Innovative Therapeutic Potential of Cannabinoid Receptors as Targets in Alzheimer’s disease and Less Well-Known Diseases.

“The discovery of cannabinoid receptors at the beginning of the 1990s, CB1 being cloned in 1990 and CB2 cloned in 1993, and the availability of selective and potent cannabimimetics could only be justified by the existence of endogenous ligands that are capable of binding to them. Thus, the characterisation and cloning of the first cannabinoid receptor (CB1) led to the isolation and characterisation of the first endocannabinoid, arachidonoylethanolamide (AEA), two years later and the subsequent identification of a family of lipid transmitters known as the fatty acid ester 2-arachidonoylglycerol (2-AG). The endogenous cannabinoid system is a complex signalling system that comprises transmembrane endocannabinoid receptors, their endogenous ligands (the endocannabinoids), the specific uptake mechanisms and the enzymatic systems related to their biosynthesis and degradation. The endocannabinoid system has been implicated in a wide diversity of biological processes, in both the central and peripheral nervous systems, including memory, learning, neuronal development, stress and emotions, food intake, energy regulation, peripheral metabolism, and the regulation of hormonal balance through the endocrine system. In this context, this article will review the current knowledge of the therapeutic potential of cannabinoid receptor as a target in Alzheimer’s disease and other less well-known diseases that include, among others, multiple sclerosis, bone metabolism, and Fragile X syndrome. The therapeutic applications will be addressed through the study of cannabinoid agonists acting as single drugs and multi-target drugs highlighting the CB2 receptor agonist.”

https://www.ncbi.nlm.nih.gov/pubmed/29484980

http://www.eurekaselect.com/160083/article

2-AG limits Theiler’s virus induced acute neuroinflammation by modulating microglia and promoting MDSCs.

 Glia

“The innate immune response is mediated by primary immune modulators such as cytokines and chemokines that together with immune cells and resident glia orchestrate CNS immunity and inflammation. Growing evidence supports that the endocannabinoid 2-arachidonoylglycerol (2-AG) exerts protective actions in CNS injury models. Here, we used the acute phase of Theiler’s virus induced demyelination disease (TMEV-IDD) as a model of acute neuroinflammation to investigate whether 2-AG modifies the brain innate immune responses to TMEV and CNS leukocyte trafficking. 2-AG or the inhibition of its hydrolysis diminished the reactivity and number of microglia at the TMEV injection site reducing their morphological complexity and modulating them towards an anti-inflammatory state via CB2 receptors. Indeed, 2-AG dampened the infiltration of immune cells into the CNS and inhibited their egress from the spleen, resulting in long-term beneficial effects at the chronic phase of the disease. Intriguingly, it is not a generalized action over leukocytes since 2-AG increased the presence and suppressive potency of myeloid derived suppressor cells (MDSCs) in the brain resulting in higher apoptotic CD4+ T cells at the injection site. Together, these data suggest a robust modulatory effect in the peripheral and central immunity by 2-AG and highlight the interest of modulating endogenous cannabinoids to regulate CNS inflammatory conditions.”

https://www.ncbi.nlm.nih.gov/pubmed/29484707

http://onlinelibrary.wiley.com/doi/10.1002/glia.23317/abstract

Medical marijuana laws and adolescent marijuana use in the United States: A systematic review and meta-analysis.

Image result for addiction journal

“To conduct a systematic review and meta-analysis of studies in order to estimate the effect of US medical marijuana laws (MMLs) on past-month marijuana use prevalence among adolescents.

METHODS:

A total of 2999 papers from 17 literature sources were screened systematically. Eleven studies, developed from four ongoing large national surveys, were meta-analyzed. Estimates of MML effects on any past-month marijuana use prevalence from included studies were obtained from comparisons of pre-post MML changes in MML states to changes in non-MML states over comparable time-periods. These estimates were standardized and entered into a meta-analysis model with fixed-effects for each study. Heterogeneity among the study estimates by national data survey was tested with an omnibus F-test. Estimates of effects on additional marijuana outcomes, of MML provisions (e.g. dispensaries) and among demographic subgroups were abstracted and summarized. Key methodological and modeling characteristics were also described. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed.

