeutic strategies.”

https://www.ncbi.nlm.nih.gov/pubmed/31237179

https://journals.sagepub.com/doi/abs/10.1177/0269881119857205?journalCode=jopa

“Therapeutic potential of cannabinoids in schizophrenia.”   https://www.ncbi.nlm.nih.gov/pubmed/24605939

Cannabinoids for the Treatment of Schizophrenia: An Overview. Cannabinoids are found to be very useful in psychiatry because of their antipsychotic properties suggesting a therapeutic use. Cannabinoids treatments are both able to reduce the typical symptoms of schizophrenia and to slow down the disease aggravation.”   https://www.ncbi.nlm.nih.gov/pubmed/26845552

http://www.thctotalhealthcare.com/category/schizophrenia/

Nabilone administration in refractory chronic diarrhea: a case series

Image result for bmc gastroenterology
“Through the years, the endocannabinoid system has been recognized in the homeostatic mechanisms of the gut, as well as in the physiological control of intestinal motility and secretion. Accordingly, cannabinoids may be a promising therapy against several gastrointestinal conditions, such as abdominal pain and motility-related disorders. After three months of therapy, oral nabilone improved the health of nearly all patients, with visible improvements in reducing diarrheal symptoms and weight gain. These findings encourage the study of cannabinoids acting on CB1 receptors in chronic gastrointestinal disorders, especially in refractory chronic diarrhea, offering a chance for a substantial improvement in the quality of life of selected patients, with a reasonable safety profile.” https://bmcgastroenterol.biomedcentral.com/articles/10.1186/s12876-019-1024-y
“Nabilone is a drug used to treat severe nausea and vomiting. It is in a family of drugs called cannabinoids (eg. marijuana).” https://hivclinic.ca/main/drugs_fact_files/nabilone.pdf

Repetitive high-frequency transcranial magnetic stimulation reverses depressive-like behaviors and protein expression at hippocampal synapses in chronic unpredictable stress-treated rats by enhancing endocannabinoid signaling.

Pharmacology Biochemistry and Behavior“The anti-depressant effect of repetitive transcranial magnetic stimulation (rTMS), a clinically-useful treatment for depression, is associated with changes to the endocannabinoid system (ECS).

However, it is currently unknown whether different frequencies of rTMS alter the ECS differently. To test this, rats exposed to chronic unpredictable stress (CUS) were treated with rTMS at two different frequencies (5 (high) or 1 Hz (low), 1.26 Tesla) for 7 consecutive days.

Interestingly, we found that only high-frequency rTMS ameliorated depressive-like behaviors and normalized the expression of hippocampal synaptic proteins in CUS-treated rats;

Collectively, our results suggest that high-frequency rTMS exerts its anti-depressant effect by up-regulating diacylglycerol lipase alpha (DAGLα) and cannabinoid type 1 receptor (CB1R).”

https://www.ncbi.nlm.nih.gov/pubmed/31229467

https://www.sciencedirect.com/science/article/pii/S0091305719301376?via%3Dihub

Transcranial magnetic stimulation.jpg

“Transcranial magnetic stimulation (TMS), also known as repetitive transcranial magnetic stimulation (rTMS), is a noninvasive form of brain stimulation in which a changing magnetic field is used to cause electric current at a specific area of the brain through electromagnetic induction. An electric pulse generator, or stimulator, is connected to a magnetic coil, which in turn is connected to the scalp. The stimulator generates a changing electric current within the coil which induces a magnetic field; this field then causes a second inductance of inverted electric charge within the brain itself. Adverse effects of TMS are rare, and include fainting and seizure. Other potential issues include discomfort, pain, hypomania, cognitive change, hearing loss, and inadvertent current induction in implanted devices such as pacemakers or defibrillators”  https://www.sciencedirect.com/science/article/pii/S0091305719301376?via%3Dihub

Quetiapine induces myocardial necroptotic cell death through bidirectional regulation of cannabinoid receptors.

Toxicology Letters

“Quetiapine is a common atypical antipsychotic used to treat mental disorders such as schizophrenia, bipolar disorder, and major depressive disorder. There has been increasing number of reports describing its cardiotoxicity. However, the molecular mechanisms underlying quetiapine-induced myocardial injury remain largely unknown.

Herein, we reported a novel cell death type, quetiapine-induced necroptosis, which accounted for quetiapine cardiotoxicity in mice and proposed novel therapeutic strategies.

Quetiapine-treated hearts showed inflammatory infiltration and evident fibrosis after 21-day continuous injection. The specific increases of protein levels of RIP3, MLKL and the phosphorylation of MLKL showed that quetiapine-induced necroptotic cell death both in vivo and in vitro. Pharmacologic blockade of necroptosis using its specific inhibitor Necrostatin-1 attenuated quetiapine-induced myocardial injury in mice.

In addition, quetiapine imbalanced the endocannabinoid system and caused opposing effects on two cannabinoid receptors (CB1R and CB2R).

Specific antagonists of CB1R (AM 281, Rimonabant), but not its agonist ACEA significantly ameliorated the heart histopathology induced by chronic quetiapine exposure. By contrast, specific agonists of CB2R (JWH-133, AM 1241), but not its antagonist AM 630 exerted beneficial roles against quetiapine cardiotoxicity.

The protective agents (AM 281, Rimonabant, AM 1241, and JWH-133) consistently inactivated the quetiapine-induced necroptosis signaling. Quetiapine bidirectionally regulates cannabinoid receptors and induces myocardial necroptosis, leading to cardiac toxic effects.

Therefore, pharmacologic inhibition of CB1R or activation of CB2R represents promising therapeutic strategies against quetiapine-induced cardiotoxicity.”

https://www.ncbi.nlm.nih.gov/pubmed/31220554

https://www.sciencedirect.com/science/article/pii/S0378427419301766?via%3Dihub

Alcohol-induced conditioned place preference is modulated by CB2 cannabinoid receptors and modifies levels of endocannabinoids in the mesocorticolimbic system.

Pharmacology Biochemistry and Behavior

“The endocannabinoid (eCB) system is a particularly important neuronal mechanism implicated in alcohol use disorders. Animal models are key to broadening our knowledge of the neurobiological mechanisms underlying alcohol dependence.

This study has two main aims: i) to assess how eCB levels in different brain areas are modified by alcohol-induced conditioning place preference (CPP), and ii) to study how cannabinoid type 2 receptor (CB2R) is involved in alcohol-rewarding properties, using pharmacological manipulation in C57BL/6 mice.

Our results suggest that the eCB system is dysregulated throughout the mesocorticolimbic system by repeated alcohol exposure during the CPP paradigm, and that levels of anandamide (AEA) and several other N-acylethanolamines are markedly decreased in the medial prefrontal cortex and ventral midbrain of alcohol-CPP mice.

We also observed that the administering an antagonist/inverse agonist of the CB2R (AM630) during the acquisition phase of CPP reduced the rewarding effects of alcohol. However, activating CB2R signalling using the agonist JWH133 seems to reduce both alcohol- and food-rewarding behaviours. Therefore, our findings indicate that the rewarding effects of alcohol are related to its disruptive effect on AEA and other N-acylethanolamine signalling pathways.

Thus, pharmacological manipulation of CB2R is an interesting candidate treatment for alcohol use disorders.”

https://www.ncbi.nlm.nih.gov/pubmed/31220547

https://www.sciencedirect.com/science/article/pii/S0091305719300656?via%3Dihub