THC Total Health Care

A comprehensive encyclopedia of THC related medical research articles

The endocannabinoid system: no longer anonymous in the control of nitrergic signalling?

Posted on January 29, 2017 by David Worrell

“The endocannabinoid system (ECS) is a key cellular signalling system that has been implicated in the regulation of diverse cellular functions. Importantly, growing evidence suggests that the biological actions of the ECS may, in part, be mediated through its ability to regulate the production and/or release of nitric oxide, a ubiquitous bioactive molecule, which functions as a versatile signalling intermediate. Herein, we review and discuss evidence pertaining to ECS-mediated regulation of nitric oxide production, as well as the involvement of reactive nitrogen species in regulating ECS-induced signal transduction by highlighting emerging work supporting nitrergic modulation of ECS function. Importantly, the studies outlined reveal that interactions between the ECS and nitrergic signalling systems can be both stimulatory and inhibitory in nature, depending on cellular context. Moreover, such crosstalk may act to maintain proper cell function, whereas abnormalities in either system can undermine cellular homoeostasis and contribute to various pathologies associated with their dysregulation. Consequently, future studies targeting these signalling systems may provide new insights into the potential role of the ECS -: nitric oxide signalling axis in disease development and/or lead to the identification of novel therapeutic targets for the treatment of nitrosative stress-related neurological, cardiovascular, and metabolic disorders.” https://www.ncbi.nlm.nih.gov/pubmed/28130308]]>

Molecular Pharmacology of Phytocannabinoids.

Posted on January 26, 2017 by David Worrell

“Cannabis sativa has been used for recreational, therapeutic and other uses for thousands of years. The plant contains more than 120 C₂₁ terpenophenolic constituents named phytocannabinoids. The Δ⁹-tetrahydrocannabinol type class of phytocannabinoids comprises the largest proportion of the phytocannabinoid content. Δ⁹-tetrahydrocannabinol was first discovered in 1971. This led to the discovery of the endocannabinoid system in mammals, including the cannabinoid receptors CB₁ and CB₂. Δ⁹-Tetrahydrocannabinol exerts its well-known psychotropic effects through the CB₁ receptor but this effect of Δ⁹-tetrahydrocannabinol has limited the use of cannabis medicinally, despite the therapeutic benefits of this phytocannabinoid. This has driven research into other targets outside the endocannabinoid system and has also driven research into the other non-psychotropic phytocannabinoids present in cannabis. This chapter presents an overview of the molecular pharmacology of the seven most thoroughly investigated phytocannabinoids, namely Δ⁹-tetrahydrocannabinol, Δ⁹-tetrahydrocannabivarin, cannabinol, cannabidiol, cannabidivarin, cannabigerol, and cannabichromene. The targets of these phytocannabinoids are defined both within the endocannabinoid system and beyond. The pharmacological effect of each individual phytocannabinoid is important in the overall therapeutic and recreational effect of cannabis and slight structural differences can elicit diverse and competing physiological effects. The proportion of each phytocannabinoid can be influenced by various factors such as growing conditions and extraction methods. It is therefore important to investigate the pharmacology of these seven phytocannabinoids further, and characterise the large number of other phytocannabinoids in order to better understand their contributions to the therapeutic and recreational effects claimed for the whole cannabis plant and its extracts.” https://www.ncbi.nlm.nih.gov/pubmed/28120231

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The Endocannabinoid System and Its Role in Eczematous Dermatoses.

Posted on January 20, 2017 by David Worrell

“The skin serves as the foremost barrier between the internal body and the external world, providing crucial protection against pathogens and chemical, mechanical, and ultraviolet damages. The skin is a central player in the intricate network of immune, neurologic, and endocrine systems. The endocannabinoid system (ECS) includes an extensive network of bioactive lipid mediators and their receptors, functions to modulate appetite, pain, mood, and memory, and has recently been implicated in skin homeostasis. Disruption of ECS homeostasis is implicated in the pathogenesis of several prevalent skin conditions. In this review, we highlight the role of endocannabinoids in maintaining skin health and homeostasis and discuss evidence on the role of ECS in several eczematous dermatoses including atopic dermatitis, asteatotic eczema, irritant contact dermatitis, allergic contact dermatitis, and chronic pruritus. The compilation of evidence may spark directions for future investigations on how the ECS may be a therapeutic target for dermatologic conditions.” https://www.ncbi.nlm.nih.gov/pubmed/28098721

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

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Cannabinoids – a new weapon against cancer?