RESULTS:

None of the 11 studies found significant estimates of pre-post MML changes compared with contemporaneous changes in non-MML states for marijuana use prevalence among adolescents. The meta-analysis yielded a non-significant pooled estimate (standardized mean difference) of -0.003 (95% confidence interval = -0.012, +0.007). Four studies compared MML with non-MML states on pre-MML differences and all found higher rates of past-month marijuana use in MML states pre-MML passage. Additional tests of specific MML provisions, of MML effects on additional marijuana outcomes and among subgroups generally yielded non-significant results, although limited heterogeneity may warrant further study.

CONCLUSIONS:

Synthesis of the current evidence does not support the hypothesis that US medical marijuana laws (MMLs) until 2014 have led to increases in adolescent marijuana use prevalence. Limited heterogeneity exists among estimates of effects of MMLs on other patterns of marijuana use, of effects within particular population subgroups and of effects of specific MML provisions.”

https://www.ncbi.nlm.nih.gov/pubmed/29468763

Exogenous Cannabinoid Efficacy: Merely a Pharmacokinetic Interaction?

Clinical Pharmacokinetics

“Endocannabinoid pharmacology is now relatively well understood with a number of endocannabinoids and endogenous cannabinoid neurotransmitters identified and the pharmacokinetics relatively well ascertained.

Further, the cannabinoid receptors are now molecularly and pharmacologically characterised and the cell processes involved in endocannabinoid transcription, synthesis, post-translational modification and protein expression are reported.

Endogenous cannabinoids have been shown to have key roles in immune and pain pathways and neuro-behavioural signalling including appetite regulation. Significant recent interest has thus been shown in understanding these pathways to guide the development of agents that inhibit the natural catabolism of endogenous cannabinoids to modify pain and appetite, and to synthesise antagonists for the treatment of disease such as obesity.

This research is concurrent with the renewed clinical interest in exogenous cannabinoids and their use in disease. However, the complex pharmacology and physiological effects of exogenous cannabinoids, either as individual components or in combination, as extracts or via administration of the whole plant in humans, are less well known.

Yet as with all other therapeutics, including those derived from plants, knowledge of the pharmacokinetics and dynamics of the complete plant, the individual chemical molecules and their synthetic versions, including formulations and excipients is a standard part of drug development.

This article covers the key pharmacological knowledge required to guide further exploration of the toxicity and efficacy of different cannabinoids and their formulations in blinded placebo-controlled studies.”

https://www.ncbi.nlm.nih.gov/pubmed/28921125

https://link.springer.com/article/10.1007%2Fs40262-017-0599-0

The Role of Cannabinoid Receptor 1 in the Immunopathology of Respiratory Syncytial Virus.

Mary Ann Liebert, Inc. publishers

“Endocannabinoid system plays an important role in pathophysiologic processes such as immune functions and impacts on disease severity.

Our previous study showed that cannabinoid receptor 2 (CB2) affects clinical course of respiratory syncytial virus (RSV) infection. In this study, we investigated the role of cannabinoid receptor 1 (CB1) in RSV immunopathology and its therapeutic potential in mice model.

This study and our previous finding indicated that endocannabinoid signaling regulates the inflammatory response to RSV infection, and is a potential therapeutic candidate for alleviation of RSV-associated immunopathology.”

https://www.ncbi.nlm.nih.gov/pubmed/29461930

http://online.liebertpub.com/doi/10.1089/vim.2017.0098

High on Life? Medical Marijuana Laws and Suicide

Image result for cato institute

“Our research examines the relationship between medical marijuana laws (hereafter MMLs) and suicides.

Our results suggest that the passage of a MML is associated with an almost 5 percent reduction in the total suicide rate.

We conclude that the legalization of medical marijuana leads to fewer suicides among young adult males.”

https://www.cato.org/publications/research-briefs-economic-policy/high-life-medical-marijuana-laws-suicide

Study: Medical Marijuana Legalization leads to decrease in suicide rates”   https://www.dailykos.com/stories/2012/2/26/1068413/-Study-Medical-Marijuana-Legalization-leads-to-decrease-in-suicide-rates

“Legal Weed Appears to Cause a Sharp Reduction in Suicides”  https://www.eastbayexpress.com/LegalizationNation/archives/2012/02/07/legal-weed-appears-to-cause-a-sharp-reduction-in-suicides-discuss

“Marijuana Can Help Prevent Suicide, Study Suggests”  http://www.laweekly.com/news/marijuana-can-help-prevent-suicide-study-suggests-2389148

The Cannabinoids Δ8THC, CBD, and HU-308 Act via Distinct Receptors to Reduce Corneal Pain and Inflammation

Mary Ann Liebert, Inc. publishers

“Corneal injury can result in dysfunction of corneal nociceptive signaling and corneal sensitization.

