Cumulative Lifetime Marijuana Use and Incident Cardiovascular Disease in Middle Age: The Coronary Artery Risk Development in Young Adults (CARDIA) Study.

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“To investigate the effects of marijuana in the development of incident cardiovascular and cerebrovascular outcomes.

Compared with no marijuana use, cumulative lifetime and recent marijuana use showed no association with incident CVD, stroke or transient ischemic attacks, coronary heart disease, or CVD mortality.

Marijuana use was not associated with CVD when stratified by age, gender, race, or family history of CVD.

Neither cumulative lifetime nor recent use of marijuana is associated with the incidence of CVD in middle age.”

https://www.ncbi.nlm.nih.gov/pubmed/28207342

http://ajph.aphapublications.org/doi/10.2105/AJPH.2017.303654

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A single dose of cannabidiol reduces blood pressure in healthy volunteers in a randomized crossover study.

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“Cannabidiol (CBD) is a nonpsychoactive phytocannabinoid used in multiple sclerosis and intractable epilepsies. Preclinical studies show CBD has numerous cardiovascular benefits, including a reduced blood pressure (BP) response to stress. The aim of this study was to investigate if CBD reduces BP in humans.

CONCLUSIONS:

This data shows that acute administration of CBD reduces resting BP and the BP increase to stress in humans, associated with increased HR. These hemodynamic changes should be considered for people taking CBD. Further research is required to establish whether CBD has a role in the treatment of cardiovascular disorders.”

https://www.ncbi.nlm.nih.gov/pubmed/28614793

“Our data show that a single dose of CBD reduces resting blood pressure and the blood pressure response to stress. This may reflect the anxiolytic and analgesic effects of CBD, as well as any potential direct cardiovascular effects. CBD has multiple desirable effects on the cardiovascular system” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5470879/

https://insight.jci.org/articles/view/93760

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Analysis of Natural Product Regulation of Cannabinoid Receptors in the treatment of Human Disease.

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“The organized tightly regulated signaling relays engaged by the cannabinoid receptors (CBs) and their ligands, G proteins and other effectors, together constitute the endocannabinoid system (ECS). This system governs many biological functions including cell proliferation, regulation of ion transport and neuronal messaging. This review will firstly examine the physiology of the ECS, briefly discussing some anomalies in the relay of the ECS signaling as these are consequently linked to maladies of global concern including neurological disorders, cardiovascular disease and cancer.

While endogenous ligands are crucial for dispatching messages through the ECS, there are also commonalities in binding affinities with copious exogenous ligands, both natural and synthetic. Therefore, this review provides a comparative analysis of both types of exogenous ligands with emphasis on natural products given their putative safer efficacy and the role of Δ9-tetrahydrocannabinol (Δ9-THC) in uncovering the ECS.

Efficacy is congruent to both types of compounds but noteworthy is the effect of a combination therapy to achieve efficacy without the unideal side-effects. An example is Sativex that displayed promise in treating Huntington’s disease (HD) in preclinical models allowing for its transition to current clinical investigation. Despite the in vitro and preclinical efficacy of Δ9-THC to treat neurodegenerative ailments, its psychotropic effects limit its clinical applicability to treating feeding disorders.

We therefore propose further investigation of other compounds and their combinations such as the triterpene, α,β-amyrin that exhibited greater binding affinity to CB1 than CB2 and was more potent than Δ9-THC and the N-alkylamides that exhibited CB2 selective affinity, the latter can be explored towards peripherally exclusive ECS modulation. The synthetic CB1 antagonist, Rimonabant was pulled from market for the treatment of diabetes, however its analogue SR144528 maybe an ideal lead molecule towards this end and HU-210 and Org27569 are also promising synthetic small molecules.”

https://www.ncbi.nlm.nih.gov/pubmed/28583800

http://www.sciencedirect.com/science/article/pii/S0163725817301511

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Activation of cannabinoid receptor type II by AM1241 protects adipose-derived mesenchymal stem cells from oxidative damage and enhances their therapeutic efficacy in myocardial infarction mice via Stat3 activation.

