Category Archives: Endocannabinoid System

The Immune Endocannabinoid System of the Tumor Microenvironment

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ijms-logo“Leukocytes are part of the tumor microenvironment (TME) and are critical determinants of tumor progression. Because of the immunoregulatory properties of cannabinoids, the endocannabinoid system (ECS) may have an important role in shaping the TME.

Members of the ECS, an entity that consists of cannabinoid receptors, endocannabinoids and their synthesizing/degrading enzymes, have been associated with both tumor growth and rejection. Immune cells express cannabinoid receptors and produce endocannabinoids, thereby forming an “immune endocannabinoid system”. Although in vitro effects of exogenous cannabinoids on immune cells are well described, the role of the ECS in the TME, and hence in tumor development and immunotherapy, is still elusive.

This review/opinion discusses the possibility that the “immune endocannabinoid system” can fundamentally influence tumor progression. The widespread influence of cannabinoids on immune cell functions makes the members of the ECS an interesting target that could support immunotherapy.”

https://pubmed.ncbi.nlm.nih.gov/33255584/

“Anti-tumour actions of cannabinoids.” https://www.ncbi.nlm.nih.gov/pubmed/30019449

https://www.mdpi.com/1422-0067/21/23/8929

Bisphenol A Deranges the Endocannabinoid System of Primary Sertoli Cells with an Impact on Inhibin B Production

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ijms-logo“Bisphenol A (BPA) is an endocrine disruptor that negatively affects spermatogenesis, a process where Sertoli cells play a central role. Thus, in the present study we sought to ascertain whether BPA could modulate the endocannabinoid (eCB) system in exposed mouse primary Sertoli cells.

Under our experimental conditions, BPA turned out to be cytotoxic to Sertoli cells with an half-maximal inhibitory concentration (IC50) of ~6.0 µM. Exposure to a non-cytotoxic dose of BPA (i.e., 0.5 μM for 48 h) increased the expression levels of specific components of the eCB system, namely: type-1 cannabinoid (CB1) receptor and diacylglycerol lipase-α (DAGL-α), at mRNA level, type-2 cannabinoid (CB2) receptor, transient receptor potential vanilloid 1 (TRPV1) receptors, and DAGL-β, at protein level. Interestingly, BPA also increased the production of inhibin B, but not that of transferrin, and blockade of either CB2 receptor or TRPV1 receptor further enhanced the BPA effect.

Altogether, our study provides unprecedented evidence that BPA deranges the eCB system of Sertoli cells towards CB2– and TRPV1-dependent signal transduction, both receptors being engaged in modulating BPA effects on inhibin B production. These findings add CB2 and TRPV1 receptors, and hence the eCB signaling, to the other molecular targets of BPA already known in mammalian cells.”

https://pubmed.ncbi.nlm.nih.gov/33256105/

https://www.mdpi.com/1422-0067/21/23/8986

“Bisphenol A (BPA) is a chemical produced in large quantities for use primarily in the production of polycarbonate plastics and epoxy resins. Polycarbonate plastics have many applications including use in some food and drink packaging, e.g., water and infant bottles, compact discs, impact-resistant safety equipment, and medical devices. Epoxy resins are used as lacquers to coat metal products such as food cans, bottle tops, and water supply pipes. Some dental sealants and composites may also contribute to BPA exposure.” https://www.niehs.nih.gov/health/topics/agents/sya-bpa/index.cfm

Use of Cannabis for Self-Management of Chronic Pelvic Pain

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 View details for Journal of Women's Health cover image“Chronic pelvic pain (CPP) affects up to 15% of women in the United States. The endocannabinoid system is a potential pharmacological target for pelvic pain as cannabinoid receptors are highly expressed in the uterus and other nonreproductive tissues.

We hypothesize that cannabis use is common for self-management of CPP, and our primary objective was to determine the prevalence of cannabis use in this population.

Results: A total of 240 patients were approached, with 113 responses (47.1% response rate). There were 26 patients who used cannabis (23%). The majority used at least once per week (n = 18, 72%). Most users (n = 24, 96%) reported improvement in symptoms, including pain, cramping, muscle spasms, anxiety, depression, sleep disturbances, libido, and irritability. Over one-third (35%) stated that cannabis use decreased the number of phone calls or messages sent to their provider, and 39% reported decreased number of clinical visits. Side effects, including dry mouth, sleepiness, and feeling “high,” were reported by 84% (n = 21).

Conclusions: Almost one-quarter of patients with CPP report regular use of cannabis as an adjunct to their prescribed therapy. Although side effects are common, most users report improvement in symptoms. Our study highlights the potential of cannabis as a therapeutic option for patients with CPP.”

https://pubmed.ncbi.nlm.nih.gov/33252316/

https://www.liebertpub.com/doi/10.1089/jwh.2020.8737

Cannabis and its Constituents for Cancer: History, Biogenesis, Chemistry and Pharmacological Activities

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Pharmacological Research “Cannabis has long been used for healing and recreation in several regions of the world. Over 400 bioactive constituents, including more than 100 phytocannabinoids, have been isolated from this plant. The non-psychoactive cannabidiol (CBD) and the psychoactive Δ9-tetrahydrocannabinol (Δ9-THC) are the major and widely studied constituents from this plant.

