Critical Role of Mast Cells and Peroxisome Proliferator-Activated Receptor γ in the Induction of Myeloid-Derived Suppressor Cells by Marijuana Cannabidiol In Vivo.

“Cannabidiol (CBD) is a natural nonpsychotropic cannabinoid from marijuana (Cannabis sativa) with anti-epileptic and anti-inflammatory properties.

Effect of CBD on naive immune system is not precisely understood. In this study, we observed that administering CBD into naive mice triggers robust induction of CD11b+Gr-1+ myeloid-derived suppressor cells (MDSC) in the peritoneum, which expressed functional arginase 1, and potently suppressed T cell proliferation ex vivo…

Together, the results suggest that CBD may induce activation of PPAR-γ in mast cells leading to secretion of G-CSF and consequent MDSC mobilization.

CBD being a major component of Cannabis, our study indicates that marijuana may modulate or dysregulate the immune system by mobilizing MDSC.”

http://www.ncbi.nlm.nih.gov/pubmed/25917103

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Cannabis has been shown to kill cancer cells

 

“The use of Cannabis for medicinal purposes dates back to ancient times.” http://www.cancer.gov/cancertopics/pdq/cam/cannabis/patient/page1

“Cannabis has been used for medicinal purposes for thousands of years.” http://www.cancer.gov/cancertopics/pdq/cam/cannabis/healthprofessional/page1

“The use of Cannabis for medicinal purposes dates back at least 3,000 years. It came into use in Western medicine in the 19th century and was said to relieve pain, inflammation, spasms, and convulsions.” http://www.cancer.gov/cancertopics/pdq/cam/cannabis/patient/page2

“Cannabis has been shown to kill cancer cells in the laboratory”  http://www.cancer.gov/cancertopics/pdq/cam/cannabis/patient/page1

“…cannabinoids may be able to kill cancer cells while protecting normal cells…

A laboratory study of delta-9-THC… showed that it damaged or killed the cancer cells…

A laboratory study of cannabidiol… showed that it caused cancer cell death…” http://www.cancer.gov/cancertopics/pdq/cam/cannabis/patient/page2

“Cannabinoids appear to kill tumor cells but do not effect their nontransformed counterparts and may even protect them from cell death.” http://www.cancer.gov/cancertopics/pdq/cam/cannabis/healthprofessional/page4

“Because cannabinoid receptors, unlike opioid receptors, are not located in the brainstem areas controlling respiration, lethal overdoses from Cannabis and cannabinoids do not occur.” http://www.cancer.gov/cancertopics/pdq/cam/cannabis/healthprofessional/page6

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

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Cannabinoid agonists and antagonists modulate lithium-induced conditioned gaping in rats.

“A series of experiments evaluated the potential of psychoactive cannabinoid agonists, delta-9-THC and HU-210, and non-psychoactive cannabinoids, Cannabidiol (CBD) and its dimethylheptyl homolog (CBD-dmh), to interfere with the establishment and the expression of conditioned gaping in rats.

All agents attenuated both the establishment and the expression of conditioned gaping.

Furthermore, the CB1 antagonist, SR-141716, reversed the suppressive effect of HU-210 on conditioned gaping.

Finally, SR-141716 potentiated lithium-induced conditioned gaping, suggesting that the endogenous cannabinoid system plays a role in the control of nausea.”

http://www.ncbi.nlm.nih.gov/pubmed/14527182

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

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Cannabidiol, a non-psychoactive component of cannabis and its synthetic dimethylheptyl homolog suppress nausea in an experimental model with rats.

“Rats display conditioned rejection reactions during an oral infusion of a flavor previously paired with an emetic drug; considerable evidence indicates that these rejection reactions reflect nausea.

Here we report that cannabidiol, a major non-psychoactive cannabinoid found in marijuana and its synthetic dimethylheptyl homolog interfere with nausea elicited by lithium chloride and with conditioned nausea elicited by a flavor paired with lithium chloride.

These results suggest that cannabinoids without psychoactive side-effects may have therapeutic value in the treatment of chemotherapy-induced nausea.”

http://www.ncbi.nlm.nih.gov/pubmed/11973447

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

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Cannabidiol in medicine: a review of its therapeutic potential in CNS disorders.

“Cannabidiol (CBD) is the main non-psychotropic component of the glandular hairs of Cannabis sativa.

It displays a plethora of actions including anticonvulsive, sedative, hypnotic, antipsychotic, antiinflammatory and neuroprotective properties.