Activation of the endocannabinoid system has been reported to be analgesic and anti-inflammatory.

The purpose of this research was to investigate the antinociceptive and anti-inflammatory effects of cannabinoids with reported actions at cannabinoid 1 (CB1R) and cannabinoid 2 (CB2R) receptors and/or noncannabinoid receptors in an experimental model of corneal hyperalgesia.

Topical cannabinoids reduce corneal hyperalgesia and inflammation.

The antinociceptive and anti-inflammatory effects of Δ8THC are mediated primarily via CB1R, whereas that of the cannabinoids CBD and HU-308, involve activation of 5-HT1A receptors and CB2Rs, respectively.

Cannabinoids could be a novel clinical therapy for corneal pain and inflammation resulting from ocular surface injury.”

https://www.ncbi.nlm.nih.gov/pubmed/29450258

http://online.liebertpub.com/doi/abs/10.1089/can.2017.0041

Exploration of Potentially Bioactive Peptides Generated from the Enzymatic Hydrolysis of Hempseed Proteins.

Journal of Agricultural and Food Chemistry

“The seed of industrial hemp is an underexploited protein source. In view of a possible use in functional foods, a hempseed protein concentrate was hydrolyzed with pepsin, trypsin, pancreatin, or a mixture of these enzymes. A detailed peptidomic analysis using data-dependent acquisition showed that the numbers of peptides identified ranged from 90 belonging to 33 parent proteins in the peptic hydrolysate to 9 belonging to 6 proteins in the pancreatin digest. The peptic and tryptic hydrolysates resulted to be the most efficient inhibitors of 3-hydroxymethyl-coenzyme A reductase activity when tested on the catalytic domain of the enzyme. Using the open access tools PeptideRanker and BIOPEP, a list of potentially bioactive peptides was generated: the alleged activities included the antioxidant property, the glucose uptake stimulating activity, the inhibition of dipeptidyl peptidase-IV and angiotensin-converting enzyme I.”

Effects of Hemp seed soft capsule on colonic ion transport in rats.

“To investigate the effect of Hemp seed soft capsule (HSCC) on colonic ion transport and its related mechanisms in constipation rats.

CONCLUSION:

HSSC ameliorates constipation by increasing colonic secretion, which is mediated via the coaction of cAMP-dependent and Ca2+-dependent Cl channels, NKCC, Na+-HCO3 cotransporter or Cl/HCO3 exchanger.”

https://www.ncbi.nlm.nih.gov/pubmed/29204056

https://www.wjgnet.com/1007-9327/full/v23/i42/7563.htm

Anti-neuroinflammatory effects of grossamide from hemp seed via suppression of TLR-4-mediated NF-κB signaling pathways in lipopolysaccharide-stimulated BV2 microglia cells.

Molecular and Cellular Biochemistry

“Grossamide, a representative lignanamide in hemp seed, has been reported to possess potential anti-inflammatory effects. However, the potential anti-neuroinflammatory effects and underlying mechanisms of action of grossamide are still unclear. Therefore, the present study investigated the possible effects and underlying mechanisms of grossamide against lipopolysaccharide (LPS)-induced inflammatory response in BV2 microglia cells.

This study demonstrated that grossamide significantly inhibited the secretion of pro-inflammatory mediators such as interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α), and decreased the level of LPS-mediated IL-6 and TNF-α mRNA. In addition, it significantly reduced the phosphorylation levels of NF-κB subunit p65 in a concentration-dependent manner and suppressed translocation of NF-κB p65 into the nucleus. Furthermore, grossamide markedly attenuated the LPS-induced expression of Toll-like receptor 4 (TLR4) and myeloid differentiation factor 88 (MyD88).

Taken together, these data suggest that grossamide could be a potential therapeutic candidate for inhibiting neuroinflammation in neurodegenerative diseases.”

https://www.ncbi.nlm.nih.gov/pubmed/28224333

https://link.springer.com/article/10.1007%2Fs11010-016-2923-7