Cannabinoids exert their effects through the endocannabinoid system (ECS) that comprises cannabinoid receptors (CB1, CB2), endogenous ligands, and metabolizing enzymes. Several preclinical studies have demonstrated the potential of cannabinoids against leukemia, lymphoma, glioblastoma, and cancers of the breast, colorectum, pancreas, cervix and prostate.

Cannabis and its constituents can modulate multiple cancer related pathways such as PKB, AMPK, CAMKK-β, mTOR, PDHK, HIF-1α, and PPAR-γ. Cannabinoids can block cell growth, progression of cell cycle and induce apoptosis selectively in tumour cells. Cannabinoids can also enhance the efficacy of cancer therapeutics. These compounds have been used for the management of anorexia, queasiness, and pain in cancer patients.

Cannabinoid based products such as dronabinol, nabilone, nabiximols, and epidyolex are now approved for medical use in cancer patients. Cannabinoids are reported to produce a favourable safety profile. However, psychoactive properties and poor bioavailability limit the use of some cannabinoids. The Academic Institutions across the globe are offering training courses on cannabis. How cannabis and its constituents exert anticancer activities is discussed in this article. We also discuss areas that require attention and more extensive research.”

https://pubmed.ncbi.nlm.nih.gov/33246167/

https://www.sciencedirect.com/science/article/abs/pii/S1043661820316108?via%3Dihub

Use of Cannabinoids to Treat Acute Respiratory Distress Syndrome and Cytokine Storm Associated with Coronavirus Disease-2019

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Frontiers in Pharmacology (@FrontPharmacol) | Twitter“Coronavirus disease 2019 (COVID-19) is a highly infectious respiratory disease caused by the severe acute respiratory syndrome coronavirus 2. A significant proportion of COVID-19 patients develop Acute Respiratory Distress Syndrome (ARDS) resulting from hyperactivation of the immune system and cytokine storm, which leads to respiratory and multi-organ failure, and death. Currently, there are no effective treatments against hyperimmune syndrome and ARDS.

We propose that because immune cells express cannabinoid receptors and their agonists are known to exhibit potent anti-inflammatory activity, targeting cannabinoid receptors, and endocannabinoids deserve intense investigation as a novel approach to treat systemic inflammation, cytokine storm, and ARDS in patients with COVID-19.”

https://pubmed.ncbi.nlm.nih.gov/33240092/

“The fact that cells of the immune system produce endocannabinoids and express both CB1 and CB2 cannabinoid receptors provides unique opportunities into investigating how the cannabinoid system can be engineered to suppress inflammation using both exogenous and endogenous cannabinoids. Because cannabinoids are potent suppressors of inflammation as evidenced by their ability to suppress cytokine storm in animal models, they may serve as novel therapeutic agents to treat cytokine storm and ARDS that are seen in patients with or without COVID-19. There is a dire need for novel anti-inflammatory agents that exert broad spectrum cytokine suppression associated with ARDS considering that currently up to 40% of such patients, including those with COVID-19, die because currently there are no FDA-approved drugs that are highly effective against cytokine storm and ARDS.”

https://www.frontiersin.org/articles/10.3389/fphar.2020.589438/full

CB2 receptor-selective agonists as candidates for targeting infection, inflammation, and immunity in SARS-CoV-2 infections

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“The COVID-19 pandemic caused by SARS-CoV-2 is a deadly disease afflicting millions. The pandemic continues affecting population due to nonavailability of drugs and vaccines. The pathogenesis and complications of infection mainly involve hyperimmune-inflammatory responses. Thus, therapeutic strategies rely on repurposing of drugs aimed at reducing infectivity and inflammation and modulate immunity favourably.

Among, numerous therapeutic targets, the endocannabinoid system, particularly activation of cannabinoid type-2 receptors (CB2R) emerged as an important one to suppress the hyperimmune-inflammatory responses. Recently, potent antiinflammatory, antiviral and immunomodulatory properties of CB2R selective ligands of endogenous, plant, and synthetic origin were showed mediating CB2R selective functional agonism.

CB2R activation appears to regulate numerous signaling pathways to control immune-inflammatory mediators including cytokines, chemokines, adhesion molecules, prostanoids, and eicosanoids. Many CB2R ligands also exhibit off-target effects mediating activation of PPARs, opioids, and TRPV, suggestive of adjuvant use with existing drugs that may maximize efficacy synergistically and minimize therapeutic doses to limit adverse/ side effects.

We hypothesize that CB2R agonists, due to immunomodulatory, antiinflammatory, and antiviral properties may show activity against COVID-19. Based on the organoprotective potential, relative safety, lack of psychotropic effects, and druggable properties, CB2R selective ligands might make available promising candidates for further investigation.”

https://pubmed.ncbi.nlm.nih.gov/33190277/

https://onlinelibrary.wiley.com/doi/10.1002/ddr.21752

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The Therapeutic Potential of Cannabinoids for Integumentary Wound Management

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“The increasing legalization of Cannabis for recreational and medicinal purposes in the United States has spurred renewed interest in the therapeutic potential of cannabinoids (CBs) for human disease.

