Cannabis use is associated with a substantial reduction in premature deaths in the United States.

Posted on August 29, 2017 by David Worrell

“Adverse effects of moderate Cannabis use on physical health are subtle and rarely fatal, while Cannabis use is associated with decreased rates of obesity, diabetes mellitus, mortality from traumatic brain injury, use of alcohol and prescription drugs, driving fatalities, and opioid overdose deaths.

These data suggest that Cannabis use may decrease premature deaths.

To date, no studies have attempted to estimate impacts of Cannabis use on premature death that include both adverse and beneficial effects on physical health. Marijuana use is estimated to reduce premature deaths from diabetes mellitus, cancer, and traumatic brain injury by 989 to 2,511 deaths for each 1% of the population using Cannabis. The analysis predicts an estimated 23,500 to 47,500 deaths prevented annually if medical marijuana were legal nationwide. A number of other potential causes of reduced mortality due to Cannabis use were revealed, but were excluded from the analysis because quantitative data were lacking. These estimates thus substantially underestimate the actual impact of Cannabis use on premature death.

Overall, prohibition is estimated to lead to similar numbers of premature deaths as drunk driving, homicide, or fatal opioid overdose. Cannabis use prevents thousands of premature deaths each year, and Cannabis prohibition is revealed as a major cause of premature death in the U.S.”

https://scholarworks.iu.edu/dspace/handle/2022/21632

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Receptor-heteromer mediated regulation of endocannabinoid signaling in activated microglia. Role of CB1 and CB2 receptors and relevance for Alzheimer’s disease and levodopa-induced dyskinesia.

Posted on August 29, 2017 by David Worrell

Cover image

We aimed at establishing the expression and signaling properties of cannabinoidreceptors in resting and LPS/IFN-γ-activated microglia. Unlike CB₁, CB₂ receptors and CB₁-CB₂Hets were upregulated in activated microglia. Resting cell refractory CB₂ receptors became robustly coupled to G_i in activated cells, in which CB₁-CB₂Hets mediated a positive cross-talk. Resting cells were refractory while activated cells were highly responsive to cannabinoids. Interestingly, similar results were obtained in cultures treated with ß-amyloid (Aß_1-42). Activation microglial markers were detected in the striatum of a Parkinson’s disease (PD) model and, remarkably, in primary microglia cultures from the hippocampus of mutant β-amyloid precursor protein (APP_Sw,Ind) mice, a transgenic Alzheimer’s disease (AD) model. Also of note was the similar cannabinoid receptor signaling found in primary cultures of microglia from APP_Sw,Ind and in cells from control animals activated using LPS plus IFN- γ. Expression of CB₁-CB₂Hets was increased in the striatum from rats rendered dyskinetic by chronic levodopa treatment.

In summary, our results showed sensitivity of activated microglial cells to cannabinoids, increased CB₁-CB₂Het expression in activated microglia and in microglia from the hippocampus of an AD model, and a correlation between levodopa-induced dyskinesia and striatal microglial activation in a PD model. Cannabinoid receptors and the CB₁-CB₂ heteroreceptor complex in activated microglia have potential as targets in the treatment of neurodegenerative diseases.”

https://www.ncbi.nlm.nih.gov/pubmed/28843453

http://www.sciencedirect.com/science/article/pii/S0889159117304038

Receptor-heteromer mediated regulation of endocannabinoid signaling in activated microglia. Role of CB1 and CB2 receptors and relevance for Alzheimer's disease and levodopa-induced dyskinesia.

Posted on August 29, 2017 by David Worrell

“Endocannabinoids are important regulators of neurotransmission and, acting on activated microglia, they are postulated as neuroprotective agents. Endocannabinoid action is mediated by CB₁ and CB₂ receptors, which may form heteromeric complexes (CB₁-CB₂Hets) with unknown function in microglia. We aimed at establishing the expression and signaling properties of cannabinoidreceptors in resting and LPS/IFN-γ-activated microglia. Unlike CB₁, CB₂ receptors and CB₁-CB₂Hets were upregulated in activated microglia. Resting cell refractory CB₂ receptors became robustly coupled to G_i in activated cells, in which CB₁-CB₂Hets mediated a positive cross-talk. Resting cells were refractory while activated cells were highly responsive to cannabinoids. Interestingly, similar results were obtained in cultures treated with ß-amyloid (Aß_1-42). Activation microglial markers were detected in the striatum of a Parkinson’s disease (PD) model and, remarkably, in primary microglia cultures from the hippocampus of mutant β-amyloid precursor protein (APP_Sw,Ind) mice, a transgenic Alzheimer’s disease (AD) model. Also of note was the similar cannabinoid receptor signaling found in primary cultures of microglia from APP_Sw,Ind and in cells from control animals activated using LPS plus IFN- γ. Expression of CB₁-CB₂Hets was increased in the striatum from rats rendered dyskinetic by chronic levodopa treatment. In summary, our results showed sensitivity of activated microglial cells to cannabinoids, increased CB₁-CB₂Het expression in activated microglia and in microglia from the hippocampus of an AD model, and a correlation between levodopa-induced dyskinesia and striatal microglial activation in a PD model. Cannabinoid receptors and the CB₁-CB₂ heteroreceptor complex in activated microglia have potential as targets in the treatment of neurodegenerative diseases.” https://www.ncbi.nlm.nih.gov/pubmed/28843453 http://www.sciencedirect.com/science/article/pii/S0889159117304038]]>

