Alterations in Brain Cannabinoid Receptor Levels Are Associated with HIV-Associated Neurocognitive Disorders in the ART Era: Implications for Therapeutic Strategies Targeting the Endocannabinoid System

viruses-logo“HIV-associated neurocognitive disorders (HAND) persist despite the advent of antiretroviral therapy (ART), suggesting underlying systemic and central nervous system (CNS) inflammatory mechanisms.

The endogenous cannabinoid receptors 1 and 2 (CB1 and CB2) modulate inflammatory gene expression and play an important role in maintaining neuronal homeostasis. Cannabis use is disproportionately high among people with HIV (PWH) and may provide a neuroprotective effect for those on ART due to its anti-inflammatory properties. However, expression profiles of CB1 and CB2 in the brains of PWH on ART with HAND have not been reported.

In this study, biochemical and immunohistochemical analyses were performed to determine CB1 and CB2 expression in the brain specimens of HAND donors.

Immunoblot revealed that CB1 and CB2 were differentially expressed in the frontal cortices of HAND brains compared to neurocognitively unimpaired (NUI) brains of PWH. CB1 expression levels negatively correlated with memory and information processing speed. CB1 was primarily localized to neuronal soma in HAND brains versus a more punctate distribution of neuronal processes in NUI brains. CB1 expression was increased in cells with glial morphology and showed increased colocalization with an astroglial marker.

These results suggest that targeting the endocannabinoid system may be a potential therapeutic strategy for HAND.”

https://pubmed.ncbi.nlm.nih.gov/34578323/

https://www.mdpi.com/1999-4915/13/9/1742

Hepatic Cannabinoid Signaling in the Regulation of Alcohol-Associated Liver Disease

Logo of arcr“Purpose: The endocannabinoid system has emerged as a key regulatory signaling pathway in the pathophysiology of alcohol-associated liver disease (ALD). More than 30 years of research have established different roles of endocannabinoids and their receptors in various aspects of liver diseases, such as steatosis, inflammation, and fibrosis. However, pharmacological applications of the endocannabinoid system for the treatment of ALD have not been successful because of psychoactive side effects, despite some beneficial effects. Thus, a more delicate and detailed elucidation of the mechanism linking the endocannabinoid system and ALD may be of paramount significance in efforts to apply the system to the treatment of ALD.

Search results: According to the inclusion and exclusion criteria, the authors selected 47 eligible full-text articles out of 2,691 searched initially. Studies in the past 3 decades revealed the opposite effects of cannabinoid receptors CB1R and CB2R on steatosis, inflammation, and fibrosis in ALD.

Discussion and conclusions: This review summarizes the endocannabinoid signaling in the general physiology of the liver, the pathogenesis of ALD, and some of the potential therapeutic implications of cannabinoid-based treatments for ALD.”

https://pubmed.ncbi.nlm.nih.gov/34646717/

“Over the past 30 years, it has been found that the endocannabinoid system is involved in a variety of pathways associated with the onset, or the progression, of several diseases, including ALD. The endocannabinoid system has been observed in both the hepatocytes and various nonparenchymal cells in the liver, in which the endocannabinoid production and its receptor activation may contribute to the development of a spectrum of ALD, ranging from simple alcoholic steatosis to more severe forms such as steatohepatitis and fibrosis. Therefore, understanding the precise physiology of the endocannabinoid system in the liver and unveiling the mechanism underlying the association between ALD progression and hepatic endocannabinoid signaling seem to bear a paramount significance for the advancement of ALD treatment, as well as for the treatment of other chronic liver diseases (e.g., NAFLD, viral hepatitis). Moreover, developing efficacious and highly selective cannabinoid receptor–modulating drugs could be a major breakthrough in the treatment of ALD.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8496755/

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Cannabidiol enhances verbal episodic memory in healthy young participants: A randomized clinical trial

Journal of Psychiatric Research“Cannabis contains a multitude of different compounds. One of them, cannabidiol – a non-psychoactive substance – might counteract negative effects of Δ-9-Tetrahydrocannabinol on hippocampus-dependent memory impairment.

The aim of the present study was to investigate the effect of vaping cannabidiol on verbal episodic memory in healthy young subjects.

We used a double-blind, placebo-controlled, randomized crossover trial in 39 healthy young subjects. Participants received once a single dose of cannabidiol e-liquid (0.25 ml, 5% cannabidiol, 12.5 mg cannabidiol) and once placebo for vaping after learning 15 unrelated nouns. The primary outcome measure was the short delay verbal memory performance (number of correctly free recalled nouns) 20 min after learning. 34 participants (mean age: 22.26 [3.04]) completed all visits and entered analyses (17 received cannabidiol and 17 received placebo first).