The skin has its own endocannabinoid system (eCS) which is a key regulator of various homeostatic processes, including those necessary for normal physiologic wound healing.

Data on the use of CBs for wound healing is scarce. Compelling pre-clinical evidence supporting the therapeutic potential of CBs to improve wound healing by modulating key molecular pathways is herein reviewed.

These findings merit further exploration in basic science, translational and clinical studies.”

https://pubmed.ncbi.nlm.nih.gov/33205468/

https://onlinelibrary.wiley.com/doi/10.1111/exd.14241

Cannabis: are there any benefits?

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“Cannabis has been used as a medicine for millennia. Prohibition in the mid-20th century precluded early scientific investigation.

‘Cannabis’ describes three separate forms – herbal cannabis, ‘hemp’ products, pharmaceutical-grade regulated cannabinoid-based medical products (CBMP).

The endocannabinoid system (ECS), delineated in the late 1990s, has increased the understanding and interest in research for appropriate clinical indications. The ubiquitous ECS has homeostatic and anti-inflammatory effects and comprises cannabinoid receptors, endocannabinoids and degrading enzymes.

Phytocannabinoids are partial agonists of the ECS. In pre-clinical studies, THC and CBD produce beneficial effects in chronic pain, anxiety, sleep and inflammation. Systematic reviews often conflate herbal cannabis and CBMP, confusing the evidence. Currently large randomised controlled trials are unlikely to be achieved. Other methodologies with quality end-points are required. Rich, valuable high-quality real-world evidence for the safe and effective use of CBMP provides an opportunity to examine benefits and potential harms.

Evidence demonstrates benefit of CBMP in multiple sclerosis, chronic neuropathic pain, chemotherapy induced nausea and vomiting, resistant paediatric epilepsy, anxiety and insomnia. CBMP are well tolerated with few serious adverse events. Additional clinical benefits are promising in many other resistant chronic conditions. Pharmaceutical grade prescribed CBMP has proven clinical benefits and provides another clinical option in the physician’s pharmacopeia.”

https://pubmed.ncbi.nlm.nih.gov/33215831/

“Medical use of cannabis has been practiced for millennia and pre‐dates recorded human history.”

https://onlinelibrary.wiley.com/doi/10.1111/imj.15052

Therapeutic Applications of Cannabinoids in Cardiomyopathy and Heart Failure

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 logo“A large number of cannabinoids have been discovered that could play a role in mitigating cardiac affections. However, none of them has been as widely studied as cannabidiol (CBD), most likely because, individually, the others offer only partial effects or can activate potential harmful pathways.

In this regard, CBD has proven to be of great value as a cardioprotective agent since it is a potent antioxidant and anti-inflammatory molecule. Thus, we conducted a review to condensate the currently available knowledge on CBD as a therapy for different experimental models of cardiomyopathies and heart failure to detect the molecular pathways involved in cardiac protection.

CBD therapy can greatly limit the production of oxygen/nitrogen reactive species, thereby limiting cellular damage, protecting mitochondria, avoiding caspase activation, and regulating ionic homeostasis. Hence, it can affect myocardial contraction by restricting the activation of inflammatory pathways and cytokine secretion, lowering tissular infiltration by immune cells, and reducing the area of infarct and fibrosis formation. These effects are mediated by the activation or inhibition of different receptors and target molecules of the endocannabinoid system.

In the final part of this review, we explore the current state of CBD in clinical trials as a treatment for cardiovascular diseases and provide evidence of its potential benefits in humans.”

https://pubmed.ncbi.nlm.nih.gov/33194003/

https://www.hindawi.com/journals/omcl/2020/4587024/

The endocannabinoidome as a substrate for noneuphoric phytocannabinoid action and gut microbiome dysfunction in neuropsychiatric disorders

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“The endocannabinoid (eCB) system encompasses the eCBs anandamide and 2-arachidonoylglycerol, their anabolic/catabolic enzymes, and the cannabinoid CB1 and CB2 receptors. Its expansion to include several eCB-like lipid mediators, their metabolic enzymes, and their molecular targets, forms the endocannabinoidome (eCBome).

This complex signaling system is deeply involved in the onset, progress, and symptoms of major neuropsychiatric disorders and provides a substrate for future therapeutic drugs against these diseases. Such drugs may include not only THC, the major psychotropic component of cannabis, but also other, noneuphoric plant cannabinoids.

These compounds, unlike THC, possess a wide therapeutic window, possibly due to their capability of hitting several eCBome and non-eCBome receptors. This is particularly true for cannabidiol, which is one of the most studied cannabinoids and shows promise for the treatment of a wide range of mental and mood disorders. The eCBome plays a role also in the microbiota-gut-brain axis, which is emerging as an important actor in the control of affective and cognitive functions and in their pathological alterations.”

https://pubmed.ncbi.nlm.nih.gov/33162769/

https://www.dialogues-cns.org/dialoguesclinneurosci-22-259/