Posted on January 20, 2017 by David Worrell

Image result for Postepy Hig Med Dosw (Online).

“Cannabis has been cultivated by man since Neolithic times. It was used, among others for fiber and rope production, recreational purposes and as an excellent therapeutic agent. The isolation and characterization of the structure of one of the main active ingredients of cannabis – Δ9 – tetrahydrocannabinol as well the discovery of its cannabinoid binding receptors CB1 and CB2, has been a milestone in the study of the possibilities of the uses of Cannabis sativa and related products in modern medicine. Many scientific studies indicate the potential use of cannabinoids in the fight against cancer. Experiments carried out on cell lines in vitro and on animal models in vivo have shown that phytocannabinoids, endocannabinoids, synthetic cannabinoids and their analogues can lead to inhibition of the growth of many tumor types, exerting cytostatic and cytotoxic neoplastic effect on cells thereby negatively influencing neo-angiogenesis and the ability of cells to metastasize. The main molecular mechanism leading to inhibition of proliferation of cancer cells by cannabinoids is apoptosis. Studies have shown, however, that the process of apoptosis in cells, treated with recannabinoids, is a consequence of induction of endoplasmic reticulum stress and autophagy. On the other hand, in the cellular context and dosage dependence, cannabinoids may enhance the proliferation of tumor cells by suppressing the immune system or by activating mitogenic factors. Leading from this there is a an obvious need to further explore cannabinoid associated molecular pathways making it possible to develop safe therapeutic drug agents for patients in the future.”

https://www.ncbi.nlm.nih.gov/pubmed/28100841

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Cannabinoid Receptors in the Central Nervous System: Their Signaling and Roles in Disease.

Posted on January 20, 2017 by David Worrell

“The identification and cloning of the two major cannabinoid (CB₁ and CB₂) receptors together with the discovery of their endogenous ligands in the late 80s and early 90s, resulted in a major effort aimed at understanding the mechanisms and physiological roles of the endocannabinoid system (ECS). Due to its expression and localization in the central nervous system (CNS), the CB₁ receptor together with its endogenous ligands (endocannabinoids (eCB)) and the enzymes involved in their synthesis and degradation, has been implicated in multiple pathophysiological events ranging from memory deficits to neurodegenerative disorders among others. In this review, we will provide a general overview of the ECS with emphasis on the CB₁ receptor in health and disease. We will describe our current understanding of the complex aspects of receptor signaling and trafficking, including the non-canonical signaling pathways such as those mediated by β-arrestins within the context of functional selectivity and ligand bias. Finally, we will highlight some of the disorders in which CB₁ receptors have been implicated. Significant knowledge has been achieved over the last 30 years. However, much more research is still needed to fully understand the complex roles of the ECS, particularly in vivo and to unlock its true potential as a source of therapeutic targets.” https://www.ncbi.nlm.nih.gov/pubmed/28101004

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Targeting Cutaneous Cannabinoid Signaling in Inflammation – A “High”-way to Heal?

Posted on January 19, 2017 by David Worrell

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“The endocannabinoid system (ECS) is a recently emerging complex regulator of multiple physiological processes. It comprises several endogenous ligands (e.g. N-arachidonoylethanolamine, a.k.a. anandamide [AEA], 2-arachidonoylglycerol [2-AG], palmitoylethanolamide [PEA], etc.), a number of endocannabinoid (eCB)-responsive receptors (e.g. CB₁ and CB₂, etc.), as well as enzymes and transporters involved in the synthesis and degradation of the eCBs.

Among many other tissues and organs, various members of the ECS were shown to be expressed in the skin as well. Indeed, AEA, 2-AG, CB₁ and CB₂ together with the major eCB-metabolizing enzymes (e.g. fatty acid amide hydrolase [FAAH], which cleaves AEA to ethanolamine and pro-inflammatory arachidonic acid) were found in various cutaneous cell types. Importantly, the eCB-tone and cannabinoid signaling in general appear to play a key role in regulating several fundamental aspects of cutaneous homeostasis, including proliferation and differentiation of epidermal keratinocytes, hair growth, sebaceous lipid production, melanogenesis, fibroblast activity, etc.

Moreover, appropriate eCB-signaling through CB₁ and CB₂ receptors was found to be crucially important in keeping cutaneous inflammatory processes under control.

Collectively, these findings (together with many other recently published data) implied keratinocytes to be “non-classical” immune competent cells, playing a central role in initiation and regulation of cutaneous immune processes, and the “c(ut)annabinoid” system is now proven to be one of their master regulators.

