Category Archives: Endocannabinoid System

The Endocannabinoid System as a Target in Cancer Diseases: Are We There Yet?

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“The endocannabinoid system (ECS) has been placed in the anti-cancer spotlight in the last decade. The immense data load published on its dual role in both tumorigenesis and inhibition of tumor growth and metastatic spread has transformed the cannabinoid receptors CB1 (CB1R) and CB2 (CB2R), and other members of the endocannabinoid-like system, into attractive new targets for the treatment of various cancer subtypes.

Although the clinical use of cannabinoids has been extensively documented in the palliative setting, clinical trials on their application as anti-cancer drugs are still ongoing. As drug repurposing is significantly faster and more economical than de novo introduction of a new drug into the clinic, there is hope that the existing pharmacokinetic and safety data on the ECS ligands will contribute to their successful translation into oncological healthcare.

CB1R and CB2R are members of a large family of membrane proteins called G protein-coupled receptors (GPCR). GPCRs can form homodimers, heterodimers and higher order oligomers with other GPCRs or non-GPCRs. Currently, several CB1R and CB2R-containing heteromers have been reported and, in cancer cells, CB2R form heteromers with the G protein-coupled chemokine receptor CXCR4, the G protein-coupled receptor 55 (GPR55) and the tyrosine kinase receptor (TKR) human V-Erb-B2 Avian Erythroblastic Leukemia Viral Oncogene Homolog 2 (HER2).

These protein complexes possess unique pharmacological and signaling properties, and their modulation might affect the antitumoral activity of the ECS. This review will explore the potential of the endocannabinoid network in the anti-cancer setting as well as the clinical and ethical pitfalls behind it, and will develop on the value of cannabinoid receptor heteromers as potential new targets for anti-cancer therapies and as prognostic biomarkers.”

https://www.ncbi.nlm.nih.gov/pubmed/31024307

https://www.frontiersin.org/articles/10.3389/fphar.2019.00339/full

The Endocannabinoid/Endovanilloid System in Bone: From Osteoporosis to Osteosarcoma.

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“Bone is a dynamic tissue, whose homeostasis is maintained by a fine balance between osteoclast (OC) and osteoblast (OB) activity. The endocannabinoid/endovanilloid (EC/EV) system’s receptors are the cannabinoid receptor type 1 (CB1), the cannabinoid receptor type 2 (CB2), and the transient receptor potential cation channel subfamily V member 1 (TRPV1). Their stimulation modulates bone formation and bone resorption. Bone diseases are very common worldwide. Osteoporosis is the principal cause of bone loss and it can be caused by several factors such as postmenopausal estrogen decrease, glucocorticoid (GC) treatments, iron overload, and chemotherapies. Studies have demonstrated that CB1 and TRPV1 stimulation exerts osteoclastogenic effects, whereas CB2 stimulation has an anti-osteoclastogenic role. Moreover, the EC/EV system has been demonstrated to have a role in cancer, favoring apoptosis and inhibiting cell proliferation. In particular, in bone cancer, the modulation of the EC/EV system not only reduces cell growth and enhances apoptosis but it also reduces cell invasion and bone pain in mouse models. Therefore, EC/EV receptors may be a useful pharmacological target in the prevention and treatment of bone diseases. More studies to better investigate the biochemical mechanisms underlining the EC/EV system effects in bone are needed, but the synthesis of hybrid molecules, targeting these receptors and capable of oppositely regulating bone homeostasis, seems to be a promising and encouraging prospective in bone disease management.”

https://www.ncbi.nlm.nih.gov/pubmed/31003519

https://www.mdpi.com/1422-0067/20/8/1919

The New Runner’s High? Examining Relationships Between Cannabis Use and Exercise Behavior in States with Legalized Cannabis

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“Results indicated that the majority (81.7%) of participants endorsed using cannabis concurrently with exercise. In addition, the majority of participants who endorsed using cannabis shortly before/after exercise reported that doing so enhances their enjoyment of and recovery from exercise, and approximately half reported that it increases their motivation to exercise.” https://www.frontiersin.org/articles/10.3389/fpubh.2019.00099/abstract
“Cannabis doesn’t make you a lazy pothead, in fact, it might actually motivate you to workout: study. A new study published in the medical journal Frontiers in Public Health has found that consuming cannabis may help motivate users to exercise and improve their workouts.” https://leaderpost.com/cannabis-health/cannabis-doesnt-make-you-a-lazy-pothead-in-fact-it-might-actually-motivate-you-to-workout-study/wcm/bb0beff4-eea0-417a-8812-c5ba10841b34
“Study finds marijuana motivates people to exercise, smashing lazy stoner stereotype. Most people who use marijuana report that consuming before or after exercising improves the experience and aids in recovery, according to a new study. And those who do use cannabis to elevate their workout tend to get a healthier amount of exercise.” https://www.bostonglobe.com/news/marijuana/2019/04/16/study-finds-marijuana-motivates-people-exercise-smashing-lazy-stoner-stereotype/FHHsXxyTrTHrSisso0GC3H/story.html
“A published scientific study claims using weed before workout either “increases motivation” to exercise or “enhances recovery from exercise.”

