Naturally Occurring Cannabinoids and their Role in Modulation of Cardiovascular Health

 Publication Cover“In recent years, the role of the endocannabinoid system (ECS) in various cardiovascular conditions has been a subject of great interest. The ECS is composed of cannabinoid receptors, their endogenous ligands, also known as endocannabinoids, and enzymes responsible for the synthesis and degradation of endocannabinoids.

Several lines of evidence suggest that the ECS plays a complex role in cardiac and vascular systems; however, under normal physiological conditions the functions of the ECS are limited. Overactivation of components of the ECS has been associated with various cardiovascular conditions.

Intriguingly, activation of the ECS may also reflect a cardioprotective compensatory mechanism. With this knowledge, a range of naturally occurring and synthetic cannabinoid receptor agonists and antagonists, as well as inhibitors of endocannabinoid metabolic enzymes have emerged as promising approaches for the treatment or management of cardiovascular health.

This review will first focus on the known role of the ECS in regulating the cardiovascular system. Secondly, we discuss emerging data highlighting the therapeutic potential of naturally occurring non-psychoactive ECS modulators within the cardiovascular system, including phytocannabinoids, terpenes, and the endocannabinoid-like molecule palmitoylethanolamide.”

https://pubmed.ncbi.nlm.nih.gov/32677481/

“Several approaches discussed here, including administration of eCB-related molecules such as PEA, or supplementing with various phytocannabinoids can be promising candidates for the management of cardiovascular risk factors and CVD.”

https://www.tandfonline.com/doi/full/10.1080/19390211.2020.1790708

The Pro-neurogenic Effects of Cannabidiol and Its Potential Therapeutic Implications in Psychiatric Disorders

Archive of "Frontiers in Behavioral Neuroscience". “During the last decades, researchers have investigated the functional relevance of adult hippocampal neurogenesis in normal brain function as well as in the pathogenesis of diverse psychiatric conditions.

Although the underlying mechanisms of newborn neuron differentiation and circuit integration have yet to be fully elucidated, considerable evidence suggests that the endocannabinoid system plays a pivotal role throughout the processes of adult neurogenesis. Thus, synthetic, and natural cannabinoid compounds targeting the endocannabinoid system have been utilized to modulate the proliferation and survival of neural progenitor cells and immature neurons.

Cannabidiol (CBD), a constituent of the Cannabis Sativa plant, interacts with the endocannabinoid system by inhibiting fatty acid amide hydrolase (FAAH) activity (the rate-limiting enzyme for anandamide hydrolysis), allosterically modulating CB1 and CB2 receptors, and activating components of the “extended endocannabinoid system.” Congruently, CBD has shown prominent pro-neurogenic effects, and, unlike Δ9-tetrahydrocannabinol, it has the advantage of being devoid of psychotomimetic effects.

Here, we first review pre-clinical studies supporting the facilitating effects of CBD on adult hippocampal neurogenesis and available data disclosing cannabinoid mechanisms by which CBD can induce neural proliferation and differentiation. We then review the respective implications for its neuroprotective, anxiolytic, anti-depressant, and anti-reward actions.

In conclusion, accumulating evidence reveals that, in rodents, adult neurogenesis is key to understand the behavioral manifestation of symptomatology related to different mental disorders. Hence, understanding how CBD promotes adult neurogenesis in rodents could shed light upon translational therapeutic strategies aimed to ameliorate psychiatric symptomatology dependent on hippocampal function in humans.”

https://pubmed.ncbi.nlm.nih.gov/32676014/

https://www.frontiersin.org/articles/10.3389/fnbeh.2020.00109/full

Opioids/cannabinoids as a potential therapeutic approach in COVID-19 patients

Publication Cover“So far, no vaccine has been successfully developed and there is no effective treatment of COVID-19.

Since intensive inflammation leads to disease-induced morbidity and mortality, inhibition of the hyperinflammatory response is a definitive drug therapy objective.