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“The poor survival of cells in ischemic sites diminishes the therapeutic efficacy of stem cell therapy. Previously we and others have reported that Cannabinoid receptor type II (CB2) is protective during heart ischemic injury for its anti-oxidative activity. However, whether CB2 activation could improve the survival and therapeutic efficacy of stem cells in ischemic myocardium and the underlying mechanisms remain elusive.

Here, we showed evidence that CB2 agonist AM1241 treatment could improve the functional survival of adipose-derived mesenchymal stem cells (AD-MSCs) in vitro as well as in vivo. Moreover, AD-MSCs adjuvant with AM1241 improved cardiac function, and inhibited cardiac oxidative stress, apoptosis and fibrosis. To unveil possible mechanisms, AD-MSCs were exposed to hydrogen peroxide/serum deprivation to simulate the ischemic environmentin myocardium. Results delineated that AM1241 blocked the apoptosis, oxidative damage and promoted the paracrine effects of AD-MSCs. Mechanistically, AM1241 activated signal transducers and activators of transcription 3 (Stat3) through the phosphorylation of Akt and ERK1/2. Moreover, the administration of AM630, LY294002, U0126 and AG490 (inhibitors for CB2, Akt, ERK1/2 and Stat3, respectively) could abolish the beneficial actions of AM1241.

Our result support the promise of CB2 activation as an effective strategy to optimize stem cell-based therapy possibly through Stat3 activation.”

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Marijuana compounds show promise in treatment of cardiac disease

Marijuana compounds show promise in treatment of cardiac disease

“A Nevada company is hoping to develop new medicines for heart failure using compounds in marijuana and a novel therapy identified by a University of Hawaiʻi at Mānoa researcher. Dr. Alexander Stokes, assistant research professor in the Department of Cell and Molecular Biology at the UH John A. Burns School of Medicine, obtained a U.S. patent for his novel therapy in 2015. The patent claims the cannabinoid receptor TRPV1 can be regulated therapeutically by plant-based cannabinoids.”  https://medicalxpress.com/news/2017-01-marijuana-compounds-treatment-cardiac-disease.html

“Marijuana compounds show promise in treatment of cardiac disease”  http://manoa.hawaii.edu/news/article.php?aId=8355

“Marijuana compounds show promise in treatment of cardiac disease”  http://www.hawaii.edu/news/2017/01/12/marijuana-compounds-show-promise-in-treatment-of-cardiac-disease/

 

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Activation of CB1 receptors by 2-arachidonoylglycerol attenuates vasoconstriction induced by U46619 and angiotensin II in human and rat pulmonary arteries.

Regulatory, Integrative and Comparative Physiology

“Recent evidence suggests that endocannabinoids acting via cannabinoid CB1 receptors may modulate vascular responses of various vasoconstrictors in the rodent systemic vasculature.

The aim of the study was to investigate whether endocannabinoids modulate the contractile responses evoked by a thromboxane A2 analog (U46619), angiotensin II (Ang II), serotonin (5-HT) and phenylephrine which stimulate distinct Gq/11-protein coupled receptors (TP, AT1, 5-HT2 and α1-adrenergic) in isolated endothelium-intact human (hPAs) and rat pulmonary arteries (rPAs).

The present study shows the protective interaction between the endocannabinoid system and vasoconstriction to U46619 and Ang II in the human and rat pulmonary circulation. U46619 and Ang II may stimulate rapid endothelial release of endocannabinoids (mainly 2-arachidonoylglycerol), leading to CB1 receptor-dependent and/or -independent vasorelaxation, which in the negative feedback mechanism reduces later agonists-induced vasoconstriction.” https://www.ncbi.nlm.nih.gov/pubmed/28356298

http://ajpregu.physiology.org/content/early/2017/03/27/ajpregu.00324.2016

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2-Arachidonoylglycerol ameliorates inflammatory stress-induced insulin resistance in cardiomyocytes.