The potential role of cannabinoids in epilepsy treatment.

Posted on August 29, 2017 by David Worrell

“Epilepsy is one of the world’s oldest recognized and prevalent neurological diseases. It has a great negative impact on patients’ quality of life (QOL) as a consequence of treatment resistant seizures in about 30% of patients together with drugs’ side effects and comorbidities. Therefore, new drugs are needed and cannabinoids, above all cannabidiol, have recently gathered attention. This review summarizes the scientific data from human and animal studies on the major cannabinoids which have been of interest in the treatment of epilepsy, including drugs acting on the endocannabinoid system. Despite the fact that cannabis has been used for many purposes over 4 millennia, the development of drugs based on cannabinoids has been very slow. Only recently, research has focused on their potential effects and CBD is the first treatment of this group with clinical evidence of efficacy in children with Dravet syndrome; moreover, other studies are currently ongoing to confirm its effectiveness in patients with epilepsy. On the other hand, it will be of interest to understand whether drugs acting on the endocannabinoid system will be able to reach the market and prove their known preclinical efficacy also in patients with epilepsy.” https://www.ncbi.nlm.nih.gov/pubmed/28845714 http://www.tandfonline.com/doi/abs/10.1080/14737175.2017.1373019

“The role of cannabinoids and endocannabinoid system in the treatment of epilepsy. Cannabis has been used for thousands of years in the treatment of various diseases. Cannabinoids have been shown in preliminary animal model studies and in studies of patients with epilepsy to have antiepileptic activity. ” https://www.degruyter.com/view/j/joepi.ahead-of-print/joepi-2015-0034/joepi-2015-0034.xml

“Phytocannabinoids produce anticonvulsant effects through the endocannabinoid system, with few adverse effects.”

http://www.ncbi.nlm.nih.gov/pubmed/25475762

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Characterization of Structurally Novel G Protein Biased CB1 Agonists: Implications for Drug Development.

Posted on August 28, 2017 by David Worrell

“The human cannabinoid subtype 1 receptor (hCB₁R) is highly expressed in the CNS and serves as a therapeutic target for endogenous ligands as well as plant-derived and synthetic cannabinoids. Unfortunately, acute use of hCB₁R agonists produces unwanted psychotropic effects and chronic administration results in development of tolerance and dependence, limiting the potential clinical use of these ligands. Studies in β-arrestin knockout mice suggest that interaction of certain GPCRs, including μ-, δ-, κ-opioid and hCB₁Rs, with β-arrestins might be responsible for several adverse effects produced by agonists acting at these receptors. Indeed, agonists that bias opioid receptor activation toward G-protein, relative to β-arrestin signaling, produce less severe adverse effects. These observations indicate that therapeutic utility of agonists acting at hCB₁Rs might be improved by development of G-protein biased hCB₁R agonists. Our laboratory recently reported a novel class of indole quinulidinone (IQD) compounds that bind cannabinoid receptors with relatively high affinity and act with varying efficacy. The purpose of this study was to determine whether agonists in this novel cannabinoid class exhibit ligand bias at hCB₁ receptors. Our studies found that a novel IQD-derived hCB₁receptor agonist PNR-4-20 elicits robust G protein-dependent signaling, with transduction ratios similar to the non-biased hCB₁R agonist CP-55,940. In marked contrast to CP-55,940, PNR-4-20 produces little to no β-arrestin 2 recruitment. Quantitative calculation of bias factors indicates that PNR-4-20 exhibits from 5.4-fold to 29.5-fold bias for G protein, relative to β-arrestin 2 signaling (when compared to G protein activation or inhibition of forskolin-stimulated cAMP accumulation, respectively). Importantly, as expected due to reduced β-arrestin 2 recruitment, chronic exposure of cells to PNR-4-20 results in significantly less desensitization and down-regulation of hCB₁Rs compared to similar treatment with CP-55,940. PNR-4-20 (i.p.) is active in the cannabinoid tetrad in mice and chronic treatment results in development of less persistent tolerance and no significant withdrawal signs when compared to animals repeatedly exposed to the non-biased full agoinst JWH-018 or Δ⁹-THC. Finally, studies of a structurally similar analog PNR- 4-02 show that it is also a G protein biased hCB₁R agonist. It is predicted that cannabinoid agonists that bias hCB₁R activation toward G protein, relative to β-arrestin 2 signaling, will produce fewer and less severe adverse effects both acutely and chronically.” https://www.ncbi.nlm.nih.gov/pubmed/28838808 http://www.sciencedirect.com/science/article/pii/S1043661816314244]]>

Cannabinoids as Anticancer Drugs.

