The endocannabinoid system: potential for reducing cardiometabolic risk.

“The endocannabinoid system (ECS) affects multiple metabolic pathways in the brain and other organs. The transmembrane CB receptors were cloned in the early 1990s, followed shortly thereafter by the discovery of endogenous ligands, now known as endocannabinoids.

Three general types of cannabimimetic compounds have been described: herbal CBs, which occur uniquely in the cannabis plant (Cannabis sativa); endogenous CBs (or endocannabinoids), which are produced in the brain and peripheral tissues; and synthetic CBs, which are functionally similar compounds synthesized in the laboratory.

Obesity is associated with increased risk for insulin resistance, type 2 diabetes, nonalcoholic fatty liver disease, atherogenic dyslipidemia, and cardiovascular disease. Recent studies indicate that the body protects itself from weight loss by lowering energy expenditure. Both energy consumption and energy expenditure are regulated by hormones from a number of organs that act on the brain, as well as neural signals emanating from the brain itself.

Lifestyle modification is the initial intervention for obesity, with emphasis on reducing calorie intake and increasing physical activity; pharmacotherapy may be indicated for certain cardiovascular and metabolic risk factors.

This review focuses on the link between the biology of the cannabinoid receptor type 1 (CB1 receptor) system and body-weight regulation, as well as clinical data from studies of the first CB1 receptor antagonist…”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2905146/

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The endocannabinoid system: a new approach to control cardiovascular disease.

“The endocannabinoid (EC) system consists of 2 types of G-protein-coupled cannabinoid receptors–cannabinoid type 1 (CB1) and cannabinoid type 2 (CB2)–and their natural ligands.

The EC system plays a key role in the regulation of food intake and fat accumulation, as well as glucose and lipid metabolism.

When overactivated, the EC system triggers dyslipidemia, thrombotic and inflammatory states, and insulin resistance.

Blocking CB1 receptors centrally and peripherally in adipose tissue can help normalize an overactivated EC system. CB1 blockade helps regulate food intake and adipose tissue metabolism, contributing to improved insulin sensitivity and other features of the metabolic syndrome.

Visceral adipose tissue is most closely associated with the metabolic syndrome, which is a constellation of conditions that place people at high risk for coronary artery disease.

Targeting the EC system represents a new approach to treating visceral obesity and reducing cardiovascular risk factors.”

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Plant-Derived and Endogenous Cannabinoids in Epilepsy.

“Cannabis is one of the oldest psychotropic drugs and its anticonvulsant properties have been known since the last century.

The aim of this reveiw was to analyze the efficacy of cannabis in the treatment of epilepsy in adults and children. In addition, a description of the involvement of the endocannabinoid system in epilepsy is given in order to provide a biochemical background to the effects of endogenous cannabinoids in our body.

General tolerability and adverse events associated with cannabis treatment are also investigated. Several anecdotal reports and clinical trials suggest that in the human population cannabis has anticonvulsant properties and could be effective in treating partial epilepsies and generalized tonic-clonic seizures, still known as “grand mal.”

They are based, among other factors, on the observation that in individuals who smoke marijuana to treat epilepsy, cessation of cannabis use precipitates the re-emergence of convulsive seizures, whereas resuming consumption of this psychotropic drug controls epilepsy in a reproducible manner.

In conclusion, there is some anecdotal evidence for the potential efficacy of cannabis in treating epilepsy.

Though there has been an increased effort by patients with epilepsy, their caregivers, growers, and legislators to legalize various forms of cannabis, there is still concern about its efficacy, relative potency, availability of medication-grade preparations, dosing, and potential short- and long-term side effects, including those on prenatal and childhood development.”

http://www.ncbi.nlm.nih.gov/pubmed/26892745

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

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Vaccenic acid suppresses intestinal inflammation by increasing the endocannabinoid anandamide and non-cannabinoid signaling molecules in a rat model of the metabolic syndrome.

“Vaccenic acid (VA), the predominant ruminant-derived trans fat in the food chain, ameliorates hyperlipidemia yet mechanisms remain elusive. We investigated whether VA could influence tissue endocannabinoids (EC) by altering the availability of their biosynthetic precursor, arachidonic acid (AA) in membrane phospholipids (PL).