Certainly, there is an urgent need for a substance that can potentially counter the effects of the virus and alleviate the symptoms and severity of the disease.

Could opioids/cannabinoids be an effective treatment for COVID-19?

Since opioids/cannabinoids receptors-based drugs can modulate immune cell migration and cytokine/chemokine secretion, they represent a promising pharmacological platform for developing anti-inflammatory therapeutics.

Therefore in the absence of effective treatments to decrease the damage associated with COVID-19 especially in those admitted to the ICU and suffer from exaggerated inflammatory response, opioids/cannabinoids receptor agonists might potentially open up an effective therapeutic approach in COVID-19 infection.

It is interesting to remember that physicians in the late 19th century used anodynes of opium tincture as a treatment of ‘bronchitis’ and other ailments in infants and children, as case reports and experience ‘demonstrated the efficacy’ of the concoction in controlling coughing and facilitating breathing.

Also, today some products of cannabinoids are used to modulate an inflammatory response. This permits us to rediscover the past and utilize the present, with hopes of finding the missing links in the pathophysiology of COVID-19, and raises the issue of opioids/cannabinoids utilization in the context of COVID-19.

It is suggested that clinical trials could be conducted on opioids/cannabinoids products with immunomodulatory activity. We hope that, with great efforts, scientific support, and sharing of information, the overcoming of COVID-19 will come soon.”

https://www.tandfonline.com/doi/full/10.1080/17476348.2020.1787836

The endocannabinoid system

Essays in Biochemistry “Thirty years ago, the discovery of a cannabinoid (CB) receptor that interacts with the psychoactive compound in Cannabis led to the identification of anandamide, an endogenous receptor ligand or endocannabinoid. Research on endocannabinoids has since exploded, and additional receptors along with their lipid mediators and signaling pathways continue to be revealed. Specifically, in humans, the release of endocannabinoids from membrane lipids occurs on demand and the signaling process is rapidly attenuated by the breakdown of the ligand suggesting a tight regulation of the endocannabinoid system (ECS). Additionally, the varying distribution of CB receptors between the central nervous system and other tissues allows for the ECS to participate in a wide range of cognitive and physiological processes. Select plant-derived ‘phyto’cannabinoids such as Δ-9-tetrahydrocannabinol (Δ9-THC) bind to the CB receptors and trigger the ECS, and in the case of Δ9-THC, while it has therapeutic value, can also produce detrimental effects. Current research is aimed at the identification of additional phytocannabinoids with minimal psychotropic effects with potential for therapeutic development. Although decades of research on the ECS and its components have expanded our understanding of the mechanisms and implications of endocannabinoid signaling in mammals, it continues to evolve. Here, we provide a brief overview of the ECS and its overlap with other related lipid-mediated signaling pathways.”

https://pubmed.ncbi.nlm.nih.gov/32648908/

“Therapeutic intervention in the dysregulation of the ECS will no doubt involve new phytocannabinoids and various synthetic CBs with which to control an increasing list of ECS- related pathologies.”

https://portlandpress.com/essaysbiochem/article/doi/10.1042/EBC20190086/225762/The-endocannabinoid-system

Anandamide and 2-AG are the principal endogenous ligands that define the classical endocannabinoid signaling system (ECS).

Cannabidiol attenuates methamphetamine-induced conditioned place preference via the Sigma1R/AKT/GSK-3β/CREB signaling pathway in rats

 Issue Cover“Methamphetamine (METH) is a highly addictive psychostimulant.

Cannabidiol (CBD) is an exogenous cannabinoid without psychostimulating activity, which has potential therapeutic effects on opioid addiction. However, it is unclear whether CBD has therapeutic effects on METH-induced motivational effects.

The present study examines whether CBD has a protective effect on METH-induced conditioned place preference (CPP) in rats by regulating the Sigma1R and AKT-GSK3β-CREB signaling pathway.