Posted on August 23, 2017 by David Worrell

“The endocannabinoid system encompassing cannabinoid receptors, endogenous receptor ligands (endocannabinoids), as well as enzymes conferring the synthesis and degradation of endocannabinoids has emerged as a considerable target for pharmacotherapeutical approaches of numerous diseases. Besides palliative effects of cannabinoids used in cancer treatment, phytocannabinoids, synthetic agonists, as well as substances that increase endogenous endocannabinoid levels have gained interest as potential agents for systemic cancer treatment. Accordingly, cannabinoid compounds have been reported to inhibit tumor growth and spreading in numerous rodent models. The underlying mechanisms include induction of apoptosis, autophagy, and cell cycle arrest in tumor cells as well as inhibition of tumor cell invasion and angiogenic features of endothelial cells. In addition, cannabinoids have been shown to suppress epithelial-to-mesenchymal transition, to enhance tumor immune surveillance, and to support chemotherapeutics’ effects on drug-resistant cancer cells. However, unwanted side effects include psychoactivity and possibly pathogenic effects on liver health. Other cannabinoids such as the nonpsychoactive cannabidiol exert a comparatively good safety profile while exhibiting considerable anticancer properties. So far experience with anticarcinogenic effects of cannabinoids is confined to in vitro studies and animal models. Although a bench-to-bedside conversion remains to be established, the current knowledge suggests cannabinoid compounds to serve as a group of drugs that may offer significant advantages for patients suffering from cancer diseases. The present review summarizes the role of the endocannabinoid system and cannabinoid compounds in tumor progression.” https://www.ncbi.nlm.nih.gov/pubmed/28826542 http://www.sciencedirect.com/science/article/pii/S105435891730039X?via%3Dihub]]>

Cannabis Pharmacology: The Usual Suspects and a Few Promising Leads.

Posted on August 23, 2017 by David Worrell

“The golden age of cannabis pharmacology began in the 1960s as Raphael Mechoulam and his colleagues in Israel isolated and synthesized cannabidiol, tetrahydrocannabinol, and other phytocannabinoids. Initially, THC garnered most research interest with sporadic attention to cannabidiol, which has only rekindled in the last 15 years through a demonstration of its remarkably versatile pharmacology and synergy with THC. Gradually a cognizance of the potential of other phytocannabinoids has developed. Contemporaneous assessment of cannabis pharmacology must be even far more inclusive. Medical and recreational consumers alike have long believed in unique attributes of certain cannabis chemovars despite their similarity in cannabinoid profiles. This has focused additional research on the pharmacological contributions of mono- and sesquiterpenoids to the effects of cannabis flower preparations. Investigation reveals these aromatic compounds to contribute modulatory and therapeutic roles in the cannabis entourage far beyond expectations considering their modest concentrations in the plant. Synergistic relationships of the terpenoids to cannabinoids will be highlighted and include many complementary roles to boost therapeutic efficacy in treatment of pain, psychiatric disorders, cancer, and numerous other areas. Additional parts of the cannabis plant provide a wide and distinct variety of other compounds of pharmacological interest, including the triterpenoid friedelin from the roots, canniprene from the fan leaves, cannabisin from seed coats, and cannflavin A from seed sprouts. This chapter will explore the unique attributes of these agents and demonstrate how cannabis may yet fulfil its potential as Mechoulam’s professed “pharmacological treasure trove.”” https://www.ncbi.nlm.nih.gov/pubmed/28826544 http://www.sciencedirect.com/science/article/pii/S1054358917300273?via%3Dihub]]>

Cannabinoids and Pain: Sites and Mechanisms of Action.