Interestingly, VA increased jejunal concentrations of anandamide and those of the non-cannabinoid signaling molecules, oleoylethanolamide and palmitoylethanolamide, relative to CD (P<0.05). This was consistent with a lower jejunal protein abundance (but not activity) of their degrading enzyme, fatty acid amide hydrolase and mRNA expression TNFα and IL-1β (P<0.05).

The ability of VA to reduce 2-AG in the liver and VAT provides a potential mechanistic explanation to alleviate ectopic lipid accumulation. The opposing regulation of EC and other non-cannabinoid lipid signaling molecules by VA suggests an activation of benefit via the EC system in the intestine.”

http://www.ncbi.nlm.nih.gov/pubmed/26891736

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The Effect of Medicinal Cannabis on Pain and Quality of Life Outcomes in Chronic Pain: A Prospective Open-label Study.

“The objective of this prospective, open-label study was to determine the long-term effect of medicinal cannabis treatment on pain and functional outcomes in subjects with treatment-resistant chronic pain.

The treatment of chronic pain with medicinal cannabis in this open-label, prospective cohort resulted in improved pain and functional outcomes, and significant reduction in opioid use.

The results suggest long-term benefit of cannabis treatment in this group of patients…”

http://www.ncbi.nlm.nih.gov/pubmed/26889611

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

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Cannabis effects on driving longitudinal control with and without alcohol.

“Although evidence suggests cannabis impairs driving, its driving-performance effects are not fully characterized. We aimed to establish cannabis‘ effects on driving longitudinal control (with and without alcohol, drivers’ most common drug combination) relative to psychoactive ∆9 -tetrahydrocannabinol (THC) blood concentrations.

Current occasional (≥1×/last 3 months, ≤3 days per week) cannabis smokers drank placebo or low-dose alcohol, and inhaled 500 mg placebo, low (2.9%), or high (6.7%) THC vaporized cannabis over 10 min ad libitum in separate sessions (within-subject, six conditions). Participants drove (National Advanced Driving Simulator, University of Iowa) simulated drives 0.5-1.3 h post-inhalation. Blood and breath alcohol samples were collected before (0.17 and 0.42 h) and after (1.4 and 2.3 h) driving.

We evaluated the mean speed (relative to limit), standard deviation (SD) of speed, percent time spent >10% above/below the speed limit (percent speed high/percent speed low), longitudinal acceleration, and ability to maintain headway relative to a lead vehicle (headway maintenance) against blood THC and breath alcohol concentrations (BrAC).

THC was associated with a decreased mean speed, increased percent speed low and increased mean following distance during headway maintenance. BrAC was associated with increased SD speed and increased percent speed high, whereas THC was not.

Neither was associated with altered longitudinal acceleration.

A less-than-additive THC*BrAC interaction was detected in percent speed high (considering only non-zero data and excluding an outlying drive event), suggesting cannabis mitigated drivers’ tendency to drive faster with alcohol.

Cannabis was associated with slower driving and greater headway, suggesting a possible awareness of impairment and attempt to compensate.”

http://www.ncbi.nlm.nih.gov/pubmed/26889769

“Stoned Drivers Safer Than Drunk Drivers”                           http://americanlivewire.com/2015-02-15-stoned-drivers-safer-drunk-drivers/

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Natural product modulators of transient receptor potential (TRP) channels as potential anti-cancer agents.

“Treatment of cancer is a significant challenge in clinical medicine, and its research is a top priority in chemical biology and drug discovery. Consequently, there is an urgent need for identifying innovative chemotypes capable of modulating unexploited drug targets.

The transient receptor potential (TRPs) channels persist scarcely explored as targets, despite intervening in a plethora of pathophysiological events in numerous diseases, including cancer.

Both agonists and antagonists have proven capable of evoking phenotype changes leading to either cell death or reduced cell migration.

Among these, natural products entail biologically pre-validated and privileged architectures for TRP recognition.

Furthermore, several natural products have significantly contributed to our current knowledge on TRP biology. In this Tutorial Review we focus on selected natural products, e.g. capsaicinoids, cannabinoids and terpenes, by highlighting challenges and opportunities in their use as starting points for designing natural product-inspired TRP channel modulators.