“Exercise activates the endocannabinoid system.”   https://www.ncbi.nlm.nih.gov/pubmed/14625449

Potential for endocannabinoid system modulation in ocular pain and inflammation: filling the gaps in current pharmacological options

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Neuronal Signaling

“Challenges in the management of ocular pain are an underappreciated topic. Currently available therapeutics lack both efficacy and clear guidelines for their use, with many also possessing unacceptable side effects. Promising novel agents would offer analgesic, anti-inflammatory, and possibly neuroprotective actions; have favorable ocular safety profiles; and show potential in managing neuropathic pain.

Growing evidence supports a link between the endocannabinoid system (ECS) and a range of physiological and disease processes, notably those involving inflammation and pain. Both preclinical and clinical data suggest analgesic and anti-inflammatory actions of cannabinoids and ECS-modifying drugs in chronic pain conditions, including those of neuropathic origin.

The ECS is present ubiquitously through the body, including a range of ocular tissues, and represents a promising target in the treatment of several physiological and pathophysiologic processes in the eye including, but not limited to, pain, inflammation, and neuronal damage. ”

http://www.neuronalsignaling.org/content/2/4/NS20170144

The Potential of Cannabinoid-Based Treatments in Tourette Syndrome.

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“Novel pharmacological treatments are needed for Tourette syndrome.

Our goal was to examine the current evidence base and biological rationale for the use of cannabis-derived medications or medications that act on the cannabinoid system in Tourette syndrome.

There is a strong biological rationale regarding how cannabis-derived medications could affect tic severity. Anecdotal case reports and series have noted that many patients report that their tics improve after using cannabis. However, only two small randomized, placebo-controlled trials of Δ9-tetrahydrocannabinol have been published; these suggested possible benefits of cannabis-derived agents for the treatment of tics.

Trials examining other agents active on the cannabinoid system for tic disorders are currently ongoing.

Cannabinoid-based treatments are a promising avenue of new research for medications that may help the Tourette syndrome population.”

 https://www.ncbi.nlm.nih.gov/pubmed/30977108
https://link.springer.com/article/10.1007%2Fs40263-019-00627-1

AM-1241 CB2 Receptor Agonist Attenuates Inflammation, Apoptosis and Stimulate Progenitor Cells in Bile Duct Ligated Rats.

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 “The cannabinoid receptor 2 (CB2) plays a pleiotropic role in the innate immunity and is considered a crucial mediator of liver disease.

Cannabinoid CB2 receptor activation has been reported to attenuate liver fibrosis in CCl4 exposed mice and also plays a potential role in liver regeneration in a mouse model of I/R and protection against alcohol-induced liver injury.

AIM:

In this study, we investigated the impact of CB2 receptors on the antifibrotic and regenerative process associated with cholestatic liver injury.

RESULTS:

Following bile duct ligation (BDL) for 3 weeks, there was increased aminotransferase levels, marked inflammatory infiltration and hepatocyte apoptosis with induced oxidative stress, as reflected by increased lipid peroxidation. Conversely, following treatment with the CB2 agonist, AM-1241, BDL rats displayed a reduction in liver injury and attenuation of fibrosis as reflected by expression of hydroxyproline and α-smooth muscle actin. AM1241 treatment also significantly attenuated lipid peroxidation end-products, p53-dependent apoptosis and also attenuated inflammatory process by stimulating IL-10 production. Moreover, AM1241 treated rats were associated with significant expression of hepatic progenitor/oval cell markers.

CONCLUSION:

In conclusion, this study points out that CB2 receptors reduce liver injury and promote liver regeneration via distinct mechanisms including IL-10 dependent inhibition of inflammation, reduction of p53-reliant apoptosis and through stimulation of oval/progenitor cells. These results suggest that CB2 agonists display potent hepatoregenrative properties, in addition to their antifibrogenic effects.”

https://www.ncbi.nlm.nih.gov/pubmed/30976335

https://www.id-press.eu/mjms/article/view/oamjms.2019.194

Ketamine-induced antidepressant like effects in mice: A possible involvement of cannabinoid system.