The present study found that METH can induce CPP in rats. When a pretreatment of CBD is applied, the CBD can weaken CPP in METH-induced rats by regulating the SigmaR1/AKT/GSK-3β/CREB signaling pathway.

The results of this study indicate that CBD has a potential therapeutic effect on METH-induced rewarding effects.”

https://pubmed.ncbi.nlm.nih.gov/32670551/

https://academic.oup.com/toxres/article-abstract/9/3/202/5831937?redirectedFrom=fulltext

Understanding the basics of cannabidiol from cannabis to apply to therapeutics in epilepsy

Page Header“The compounds present in cannabis have been in use for both recreational and medicinal purposes for many centuries. Changes in the legislation in South Africa have led to an increase in the number of people interested in using these compounds for self-medication. Many of them may approach their general practitioner as the first source of information about possible therapeutic effects. It is important that medical professionals are able to give patients the correct information. Cannabidiol (CBD) is one of the main compounds in cannabis plants, and there is evidence that it can successfully treat certain patients with epilepsy. This review looks at the most recent evidence on the use of CBD in the treatment of epilepsy and explores the mechanisms behind these beneficial effects.”

https://pubmed.ncbi.nlm.nih.gov/32657678/

http://www.samj.org.za/index.php/samj/article/view/12839

Cannabidiol induces osteoblast differentiation via angiopoietin1 and p38 MAPK

Publication cover image“In this study, we report the potential of cannabidiol, one of the major cannabis constituents, for enhancing osteoblastic differentiation in U2OS and MG-63 cells.

Cannabidiol increased the expression of Angiopoietin1 and the enzyme activity of alkaline phosphatase in U2OS and MG-63. Invasion and migration assay results indicated that the cell mobility was activated by cannabidiol in U2OS and MG-63. Western blotting analysis showed that the expression of tight junction related proteins such as Claudin1, Claudin4, Occuludin1, and ZO1 was increased by cannabidiol in U2OS and MG-63.

Alizarin Red S staining analysis showed that calcium deposition and mineralization was enhanced by cannabidiol in U2OS and MG-63. Western blotting analysis indicated that the expression of osteoblast differentiation related proteins such as distal-less homeobox 5, bone sialoprotein, osteocalcin, type I collagen, Runt-related transcription factor 2 (RUNX2), osterix (OSX), and alkaline phosphatase was time dependently upregulated by cannabidiol in U2OS and MG-63. Mechanistically, cannabidiol-regulated osteoblastic differentiation in U2OS and MG-63 by strengthen the protein-protein interaction among RUNX2, OSX, or the phosphorylated p38 mitogen-activated protein kinase (MAPK).

In conclusion, cannabidiol increased Angiopoietin1 expression and p38 MAPK activation for osteoblastic differentiation in U2OS and MG-63 suggesting that cannabidiol might provide a novel therapeutic option for the bone regeneration.”

https://pubmed.ncbi.nlm.nih.gov/32656944/

https://onlinelibrary.wiley.com/doi/abs/10.1002/tox.22996

Impact of Cannabis-Based Medicine on Alzheimer’s Disease by Focusing on the Amyloid β- Modifications: A Systematic Study

 “Deposition of amyloid-beta (Aβ) peptide in the brain is the leading source of the onset and progression of Alzheimer’s disease (AD). Recent studies have suggested that anti-amyloidogenic agents may be a suitable therapeutic strategy for AD.

Aim: The current review was proposed to address the beneficial effects of cannabis-based drugs for the treatment of AD, focusing primarily on Aβ modifications.

Result: A total of 17 studies were identified based on the inclusion criteria; however, nine studies qualified for this systematic review. The maximum and minimum cannabis dosages, mostly CBD and THC in animal studies, were 0.75 and 50 mg/kg, respectively. Cannabis (CBD and THC) was injected for 10 to 21 days. The findings of the 9 articles indicated that cannabis-based drugs might modulate Aβ modifications in several AD models.