Importantly, the de-orphanization of natural products as TRP channel ligands may leverage their exploration as viable strategy for developing anticancer therapies.

Finally, we foresee that TRP channels may be explored for the selective pharmacodelivery of cytotoxic payloads to diseased tissues, providing an innovative platform in chemical biology and molecular medicine.”

http://www.ncbi.nlm.nih.gov/pubmed/26890476

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

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Cannabinoid Receptor 2 Participates in Amyloid-β Processing in a Mouse Model of Alzheimer’s Disease but Plays a Minor Role in the Therapeutic Properties of a Cannabis-Based Medicine.

“The endogenous cannabinoid system represents a promising therapeutic target to modify neurodegenerative pathways linked to Alzheimer’s disease (AD).

The aim of the present study was to evaluate the specific contribution of CB2 receptor to the progression of AD-like pathology and its role in the positive effect of a cannabis-based medicine (1:1 combination of Δ9-tetrahidrocannabinol and cannabidiol) previously demonstrated to be beneficial in the AβPP/PS1 transgenic model of the disease.

A new mouse strain was generated by crossing AβPP/PS1 transgenic mice with CB2 knockout mice. Results show that lack of CB2 exacerbates cortical Aβ deposition and increases the levels of soluble Aβ40. However, CB2 receptor deficiency does not affect the viability of AβPP/PS1 mice, does not accelerate their memory impairment, does not modify tau hyperphosphorylation in dystrophic neurites associated to Aβ plaques, and does not attenuate the positive cognitive effect induced by the cannabis-based medicine in these animals.

These findings suggest a minor role for the CB2 receptor in the therapeutic effect of the cannabis-based medicine in AβPP/PS1 mice, but also constitute evidence of a link between CB2 receptor and Aβ processing.”

http://www.ncbi.nlm.nih.gov/pubmed/26890764

http://www.thctotalhealthcare.com/category/alzheimers-disease-ad/

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Development and Pharmacological Characterization of Selective Blockers of 2-Arachidonoyl Glycerol Degradation with Efficacy in Rodent Models of Multiple Sclerosis and Pain.

“We report the discovery of compound 4a, a potent β-lactam-based monoacylglycerol lipase (MGL) inhibitor characterized by an irreversible and stereoselective mechanism of action, high membrane permeability, high brain penetration evaluated using a human in vitro blood brain barrier model, high selectivity in binding and affinity-based proteomic profiling assays, and low in vitro toxicity.

Mode-of-action studies demonstrate that 4a, by blocking MGL, increases 2-arachidonoylglycerol, and behaves as cannabinoid (CB1/CB2) receptor indirect agonist.

Administration of 4a in mice suffering from experimental autoimmune encephalitis ameliorates the severity of the clinical symptoms in a CB1/CB2-dependent manner. Moreover, 4a produced analgesic effects in a rodent model of acute inflammatory pain, which was antagonized by CB1 and CB2 receptor antagonists/inverse agonists. 4a also relieves the neuropathic hypersensitivity induced by oxaliplatin.

Given these evidences, 4a, as MGL selective inhibitor, could represent a valuable lead for the future development of therapeutic options for multiple sclerosis and chronic pain.”

http://www.ncbi.nlm.nih.gov/pubmed/26888301

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Blockade of Nicotine and Cannabinoid Reinforcement and Relapse by a Cannabinoid CB1-Receptor Neutral Antagonist AM4113 and Inverse Agonist Rimonabant in Squirrel Monkeys.

“Nicotine, the main psychoactive component of tobacco, and (-)-Δ9-tetrahydrocannabinol (THC), the main psychoactive ingredient in cannabis, play major roles in tobacco and marijuana dependence as reinforcers of drug-seeking and drug-taking behavior.

Drugs that act as inverse agonists of cannabinoid CB1 receptors in the brain can attenuate the rewarding and abuse-related effects of nicotine and THC…

Recently-developed CB1-receptor neutral antagonists may provide an alternative therapeutic approach to nicotine and cannabinoid dependence.

These findings point to CB1-receptor neutral antagonists as a new class of medications for treatment of both tobacco dependence and cannabis dependence.”

http://www.ncbi.nlm.nih.gov/pubmed/26888056

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