Another recently emerging, fascinating possibility to manage cutaneous inflammation through the cannabinoid signaling is the administration of phytocannabinoids (pCB). Cannabis sativa contains over 100 different pCBs, the vast majority of which have no psychotropic activity, and usually possess a “favorable” side-effect profile, which makes these substances particularly interesting drug candidates in treating several inflammation-accompanied diseases.

With respect to the skin, we have recently shown that one of the best studied pCBs, (−)-cannabidiol (CBD), may have great potential in managing acne, an inflammation-accompanied, extremely prevalent cutaneous disease.

Collectively, in light of the above results, both increase/restoration of the homeostatic cutaneous eCB-tone by FAAH-inhibitors and topical administration of non-psychotropic pCBs hold out the promise to exert remarkable anti-inflammatory actions, making them very exciting drug candidates, deserving full clinical exploration as potent, yet safe novel class of anti-inflammatory agents.”

http://www.ebiomedicine.com/article/S2352-3964(17)30003-8/fulltext]]>

Alteration of the endocannabinoid system in mouse brain during prion disease.

Posted on January 19, 2017 by David Worrell

“Prion diseases are neurodegenerative disorders characterized by deposition of the pathological prion protein (PrPsc) within the brain of affected humans and animals. Microglial cell activation is a common feature of prion diseases; alterations of various neurotransmitter systems and neurotransmission have been also reported. Owing to its ability to modulate both neuroimmune responses and neurotransmission, it was of interest to study the brain endocannabinoid system in a prion-infected mouse model. The production of the endocannabinoid, 2-arachidonoyglycerol (2-AG), was enhanced 10 weeks post-infection, without alteration of the other endocannabinoid, anandamide. The CB2 receptor expression was up-regulated in brains of prion-infected mice as early as 10 weeks and up to 32 weeks post-infection whereas the mRNAs of other cannabinoid receptors (CBRs) remain unchanged. The observed alterations of the endocannabinoid system were specific for prion infection since no significant changes were observed in the brain of prion-resistant mice, that is, mice devoid of the Prnp gene. Our study highlights important alterations of the endocannabinoid system during early stages of the disease long before the clinical signs of the disease.” https://www.ncbi.nlm.nih.gov/pubmed/21195746

“Prion diseases are a group of neurodegenerative diseases caused by prions, which are “proteinaceous infectious particles.” Prion diseases are caused by misfolded forms of the prion protein, also known as PrP. These diseases affect a lot of different mammals in addition to humans. The human forms of prion disease are most often the names Creutzfeldt-Jakob disease (CJD), fatal familial insomnia (FFI), Gertsmann-Straussler-Scheinker syndrome (GSS), kuru and variably protease-sensitive prionopathy (VPSPr). All of these diseases are caused by just slightly different versions of the same protein, so we refer to them all as prion diseases.” http://www.prionalliance.org/2013/12/02/what-are-human-prion-diseases/

“Eating meat contaminated with bovine spongiform encephalopathy and its hallmark misshapen proteins, called prions, can cause a fatal and untreatable brain disorder,” http://www.sciencemag.org/news/2016/12/mad-cow-disease-remains-threat-new-blood-tests-could-detect-it

“Prions are terrifying.”

http://www.sciencealert.com/mad-cow-disease-is-still-out-there-but-we-might-finally-have-a-blood-test-for-it

“Marijuana Kills MRSA and Inhibits Prions That Cause Neurodegenerative Disease; Still Recognized by Feds As a Dangerous Drug.” http://www.medicaldaily.com/marijuana-kills-mrsa-and-inhibits-prions-cause-neurodegenerative-disease-still-recognized-feds

“Fact: Cannabis Kills MRSA, Disrupts Prion Diseases” http://www.eastbayexpress.com/LegalizationNation/archives/2013/07/29/fact-cannabis-kills-mrsa-disrupts-prion-diseases

“Antibacterial cannabinoids from Cannabis sativa: a structure-activity study.” http://www.ncbi.nlm.nih.gov/pubmed/18681481

“Nonpsychoactive Cannabidiol Prevents Prion Accumulation and Protects Neurons against Prion Toxicity. Our results suggest that CBD may protect neurons against the multiple molecular and cellular factors involved in the different steps of the neurodegenerative process, which takes place during prion infection. When combined with its ability to target the brain and its lack of toxic side effects, CBD may represent a promising new anti-prion drug. ” http://www.jneurosci.org/content/27/36/9537.full

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Pharmacology of cannabinoids in the treatment of epilepsy.