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Biomedicine & Pharmacotherapy

“The purpose of this study was to explore the possible interaction between ketamine and cannabinoid system in the modulation of depression-related responses.

It seems that possible interaction between ketamine and cannabinoid system may modulate depression-related behavior.”

https://www.ncbi.nlm.nih.gov/pubmed/30970516

https://www.sciencedirect.com/science/article/pii/S0753332218375309?via%3Dihub

“Antidepressant-like effect of Δ9-tetrahydrocannabinol and other cannabinoids isolated from Cannabis sativa L” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2866040/
http://www.thctotalhealthcare.com/category/depression-2/

Circulating endocannabinoid concentrations and sexual arousal in women.

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The Journal of Sexual Medicine - Click here to go back to the homepage

“Several lines of evidence point to the potential role of the endocannabinoid system in female sexual functioning. These include results from studies describing the subjective effects of exogenous cannabinoids on sexual functioning in humans and the observable effects of exogenous cannabinoids on sexual functioning in other species, as well as results from studies investigating the location of cannabinoid receptors in the brain and periphery, and the effects of cannabinoid receptor activation on neurotransmitters implicated in sexual functioning. While these lines of research suggest a role for the endocannabinoid system in female sexual functioning, no studies investigating the relationship between concentrations of endogenous cannabinoids (i.e., arachidonoylethanolamide [AEA] and 2-arachidonoylglycerol [2-AG]) and sexual functioning have been conducted in any species.

AIM:

To measure circulating endocannabinoid concentrations in relation to subjective and physiological indices of sexual arousal in women (N = 21).

METHODS:

Serum endocannabinoid (AEA and 2-AG) concentrations were measured immediately prior to, and immediately following, viewing of neutral (control) and erotic (experimental) film stimuli in a repeated measures design. Physiological sexual arousal was measured via vaginal photoplethysmography. Subjective sexual arousal was measured both continuously and noncontinuously. Pearson’s correlations were used to investigate the relationships between endocannabinoid concentrations and sexual arousal.

MAIN OUTCOME MEASURES:

Changes in AEA and 2-AG concentrations from pre- to post-film and in relation to physiological and subjective indices of sexual arousal.

RESULTS:

Results revealed a significant relationship between endocannabinoid concentrations and female sexual arousal, whereby increases in both physiological and subjective indices of sexual arousal were significantly associated with decreases in AEA, and increases in subjective indices of sexual arousal were significantly associated with decreases in 2-AG.

CONCLUSIONS:

These findings support the hypothesis that the endocannabinoid system is involved in female sexual functioning, with implications for furthering understanding of the biological mechanisms underlying female sexual functioning.”

https://www.ncbi.nlm.nih.gov/pubmed/22462722

https://www.jsm.jsexmed.org/article/S1743-6095(15)33996-5/fulltext

[Significance of the endocannabinoid system in migraine].

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“Based on the traditional pain-relieving effect of Cannabis species an endogenous cannabinoid like system was discovered in the human body. Endocannabinoids have important role in the homeostasis of the body, such as stress response and mood control, feeding behaviour, energy balance and metabolism, immunological processes, and also play important role in controlling pain processing. Previous studies suggested that an endocannabinoid dysfunction, namely endocannabinoid deficit, might contribute to the development of migraine and its chronification. Although, the exact nature of the relationship between migraine and endocannabinoid system is not fully understood yet, in this brief review we summarise research results suggesting that the endocannabinoid system may be a potential drug target in the migraine therapy.”

https://www.ncbi.nlm.nih.gov/pubmed/30962405

Cannabinoid interventions for PTSD: Where to next?

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Progress in Neuro-Psychopharmacology and Biological Psychiatry

“Cannabinoids are a promising method for pharmacological treatment of post-traumatic stress disorder (PTSD). Despite considerable research devoted to the effect of cannabinoid modulation on PTSD symptomology, there is not a currently agreed way by which the cannabinoid system should be targeted in humans. In this review, we present an overview of recent research identifying neurological pathways by which different cannabinoid-based treatments may exert their effects on PTSD symptomology. We evaluate the strengths and weaknesses of each of these different approaches, including recent challenges presented to favourable options such as fatty acid amide hydrolase (FAAH) inhibitors. This article makes the strengths and challenges of different potential cannabinoid treatments accessible to psychological researchers interested in cannabinoid therapeutics and aims to aid selection of appropriate tools for future clinical trials.”

https://www.ncbi.nlm.nih.gov/pubmed/30946942

https://www.sciencedirect.com/science/article/pii/S027858461930034X?via%3Dihub