Endocannabinoids and Stroke Prevention: Review of Clinical Studies.

View details for Cannabis and Cannabinoid Research cover image“The societal burden of ischemic stroke suggests a need for additional therapeutic categories in stroke prevention.

Modulation of the endocannabinoid system (ECS) is a rational target for stroke prevention because of its effects on inflammation, vascular tone, and metabolic balance, all well-described stroke risk factors.

In this article, we summarize the existing ECS clinical studies in human subjects’ research as they relate to conventional vascular risk factors associated with ischemic stroke.”

https://www.ncbi.nlm.nih.gov/pubmed/32322672

https://www.liebertpub.com/doi/10.1089/can.2018.0066

“The endocannabinoid system and stroke: A focused review. This review seeks to summarize the recent evidence for the role of the endocannabinoid signaling system in stroke pathophysiology, as well as the evidence from preclinical studies regarding the efficacy of cannabinoids as neuroprotective therapies in the treatment of stroke.” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6458776/

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Editorial: The Canonical and Non-Canonical Endocannabinoid System as a Target in Cancer and Acute and Chronic Pain

frontiers in pharmacology – Retraction Watch“The endocannabinoid system (ECS) comprises the canonical receptor subtypes CB1R and CB2R and endocannabinoids (anandamide, AEA and 2-arachidonoylglycerol, 2-AG), and a “non-canonical” extended signaling network consisting of: (i) other fatty acid derivatives; (ii) the defined “ionotropic cannabinoid receptors” (TRP channels); other GPCRs (GPR55, PPARα); (iii) enzymes involved in the biosynthesis and degradation of endocannabinoids (FAAH and MAGL); and (iv) protein transporters (FABP family).The ECS is currently a hot topic due to its involvement in cancer and pain.

The current Research Topic highlights various ways the endocannabinoid system (ECS) can impact cancer and pain. Ramer et al. review the anticancer potential of the canonical and noncanonical endocannabinoid system. Morales and Jagerovic provide a much needed summary of cannabinoid ligands as promising antitumor agents in a wide variety of tumors, in contrast to their palliative applications. In their article, the authors classify cannabinoids with anticancer potential in endocannabinoids, phytocannabinoids, and synthetic cannabinoids. Moreno et al. in their review explored the value of cannabinoid receptor heteromers as potential new targets for anti-cancer therapies and as prognostic biomarkers, showing the potential of the endocannabinoid network in the anti-cancer setting as well as the clinical and ethical pitfalls behind it.

As an ensemble, these studies provide further fuel to the discussion and underline the potential for targeting the ECS at multiple levels to treat certain cancers and for pain relief. Importantly, they also help to move the focal point of the discussion beyond THC, CBD, and the cannonical receptors. Several of these reports either review or provide data to support the use of/targeting of other members of the ECS system as well as alternative natural products beyond THC and CBD.”

https://www.frontiersin.org/articles/10.3389/fphar.2020.00312/full

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Endocannabinoid system and cardiometabolic risk factors: A comprehensive systematic review insight into the mechanistic effects of omega-3 fatty acids.

Life Sciences“Increased levels of endocannabinoids, 2-arachidonoylglycerol (2-AG) and arachidonoyl ethanolamide (AEA) have a pathophysiological role in the setting of cardiometabolic diseases. This systematic review was carried out to appraise the effect of omega-3 on cardiometabolic risk factors by highlighting the mediating effect of endocannabinoids.

Eleven animal studies and two human studies showed a marked reduction in 2-AG and AEA levels following intake of omega-3 which correlated with decreased adiposity, weight gain and improved glucose homeostasis. Moreover, endocannabinoids were elevated in three studies that replaced omega-3 with omega-6.

Omega-3 showed anti-inflammatory properties due to reduced levels of inflammatory cytokines, regulation of T-cells function and increased levels of eicosapentaenoyl ethanolamide, docosahexaenoyl ethanolamide and oxylipins; however, a limited number of studies examined a correlation between inflammatory cytokines and endocannabinoids following omega-3 administration.