Posted on August 23, 2017 by David Worrell

“The endocannabinoid system, consisting of the cannabinoid₁ receptor (CB₁R) and cannabinoid₂ receptor (CB₂R), endogenous cannabinoid ligands (endocannabinoids), and metabolizing enzymes, is present throughout the pain pathways. Endocannabinoids, phytocannabinoids, and synthetic cannabinoid receptor agonists have antinociceptive effects in animal models of acute, inflammatory, and neuropathic pain. CB₁R and CB₂R located at peripheral, spinal, or supraspinal sites are important targets mediating these antinociceptive effects. The mechanisms underlying the analgesic effects of cannabinoids likely include inhibition of presynaptic neurotransmitter and neuropeptide release, modulation of postsynaptic neuronal excitability, activation of the descending inhibitory pain pathway, and reductions in neuroinflammatory signaling. Strategies to dissociate the psychoactive effects of cannabinoids from their analgesic effects have focused on peripherally restricted CB₁R agonists, CB₂R agonists, inhibitors of endocannabinoid catabolism or uptake, and modulation of other non-CB₁R/non-CB₂R targets of cannabinoids including TRPV1, GPR55, and PPARs. The large body of preclinical evidence in support of cannabinoids as potential analgesic agents is supported by clinical studies demonstrating their efficacy across a variety of pain disorders.” https://www.ncbi.nlm.nih.gov/pubmed/28826543 http://www.sciencedirect.com/science/article/pii/S1054358917300443?via%3Dihub]]>

Cannabinoids in the Cardiovascular System.

Posted on August 23, 2017 by David Worrell

“Cannabinoids are known to modulate cardiovascular functions including heart rate, vascular tone, and blood pressure in humans and animal models. Essential components of the endocannabinoid system, namely, the production, degradation, and signaling pathways of endocannabinoids have been described not only in the central and peripheral nervous system but also in myocardium, vasculature, platelets, and immune cells. The mechanisms of cardiovascular responses to endocannabinoids are often complex and may involve cannabinoid CB₁ and CB₂ receptors or non-CB_1/2 receptor targets. Preclinical and some clinical studies have suggested that targeting the endocannabinoid system can improve cardiovascular functions in a number of pathophysiological conditions, including hypertension, metabolic syndrome, sepsis, and atherosclerosis. In this chapter, we summarize the local and systemic cardiovascular effects of cannabinoids and highlight our current knowledge regarding the therapeutic potential of endocannabinoid signaling and modulation.” https://www.ncbi.nlm.nih.gov/pubmed/28826540 http://www.sciencedirect.com/science/article/pii/S1054358917300431?via%3Dihub]]>

Is the Cannabinoid CB2 Receptor a Major Regulator of the Neuroinflammatory Axis of the Neurovascular Unit in Humans?

Posted on August 23, 2017 by David Worrell

“The central nervous system (CNS) is an immune privileged site where the neurovascular unit (NVU) and the blood-brain barrier (BBB) act as a selectively permeable interface to control the passage of nutrients and inflammatory cells into the brain parenchyma. However, in response to injury, infection, or disease, CNS cells become activated, and release inflammatory mediators to recruit immune cells to the site of inflammation. Increasing evidence suggests that cannabinoids may have a neuroprotective role in CNS inflammatory conditions. For many years, it was widely accepted that cannabinoid receptor type 1 (CB₁) modulates neurological function centrally, while peripheral cannabinoid receptor type 2 (CB₂) modulates immune function. As knowledge about the physiology and pharmacology of the endocannabinoid system advances, there is increasing interest in targeting CB₂ as a potential treatment for inflammation-dependent CNS diseases (Ashton & Glass, 2007), where recent rodent and human studies have implicated intervention at the level of the NVU and BBB. These are incredibly important in brain health and disease. Therefore, this review begins by explaining the cellular and molecular components of these systems, highlighting important molecules potentially regulated by cannabinoid ligands and then takes an unbiased look at the evidence in support (or otherwise) of cannabinoid receptor expression and control of the NVU and BBB function in humans.” https://www.ncbi.nlm.nih.gov/pubmed/28826541 http://www.sciencedirect.com/science/article/pii/S1054358917300376?via%3Dihub]]>

THC Total Health Care

A comprehensive encyclopedia of THC related medical research articles

Cannabis use is associated with a substantial reduction in premature deaths in the United States.

Receptor-heteromer mediated regulation of endocannabinoid signaling in activated microglia. Role of CB1 and CB2 receptors and relevance for Alzheimer’s disease and levodopa-induced dyskinesia.

Receptor-heteromer mediated regulation of endocannabinoid signaling in activated microglia. Role of CB1 and CB2 receptors and relevance for Alzheimer's disease and levodopa-induced dyskinesia.

The potential role of cannabinoids in epilepsy treatment.

Characterization of Structurally Novel G Protein Biased CB1 Agonists: Implications for Drug Development.

Cannabinoids as Anticancer Drugs.

Cannabis Pharmacology: The Usual Suspects and a Few Promising Leads.

Cannabinoids and Pain: Sites and Mechanisms of Action.

Cannabinoids in the Cardiovascular System.

Is the Cannabinoid CB2 Receptor a Major Regulator of the Neuroinflammatory Axis of the Neurovascular Unit in Humans?