Posted on January 15, 2017 by David Worrell

“The use of cannabis products in the treatment of epilepsy has long been of interest to researchers and clinicians alike; however, until recently very little published data were available to support its use. This article summarizes the available scientific data of pharmacology from human and animal studies on the major cannabinoids which have been of interest in the treatment of epilepsy, including ∆9-tetrahydrocannabinol (∆9-THC), cannabidiol (CBD), ∆9-tetrahydrocannabivarin (∆9-THCV), cannabidivarin (CBDV), and ∆9-tetrahydrocannabinolic acid (Δ9-THCA). It has long been known that ∆9-THC has partial agonist activity at the endocannabinoid receptors CB1 and CB2, though it also binds to other targets which may modulate neuronal excitability and neuroinflammation. The actions of Δ9-THCV and Δ9-THCA are less well understood. In contrast to ∆9-THC, CBD has low affinity for CB1 and CB2 receptors and other targets have been investigated to explain its anticonvulsant properties including TRPV1, voltage gated potassium and sodium channels, and GPR55, among others. We describe the absorption, distribution, metabolism, and excretion of each of the above mentioned compounds. Cannabinoids as a whole are very lipophilic, resulting in decreased bioavailability, which presents challenges in optimal drug delivery. Finally, we discuss the limited drug-drug interaction data available on THC and CBD. As cannabinoids and cannabis-based products are studied for efficacy as anticonvulsants, more investigation is needed regarding the specific targets of action, optimal drug delivery, and potential drug-drug interactions.” https://www.ncbi.nlm.nih.gov/pubmed/28087250]]>

Manipulation of the Endocannabinoid System in Colitis: A Comprehensive Review.

Posted on January 13, 2017 by David Worrell

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“Inflammatory bowel disease (IBD) is a lifelong disease of the gastrointestinal tract whose annual incidence and prevalence is on the rise. Current immunosuppressive therapies available for treatment of IBD offer limited benefits and lose effectiveness, exposing a significant need for the development of novel therapies. In the clinical setting, cannabis has been shown to provide patients with IBD symptomatic relief, although the underlying mechanisms of their anti-inflammatory effects remain unclear.

RESULTS:

Cannabinoid receptors 1 and 2, endogenous cannabinoids, and atypical cannabinoids are upregulated in inflammation, and their presence and stimulation attenuate murine colitis, whereas cannabinoid receptor antagonism and cannabinoid receptor deficient models reverse these anti-inflammatory effects. In addition, inhibition of endocannabinoid degradation through monoacylglycerol lipase and fatty acid amide hydrolase blockade can also attenuate colitis development, and is closely linked to cannabinoid receptor expression.

CONCLUSIONS:

Although manipulation of the endocannabinoid system in murine colitis has proven to be largely beneficial in attenuating inflammation, there is a paucity of human study data. Further research is essential to clearly elucidate the specific mechanisms driving this anti-inflammatory effect for the development of therapeutics to target inflammatory disease such as IBD.” https://www.ncbi.nlm.nih.gov/pubmed/28079617 “Plant cannabinoids THC and CBD proved beneficial in DNBS-induced colitis in a bell-shaped dose-related response, but more importantly, the effects of the phytocannabinoids were additive, as CBD increased an ineffective THC dose to the level of an effective one.” https://academic.oup.com/ibdjournal/article/23/2/192/4347176

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Up-regulation of CB2 receptors in reactive astrocytes in canine degenerative myelopathy, a disease model of amyotrophic lateral sclerosis.

Posted on January 11, 2017 by David Worrell

“Targeting the CB₂ receptor afforded neuroprotection in SOD1^G93A mutant mice, a model of amyotrophic lateral sclerosis (ALS). The neuroprotective effects of CB₂ receptors were facilitated by their up-regulation in the spinal cord in SOD1^G93A mutant mice. Herein, we have investigated whether a similar CB₂ receptor up-regulation, as well as parallel changes in other endocannabinoid elements, are evident in the spinal cord of dogs with degenerative myelopathy (DM), caused from mutations in the superoxide dismutase 1 gene (SOD1). In summary, our results demonstrated a marked up-regulation of CB₂ receptors occurring in the spinal cord in canine DM, which was concentrated in activated astrocytes. Such receptors may be used as a potential target to enhance the neuroprotective effects exerted by these glial cells.” https://www.ncbi.nlm.nih.gov/pubmed/28069688]]>