In conclusion, omega-3 modulates endocannabinoid tone, which subsequently attenuates inflammation and cardiometabolic risk factors. However, further randomized clinical trials are needed before any recommendations are made to target the ECS using omega-3 as an alternative therapy to drugs for cardiometabolic disease improvement.”

https://www.ncbi.nlm.nih.gov/pubmed/32184122

“Endocannabinoid system (ECS) may mediate favorable effects of omega-3 fatty acids in cardiometabolic disorders. Omega-3 fatty acids showed anti-inflammatory effects due to increased levels of ethanolamide and oxylipins. Plant-derived omega-3 may be as effective as animal-derived omega-3 in ECS modulation. Omega-3 may have a potential to be an alternative to drugs for cardiometabolic disease improvement.”

https://www.sciencedirect.com/science/article/abs/pii/S0024320520303040?via%3Dihub

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2-Arachidonoylglycerol Modulation of Anxiety and Stress Adaptation: From Grass Roots to Novel Therapeutics.

Biological Psychiatry Home“Over the past decade there has been a surge of interest in the development of endocannabinoid-based therapeutic approaches for the treatment of diverse neuropsychiatric conditions. Although initial preclinical and clinical development efforts focused on pharmacological inhibition of fatty acid amide hydrolase to elevate levels of the endocannabinoid anandamide, more recent efforts have focused on inhibition of monoacylglycerol lipase (MAGL) to enhance signaling of the most abundant and efficacious endocannabinoid ligand, 2-arachidonoylglycerol (2-AG). We review the biochemistry and physiology of 2-AG signaling and preclinical evidence supporting a role for this system in the regulation of anxiety-related outcomes and stress adaptation. We review preclinical evidence supporting MAGL inhibition for the treatment of affective, trauma-related, and stress-related disorders; describe the current state of MAGL inhibitor drug development; and discuss biological factors that could affect MAGL inhibitor efficacy. Issues related to the clinical advancement of MAGL inhibitors are also discussed. We are cautiously optimistic, as the field of MAGL inhibitor development transitions from preclinical to clinical and theoretical to practical, that pharmacological 2-AG augmentation could represent a mechanistically novel therapeutic approach for the treatment of affective and stress-related neuropsychiatric disorders.”

https://www.ncbi.nlm.nih.gov/pubmed/32197779

https://www.biologicalpsychiatryjournal.com/article/S0006-3223(20)30049-4/fulltext

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Influence of cannabinoids upon nerve-evoked skeletal muscle contraction.

Neuroscience Letters“Endocannabinoids play important roles in regulating CNS synaptic function and peripheral metabolism, but cannabinoids can also act acutely to modulate contraction strength in skeletal muscle.

Nerve terminals and the skeletal muscle sarcolemma express components of the cannabinoid signaling system.

Endocannabinoids, N-arachidonylethanolamine (anandamide, AEA) and 2-arachidonoyl-glycerol (2-AG), are produced by skeletal muscle. They may be involved in the acute regulation of neuromuscular transmission, by adjusting the parameters for quantal acetylcholine release from the motor nerve terminal. Downstream of neuromuscular transmission, cannabinoids may also act to limit the efficiency of excitation-contraction coupling.

Improved understanding of the distinct signaling actions of particular cannabinoid compounds and their receptor/transduction systems will help advance our understanding of the role of endocannabinoids in skeletal muscle physiology.

Cannabinoids might also offer the potential to develop new pharmacotherapeutics to treat neuromuscular disorders that affect muscle strength.”

https://www.ncbi.nlm.nih.gov/pubmed/32156612

https://www.sciencedirect.com/science/article/abs/pii/S0304394020301701?via%3Dihub

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Role of cannabis in inflammatory bowel diseases.

