Cannabinoids in Medicine: Cancer, Immunity, and Microbial Diseases

ijms-logo“Recently, there has been a growing interest in the medical applications of Cannabis plants. They owe their unique properties to a group of secondary metabolites known as phytocannabinoids, which are specific for this genus. Phytocannabinoids, and cannabinoids generally, can interact with cannabinoid receptors being part of the endocannabinoid system present in animals. Over the years a growing body of scientific evidence has been gathered, suggesting that these compounds have therapeutic potential.

In this article, we review the classification of cannabinoids, the molecular mechanisms of their interaction with animal cells as well as their potential application in the treatment of human diseases. Specifically, we focus on the research concerning the anticancer potential of cannabinoids in preclinical studies, their possible use in cancer treatment and palliative medicine, as well as their influence on the immune system. We also discuss their potential as therapeutic agents in infectious, autoimmune, and gastrointestinal inflammatory diseases.

We postulate that the currently ongoing and future clinical trials should be accompanied by research focused on the cellular and molecular response to cannabinoids and Cannabis extracts, which will ultimately allow us to fully understand the mechanism, potency, and safety profile of cannabinoids as single agents and as complementary drugs.”

https://pubmed.ncbi.nlm.nih.gov/33383838/

“Additionally, much evidence from pre-clinical and clinical studies has been gathered over the last decade, suggesting that multiple substances produced by Cannabis plants have a therapeutic potential, including anticancer properties.”

https://www.mdpi.com/1422-0067/22/1/263/htm

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(Endo)Cannabinoids and Gynaecological Cancers

cancers-logo“Gynaecological cancers can be primary neoplasms, originating either from the reproductive tract or the products of conception, or secondary neoplasms, representative of metastatic disease. For some of these cancers, the exact causes are unknown; however, it is recognised that the precise aetiopathogeneses for most are multifactorial and include exogenous (such as diet) and endogenous factors (such as genetic predisposition), which mutually interact in a complex manner.

One factor that has been recognised to be involved in the pathogenesis and progression of gynaecological cancers is the endocannabinoid system (ECS). The ECS consists of endocannabinoids (bioactive lipids), their receptors, and metabolic enzymes responsible for their synthesis and degradation. In this review, the impact of plant-derived (Cannabis species) cannabinoids and endocannabinoids on gynaecological cancers will be discussed within the context of the complexity of the proteins that bind, transport, and metabolise these compounds in reproductive and other tissues. In particular, the potential of endocannabinoids, their receptors, and metabolic enzymes as biomarkers of specific cancers, such as those of the endometrium, will be addressed. Additionally, the therapeutic potential of targeting selected elements of the ECS as new action points for the development of innovative drugs will be presented.”

https://pubmed.ncbi.nlm.nih.gov/33375539/

“Cancers of the female reproductive system are common and are responsible for a large number of deaths in women. The exact reasons why some of these cancers occur are unknown. It is, however, known that for most of these cancers, several factors interact for them to happen. These interactions involve factors external and internal to the woman. An understanding of some of the internal factors involved in how these cancers arise will not only help drive preventive strategies, but will speed the development of new treatment approaches.

The endocannabinoid system is a family including chemicals (known as endocannabinoids) produced in the body that are similar to those derived from the cannabis plant. This system, which is widely distributed in the body, has been shown to be involved in various functions. Its disruption has been shown to lead to various diseases, one of which is cancer. In this review, we summarise current knowledge of this system, its various constituents, and how they are involved in reproductive events and their pathologies, especially cancers. Furthermore, we discuss the role of the endocannabinoid system in these cancers and how targeting it could lead to new approaches to diagnosis and treatment of cancers of the female reproductive system.”

https://www.mdpi.com/2072-6694/13/1/37

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Phytocannabinoid Pharmacology: Medicinal Properties of Cannabis sativa Constituents Aside from the “Big Two”

 Go to Volume 0, Issue 0“Plant-based therapies date back centuries. Cannabis sativa is one such plant that was used medicinally up until the early part of the 20th century.

Although rich in diverse and interesting phytochemicals, cannabis was largely ignored by the modern scientific community due to its designation as a schedule 1 narcotic and restrictions on access for research purposes. There was renewed interest in the early 1990s when the endocannabinoid system (ECS) was discovered, a complex network of signaling pathways responsible for physiological homeostasis. Two key components of the ECS, cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2), were identified as the molecular targets of the phytocannabinoid Δ9-tetrahydrocannabinol (Δ9-THC).

Restrictions on access to cannabis have eased worldwide, leading to a resurgence in interest in the therapeutic potential of cannabis. Much of the focus has been on the two major constituents, Δ9-THC and cannabidiol (CBD). Cannabis contains over 140 phytocannabinoids, although only a handful have been tested for pharmacological activity. Many of these minor cannabinoids potently modulate receptors, ionotropic channels, and enzymes associated with the ECS and show therapeutic potential individually or synergistically with other phytocannabinoids.

The following review will focus on the pharmacological developments of the next generation of phytocannabinoid therapeutics.”

https://pubmed.ncbi.nlm.nih.gov/33356248/

https://pubs.acs.org/doi/10.1021/acs.jnatprod.0c00965

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Healing autism spectrum disorder with cannabinoids: a neuroinflammatory story

 Neuroscience & Biobehavioral Reviews“Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with a multifactorial etiology. Latest researches are raising the hypothesis of a link between the onset of the main behavioral symptoms of ASD and the chronic neuroinflammatory condition of the autistic brain; increasing evidence of this connection is shedding light on new possible players in the pathogenesis of ASD.

The endocannabinoid system (ECS) has a key role in neurodevelopment as well as in normal inflammatory responses and it is not surprising that many preclinical and clinical studies account for alterations of the endocannabinoid signaling in ASD. These findings lay the foundation for a better understanding of the neurochemical mechanisms underlying ASD and for new therapeutic attempts aimed at exploiting the renowned anti-inflammatory properties of cannabinoids to treat pathologies encompassed in the autistic spectrum.

This review discusses the current preclinical and clinical evidence supporting a key role of the ECS in the neuroinflammatory state that characterizes ASD, providing hints to identify new biomarkers in ASD and promising therapies for the future.”

https://pubmed.ncbi.nlm.nih.gov/33358985/

“Autism spectrum disorder has a multifactorial and complex etiology. Changes in the endocannabinoid system are found in autistic patients. Neuroinflammation is detected in autistic patients. The endocannabinoid system has a key role in neuroinflammation. Future therapies exploiting cannabinoid drugs.”

https://www.sciencedirect.com/science/article/abs/pii/S0149763420306850?via%3Dihub

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The Immune Endocannabinoid System of the Tumor Microenvironment

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

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

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

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Use of Cannabis for Self-Management of Chronic Pelvic Pain

 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

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

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

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

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

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

“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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