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“Several studies have linked impaired glucose uptake and insulin resistance (IR) to functional impairment of the heart. Recently, endocannabinoids have been implicated in cardiovascular disease. However, the mechanisms involving endocannabinoid signaling, glucose uptake and IR in cardiomyocytes are understudied.

Here, we report the endocannabinoid 2-Arachidonoylglycerol (2-AG) via stimulation of cannabinoid type-1 (CB1) receptor and Ca2+/Calmodulin-dependent protein kinase β (CaMKKβ) activates AMPK leading to increased glucose uptake. Interestingly, we have observed that the mRNA expression of CB1 and CB2 receptors was decreased in diabetic mice, indicating reduced endocannabinoid signaling in diabetic heart. We further establish that TNFα induces IR in cardiomyocytes.

Treatment with 2-AG suppresses TNFα-induced pro-inflammatory markers, and improves IR and glucose uptake. Conversely, pharmacological inhibition or knockdown of AMPK attenuates the anti-inflammatory effect and reversal of IR elicited by 2-AG. Additionally, in human embryonic stem cell-derived cardiomyocytes challenged with TNFα or free fatty acid (FFA), we demonstrate that 2-AG improves insulin sensitivity and glucose uptake.

In conclusion, 2-AG abates inflammatory responses, increases glucose uptake and overcomes IR in an AMPK-dependent manner in cardiomyocytes.”

https://www.ncbi.nlm.nih.gov/pubmed/28320859

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A Systematic Review and Meta-Analysis of the Haemodynamic Effects of Cannabidiol

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“Cannabidiol (CBD) is the second most abundant phytocannabinoid, after Δ9-tetrahydrocannabinol (THC) and was first isolated from the cannabis extract in 1940.

Given the increasing clinical use of CBD, and the numerous effects of CBD in the cardiovascular system, the aim of the present study was to systematically review and analyse in vivo studies evaluating the effects of CBD on alterations in haemodynamics.

From the limited data available, we conclude that acute and chronic administration of CBD had no effect on BP or HR under control conditions, but reduces BP and HR in stressful conditions, and increases cerebral blood flow (CBF) in mouse models of stroke.

This meta-analysis and systematic review has highlighted the haemodynamic effects of CBD administration in vivo.

The positive effects induced by CBD include maintaining the fall in BP after global hypoxia, reducing the increase in MBP and HR post-stress, and increasing BF in ischaemia-reperfusion models.

It is possible that beneficial effects of CBD on haemodynamics occurs when the cardiovascular system is abnormally altered, suggesting that CBD may be used as a treatment for various cardiovascular disorders, such as hypertension, myocardial infarction and stroke.”

http://journal.frontiersin.org/article/10.3389/fphar.2017.00081/full

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Cannabinoid signaling in health and disease.

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“Cannabis sativa has long been used for medicinal purposes.

To improve safety and efficacy, compounds from C. sativa were purified or synthesized and named under an umbrella group as cannabinoids.

Currently, several cannabinoids may be prescribed in Canada for a variety of indications such as nausea and pain.

More recently, an increasing number of reports suggest other salutary effects associated with endogenous cannabinoid signaling including cardioprotection.

The therapeutic potential of cannabinoids is therefore extended; however, evidence is limited and mechanisms remain unclear.

In addition, the use of cannabinoids clinically has been hindered due to pronounced psychoactive side effects.

This review provides an overview on the endocannabinoid system, including known physiological roles, and conditions in which cannabinoid receptor signaling has been implicated.”

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The role of exercise training and the endocannabinoid system in atherosclerotic plaque burden and composition in Apo-E-deficient mice.

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“We investigated the effect of combining exercise training and treatment with an endocannabinoid receptor 1 inhibitor (Rimonabant) on atherosclerosis burden and composition.

Both exercise and rimonabant treatments induced plaque regression and promoted plaque stability. The combined treatment failed to show additive or synergistic benefits relative to either intervention alone.”

https://www.ncbi.nlm.nih.gov/pubmed/28254386

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