Image result for Ann Gastroenterol“For many centuries, cannabis (marijuana) has been used for both recreational and medicinal purposes. Currently, there are about 192 million cannabis users worldwide, constituting approximately 3.9% of the global population. Cannabis comprises more than 70 aromatic hydrocarbon compounds known as cannabinoids. Endogenous circulating cannabinoids, or endocannabinoids, such as anandamide and 2-arachidonoyl-glycerol, their metabolizing enzymes (fatty acid amide hydrolase and monoacylglycerol lipase) and 2 G-protein coupled cannabinoid receptors, CB1 and CB2, together represent the endocannabinoid system and are present throughout the human body. In the gastrointestinal (GI) tract, the activated endocannabinoid system reduces gut motility, intestinal secretion and epithelial permeability, and induces inflammatory leukocyte recruitment and immune modulation through the cannabinoid receptors present in the enteric nervous and immune systems. Because of the effects of cannabinoids on the GI tract, attempts have been made to investigate their medicinal properties, particularly for GI disorders such as pancreatitis, hepatitis, and inflammatory bowel diseases (IBD). The effects of cannabis on IBD have been elucidated in several small observational and placebo-controlled studies, but with varied results. The small sample size and short follow-up duration in these studies make it difficult to show the clear benefits of cannabis in IBD. However, cannabis is now being considered as a potential drug for inflammatory GI conditions, particularly IBD, because of its spreading legalization in the United States and other countries and the growing trend in its use. More high-quality controlled studies are warranted to elucidate the mechanism and benefits of cannabis use as a possible option in IBD management.”

https://www.ncbi.nlm.nih.gov/pubmed/32127734

http://www.annalsgastro.gr/files/journals/1/earlyview/2020/ev-02-2020-03-AG4866-0452.pdf

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Cannabinoid Signaling in Glioma Cells.

 “Cannabinoids are a group of structurally heterogeneous but pharmacologically related compounds, including plant-derived cannabinoids, synthetic substances and endogenous cannabinoids, such as anandamide and 2-arachidonoylglycerol.

Cannabinoids elicit a wide range of central and peripheral effects mostly mediated through cannabinoid receptors. There are two types of specific Gi/o-protein-coupled receptors cloned so far, called CB1 and CB2, although an existence of additional cannabinoid-binding receptors has been suggested. CB1 and CB2 differ in their predicted amino acid sequence, tissue distribution, physiological role and signaling mechanisms.

Significant alterations of a balance in the cannabinoid system between the levels of endogenous ligands and their receptors occur during malignant transformation in various types of cancer, including gliomas.

Cannabinoids exert anti-proliferative action in tumor cells.

Induction of cell death by cannabinoid treatment relies on the generation of a pro-apoptotic sphingolipid ceramide and disruption of signaling pathways crucial for regulation of cellular proliferation, differentiation or apoptosis. Increased ceramide levels lead also to ER-stress and autophagy in drug-treated glioblastoma cells.

Beyond blocking of tumor cells proliferation cannabinoids inhibit invasiveness, angiogenesis and the stem cell-like properties of glioma cells, showing profound activity in the complex tumor microenvironment. Advances in translational research on cannabinoid signaling led to clinical investigations on the use of cannabinoids in treatments of glioblastomas.”

https://www.ncbi.nlm.nih.gov/pubmed/32034716

https://link.springer.com/chapter/10.1007%2F978-3-030-30651-9_11

“Cannabinoids exert anti-proliferative action in tumor cells.” https://www.ncbi.nlm.nih.gov/pubmed/22879071

“A glioma is a primary brain tumor that originates from the supportive cells of the brain, called glial cells.” http://neurosurgery.ucla.edu/body.cfm?id=159

“Remarkably, cannabinoids kill glioma cells selectively and can protect non-transformed glial cells from death.” http://www.ncbi.nlm.nih.gov/pubmed/15275820

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Organophosphate agent induces ADHD-like behaviors via inhibition of brain endocannabinoid-hydrolyzing enzyme(s) in adolescent male rats.