Conclusion: Our findings establish that cannabis-based drugs inhibited the progression of AD by modulating Aβ modifications.”

https://pubmed.ncbi.nlm.nih.gov/32640965/

https://www.eurekaselect.com/183559/article

Evaluation of the Potential Use of Cannabidiol in the Treatment of Cocaine Use Disorder: A Systematic Review

 Pharmacology Biochemistry and BehaviorCannabinoids may have an important therapeutic potential for the treatment of dependence on crack cocaine.

Cannabidiol (CBD), in particular, has anxiolytic, antipsychotic and anticonvulsant properties and plays a role in regulating motivation circuitry and controlling sleep disorders. Several studies were performed evaluating CBD in experimental models for cocaine.

This systematic review aims evaluate the potential use of CBD in the treatment of cocaine use disorder.

Major findings: Fifty-one studies were analyzed, and 14 were selected. No studies conducted with humans were found; only one clinical trial was ongoing. The results were grouped into the following categories: cocaine self-administration, brain-stimulation reward, conditioned place preference, neuronal proliferation, anxiety, hepatic protection, anticonvulsant effect and locomotor sensitization response Only four studies had a low risk of bias. CBD promotes reduction on cocaine self-administration. Also, it interferes in cocaine induce brain reward stimulation and dopamine release. CBD promotes alteration in contextual memory associated with cocaine and in the neuroadaptations, hepatotoxicity and seizures induced by cocaine.

Conclusion: The evidence indicates that CBD is a promising adjunct therapy for the treatment of cocaine dependence due to its effect on: cocaine reward effects, cocaine consumption, behavioral responses, anxiety, neuronal proliferation, hepatic protection and safety. Moreover, clinical trials are strongly required to determine whether the findings in animal models occur in humans diagnosed for cocaine or crack cocaine use disorder.”

https://pubmed.ncbi.nlm.nih.gov/32645315/

“CBD is a promising adjunct therapy for the treatment of cocaine dependence. CBD promotes reduction on cocaine self-administration.”

https://www.sciencedirect.com/science/article/pii/S0091305720300307?via%3Dihub

Anticancer Effect of New Cannabinoids Derived From Tetrahydrocannabinolic Acid on PANC-1 and AsPC-1 Human Pancreas Tumor Cells

View details for Journal of Pancreatic Cancer cover image

“New tetrahydrocannabinolic acid (THCA) derivatives ALAM027 and ALAM108 were proposed for the treatment of the pancreatic cancer disease.

Methods: The in vitro effect of new cannabinoids ALAM027 and ALAM108 was tested against PANC-1 and AsPC-1 cell lines by CellTiter Glo assay. Pancreatic cancer xenograft model was used for the in vivo anticancer activity study of these compounds on PANC-1 cells.

Results: The in vitro study of new cannabinoids showed greater activity of ALAM108 than ALAM027 both for PANC-1 and AsPC-1 cells. The in vivo study of new cannabinoids on PANC-1 cells showed that their oral administration was effective in reducing tumor volume and tumor weight, and did not lead to any discomfort and weight loss of mice.

Conclusion: The cannabinoids ALAM108 and ALAM027 inhibited the tumor growing 1.6-2 times in mice with human PANC-1 cells.”

https://pubmed.ncbi.nlm.nih.gov/32642629/

“The in vitro study of new cannabinoids showed greater activity of ALAM108 than of ALAM027 both for PANC-1 and AsPC-1 pancreas tumor cells. The in vivo study of these cannabinoids on PANC-1 cells showed that their oral administration decreased the tumor size 1.6–2 times and did not lead to any discomfort, psychotic effects, and weight loss of mice. Further study of these compounds will allow to determine the mechanism of their action on cancer cells and may open the way to new therapeutic drugs based on THCA.”

https://www.liebertpub.com/doi/10.1089/pancan.2020.0003

FIG. 1.