However, it is well established that CBD produces its biological effects without exerting significant intrinsic activity upon cannabinoid receptors.

For this reason, CBD lacks the unwanted psychotropic effects characteristic of marijuana derivatives, so representing one of the bioactive constituents of Cannabis sativa with the highest potential for therapeutic use.

The present review reports the pharmacological profile of CBD and summarizes results from preclinical and clinical studies utilizing CBD, alone or in combination with other phytocannabinoids, for the treatment of a number of CNS disorders.”

http://www.ncbi.nlm.nih.gov/pubmed/18844286

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Cannabidiol stimulates Aml-1a-dependent glial differentiation and inhibits glioma stem-like cells proliferation by inducing autophagy in a TRPV2-dependent manner.

“Glioma stem-like cells (GSCs) correspond to a tumor cell subpopulation, involved in glioblastoma multiforme (GBM) tumor initiation and acquired chemoresistance. Currently, drug-induced differentiation is considered as a promising approach to eradicate this tumor-driving cell population.

Recently, the effect of cannabinoids (CBs) in promoting glial differentiation and inhibiting gliomagenesis has been evidenced. Herein, we demonstrated that cannabidiol (CBD) by activating Transient Receptor Potential Vanilloid-2 (TRPV2) triggers GSCs differentiation activating the autophagic process and inhibits GSCs proliferation and clonogenic capability.

Above all, CBD and carmustine (BCNU) in combination overcome the high resistance of GSCs to BCNU treatment, by inducing apoptotic cell death…

Altogether, these results support a novel mechanism by which CBD inducing TRPV2-dependent autophagic process stimulates Aml-1a-dependent GSCs differentiation, abrogating the BCNU chemoresistance in GSCs.”

http://www.ncbi.nlm.nih.gov/pubmed/25903924

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

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The endocannabinoid system and plant-derived cannabinoids in diabetes and diabetic complications.

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“Oxidative stress and inflammation play critical roles in the development of diabetes and its complications.

Recent studies provided compelling evidence that the newly discovered lipid signaling system (ie, the endocannabinoid system) may significantly influence reactive oxygen species production, inflammation, and subsequent tissue injury, in addition to its well-known metabolic effects and functions.

The modulation of the activity of this system holds tremendous therapeutic potential in a wide range of diseases, ranging from cancer, pain, neurodegenerative, and cardiovascular diseases to obesity and metabolic syndrome, diabetes, and diabetic complications.

This review focuses on the role of the endocannabinoid system in primary diabetes and its effects on various diabetic complications, such as diabetic cardiovascular dysfunction, nephropathy, retinopathy, and neuropathy, particularly highlighting the mechanisms beyond the metabolic consequences of the activation of the endocannabinoid system.

The therapeutic potential of targeting the endocannabinoid system and certain plant-derived cannabinoids, such as cannabidiol and Δ9-tetrahydrocannabivarin, which are devoid of psychotropic effects and possess potent anti-inflammatory and/or antioxidant properties, in diabetes and diabetic complications is also discussed.

Although there is much controversy in the field of EC research, experimental evidence and clinical trials have clearly shown that ECS plays a key role in the development of primary diabetes and various diabetic complications. Although inhibition of CB1 receptors has proven to be effective in clinical trials of obesity and metabolic syndrome, this approach has ultimately failed because of increasing patient anxiety. However, recent preclinical studies clearly showed that peripherally restricted CB1 antagonists may represent a viable therapeutic strategy to avoid the previously mentioned adverse effects.

Importantly, CB1 inhibition, as discussed in this review, may also directly attenuate inflammatory responses and ROS and reactive nitrogen species generation in endothelial, immune, and other cell types, as well as in target tissues of diabetic complications, far beyond its known beneficial metabolic consequences. The main effects of CB1 receptor activation on the development of diabetes and diabetic complications are summarized in Figure 1. CB2 agonists may exert beneficial effects on diabetes and diabetic complications by attenuating inflammatory response and ensuing oxidative stress (Figure 2).

Natural cannabinoids, such as CBD and THCV, also have tremendous therapeutic potential.

CBD is a potent antioxidant and anti-inflammatory agent that does not appear to exert its beneficial effects through conventional CB receptors and is already approved for human use.