 Go to Volume 0, Issue ja“Anticholinergic organophosphate (OP) agents act on the diverse serine hydrolases, thereby revealing unexpected biological effects. Epidemiological studies indicate a relationship between OP exposure and development of attention-deficit/hyperactivity disorder (ADHD)-like symptoms, whereas no plausible mechanism for the OP-induced ADHD has been established.

The present investigation employs ethyl octylphosphonofluoridate (EOPF) as an OP-probe which is an extremely potent inhibitor of endocannabinoid (EC, anandamide and 2-arachidonoylglycerol)-hydrolyzing enzymes: i.e., fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL).

Ex vivo experiment shows that EOPF treatment decreases FAAH and MAGL activities and conversely increases EC levels in rat brain. Subsequently, EOPF (treated intraperitoneally once at 0, 1, 2, or 3 mg/kg) clearly induces ADHD-like behaviors (in elevated plus-maze test) in both Wistar and spontaneously hypertensive rats. The EOPF-induced behaviors are reduced by a concomitant administration of cannabinoid receptor inverse agonist SLV-319.

Accordingly, EC system is a feasible target for OP-caused ADHD-like behaviors in adolescent rats.”

https://www.ncbi.nlm.nih.gov/pubmed/31995978

https://pubs.acs.org/doi/abs/10.1021/acs.jafc.9b08195

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The endocannabinoid system: Novel targets for treating cancer induced bone pain.

Biomedicine & Pharmacotherapy“Treating Cancer-induced bone pain (CIBP) continues to be a major clinical challenge and underlying mechanisms of CIBP remain unclear.

Recently, emerging body of evidence suggested the endocannabinoid system (ECS) may play essential roles in CIBP. Here, we summarized the current understanding of the antinociceptive mechanisms of endocannabinoids in CIBP and discussed the beneficial effects of endocannabinoid for CIBP treatment.

Targeting non-selective cannabinoid 1 receptors or selective cannabinoid 2 receptors, and modulation of peripheral AEA and 2-AG, as well as the inhibition the function of fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) have produced analgesic effects in animal models of CIBP.

Management of ECS therefore appears to be a promising way for the treatment of CIBP in terms of efficacy and safety. Further clinical studies are encouraged to confirm the possible translation to humans of the very promising results already obtained in the preclinical studies.”

https://www.ncbi.nlm.nih.gov/pubmed/31627091

“Thus, cannabinoids may be clinically useful for treating chronic pain and CIBP.”

https://www.sciencedirect.com/science/article/pii/S075333221933731X?via%3Dihub

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Beyond THC and Endocannabinoids.

Image result for AR Annual Reviews“Research in the cannabinoid field, namely on phytocannabinoids, the endogenous cannabinoids anandamide and 2-arachidonoyl glycerol and their metabolizing and synthetic enzymes, the cannabinoid receptors, and anandamide-like cannabinoid compounds, has expanded tremendously over the last few years. Numerous endocannabinoid-like compounds have been discovered. The Cannabis plant constituent cannabidiol (CBD) was found to exert beneficial effects in many preclinical disease models ranging from epilepsy, cardiovascular disease, inflammation, and autoimmunity to neurodegenerative and kidney diseases and cancer. CBD was recently approved in the United States for the treatment of rare forms of childhood epilepsy. This has triggered the development of many CBD-based products for human use, often with overstated claims regarding their therapeutic effects. In this article, the recently published research on the chemistry and biological effects of plant cannabinoids (specifically CBD), endocannabinoids, certain long-chain fatty acid amides, and the variety of relevant receptors is critically reviewed. ”

https://www.ncbi.nlm.nih.gov/pubmed/31580774

https://www.annualreviews.org/doi/10.1146/annurev-pharmtox-010818-021441

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