THCV and its derivatives, which may combine the beneficial effects of simultaneous CB1 inhibition and CB2 stimulation, are still under intense preclinical investigation. It will be interesting to see how newly developed, peripherally restricted CB1 receptor antagonists and/or CB2 receptor agonists and certain natural cannabinoids, such as CBD and THCV, will influence the clinical outcomes of diabetic patients.

We hope that some of these new approaches will be useful in clinical practice in the near future to aid patients with diabetes.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3349875/

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

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Pure cannabidiol in the treatment of malignant migrating partial seizures in infancy: a case report.

“Malignant migrating partial seizures in infancy is a devastating pharmacoresistent epileptic encephalopathy of unknown etiology characterized by onset in the first 6 months of life, continuous migrating focal seizures with corresponding multifocal electroencephalographic discharges, developmental deterioration, and early mortality.

Recent widespread interest in the nonpsychoactive component of the cannabis plant, cannabidiol, as a potential treatment for refractory devastating epilepsies has led to individual trials initiated by families or physicians in states that have legalized medical marijuana with anecdotal success.

We describe a now 10-month-old boy with malignant migrating partial seizures in infancy who made developmental gains and demonstrated sustained seizure reduction with the addition of cannabidiol to his antiepileptic regimen.

This report supports a role for cannabidiol in the treatment of malignant migrating partial seizures in infancy.”

http://www.ncbi.nlm.nih.gov/pubmed/25882081

http://www.thctotalhealthcare.com/category/epilepsy-2/

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Cannabidiol, a non-psychoactive cannabinoid, leads to EGR2-dependent anergy in activated encephalitogenic T cells.

“Cannabidiol (CBD), the main non-psychoactive cannabinoid, has been previously shown by us to ameliorate clinical symptoms and to decrease inflammation in myelin oligodendrocyte glycoprotein (MOG)35-55-induced mouse experimental autoimmune encephalomyelitis model of multiple sclerosis as well as to decrease MOG35-55-induced T cell proliferation and IL-17 secretion. However, the mechanisms of CBD anti-inflammatory activities are unclear.

We found that CBD leads to upregulation of CD69 and lymphocyte-activation gene 3 (LAG3) regulatory molecules on CD4+CD25-accessory T cells. This subtype of CD4+CD25-CD69+LAG3+ T cells has been recognized as induced regulatory phenotype promoting anergy in activated T cells.

Indeed, we observed that CBD treatment results in upregulation of EGR2 (a key T cell anergy inducer) mRNA transcription in stimulated TMOG cells. This was accompanied by elevated levels of anergy promoting genes such as IL-10 (anti-inflammatory cytokine), STAT5 (regulatory factor), and LAG3 mRNAs, as well as of several enhancers of cell cycle arrest (such as Nfatc1, Casp4, Cdkn1a, and Icos).

Moreover, CBD exposure leads to a decrease in STAT3 and to an increase in STAT5 phosphorylation in TMOG cells, positive and negative regulators of Th17 activity, respectively. In parallel, we observed decreased levels of major histocompatibility complex class II (MHCII), CD25, and CD69 on CD19+ B cells following CBD treatment, showing diminished antigen presenting capabilities of B cells and reduction in their pro-inflammatory functions.

CONCLUSIONS:

Our data suggests that CBD exerts its immunoregulatory effects via induction of CD4+CD25-CD69+LAG3+ cells in MOG35-55-activated APC/TMOG co-cultures. This is accompanied by EGR2-dependent anergy of stimulated TMOG cells as well as a switch in their intracellular STAT3/STAT5 activation balance leading to the previously observed decrease in Th17 activity.”

http://www.ncbi.nlm.nih.gov/pubmed/25880134

Full-text: http://www.jneuroinflammation.com/content/12/1/52

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Drug repurposing and emerging adjunctive treatments for schizophrenia.

“Schizophrenia is a frequent disorder, which substantially impairs patients’ quality of life. Moreover, the burden of illness for patients, their families and for the society, in general, is substantial.

Given the current failure of a number of mechanistically new drugs, repurposed compounds may serve as alternative and/or adjunctive agents for schizophrenic patients and for treatment refractory patients in particular. Anti-inflammatory drugs, as well as N-acetylcysteine, a precursor of the major antioxidant glutathione, hormones, glutamatergic and nicotinergic compounds, ‘nutraceuticals’ (e.g., ω-3 fatty acids) and cannabidiol, an endocannabinoid modulator, represent promising agents in this field.”

http://www.ncbi.nlm.nih.gov/pubmed/25866122

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