Cannabidiol enhanced verbal episodic memory performance (placebo: 7.03 [2.34]; cannabidiol 7.71 [2.48]; adjusted group difference 0.68, 95% CI 0.01 to 1.35; R = .028, p = .048). Importantly, we did not detect medication effects on secondary outcome measures attention or working memory performance, suggesting that CBD has no negative impact on these basic cognitive functions.

The results are in line with the idea that vaping cannabidiol interacts with the central endocannabinoid system and is capable to modulate memory processes, a phenomenon with possible therapeutic potential. Further studies are needed to investigate optimal dose-response and time-response relationships.”

https://pubmed.ncbi.nlm.nih.gov/34536664/

“To conclude, while further research is needed to identify dose-response and time-response relationships, our results show that CBD can improve episodic memory, a drug effect with possible therapeutic potential.”

https://www.sciencedirect.com/science/article/pii/S002239562100546X?via%3Dihub

Cannabinoids induce functional Tregs by promoting tolerogenic DCs via autophagy and metabolic reprograming

Mucosal Immunology“The generation of functional regulatory T cells (Tregs) is essential to keep tissue homeostasis and restore healthy immune responses in many biological and inflammatory contexts.

Cannabinoids have been pointed out as potential therapeutic tools for several diseases.

Dendritic cells (DCs) express the endocannabinoid system, including the cannabinoid receptors CB1 and CB2. However, how cannabinoids might regulate functional properties of DCs is not completely understood.

We uncover that the triggering of cannabinoid receptors promote human tolerogenic DCs that are able to prime functional FOXP3+ Tregs in the context of different inflammatory diseases. Mechanistically, cannabinoids imprint tolerogenicity in human DCs by inhibiting NF-κB, MAPK and mTOR signalling pathways while inducing AMPK and functional autophagy flux via CB1- and PPARα-mediated activation, which drives metabolic rewiring towards increased mitochondrial activity and oxidative phosphorylation.

Cannabinoids exhibit in vivo protective and anti-inflammatory effects in LPS-induced sepsis and also promote the generation of FOXP3+ Tregs. In addition, immediate anaphylactic reactions are decreased in peanut allergic mice and the generation of allergen-specific FOXP3+ Tregs are promoted, demonstrating that these immunomodulatory effects take place in both type 1- and type 2-mediated inflammatory diseases.

Our findings might open new avenues for novel cannabinoid-based interventions in different inflammatory and immune-mediated diseases.”

https://pubmed.ncbi.nlm.nih.gov/34548620/

“Cannabinoids have been pointed out as potential therapeutic tools for several diseases. Our results might well contribute to pave the way for the future development of novel cannabinoid-based strategies for different inflammatory and immune-mediated diseases.”

https://www.nature.com/articles/s41385-021-00455-x

Cannabinoid Receptor Type 2 is Upregulated in Synovium following Joint Injury and Mediates Anti-Inflammatory Effects in Synovial Fibroblasts and Macrophages

The effect of protease inhibitors on the indcution of  osteoarthritis-related biomarkers in bovine full-depth cartilage explants -  Osteoarthritis and Cartilage“Objective: Joint injury-induced perturbations to the endocannabinoid system (ECS), a regulator of both inflammation and nociception, remain largely uncharacterized. We employed a mouse model of ACL rupture to assess alterations to nociception, inflammation, and the ECS while using in vitro models to determine whether CB2 agonism can mitigate inflammatory signaling in macrophages and fibroblast-like synoviocytes (FLS).

Conclusions: Joint injury perturbs the intra-articular ECS, characterized by an increase in synovial F4/80(+) cells, which express CB2, but not CB1. Targeting CB2 in murine macrophages and human FLS induced potent anti-inflammatory and anti-catabolic effects, which indicates that the CB2 receptor plays a key role in regulating inflammatory signaling in the two primary effector cells in the synovium. The intraarticular ECS is therefore a potential therapeutic target for blocking pathological inflammation in future disease-modifying PTOA treatments.”

https://pubmed.ncbi.nlm.nih.gov/34537380/

https://www.oarsijournal.com/article/S1063-4584(21)00888-8/fulltext

Cannabinoid receptor 1 expression is higher in muscle of old vs. young males, and increases upon resistance exercise in older adults

Scientific Reports“Aged skeletal muscle undergoes metabolic and structural alterations eventually resulting in a loss of muscle strength and mass, i.e. age-related sarcopenia. Therefore, novel targets for muscle growth purposes in elderly are needed.

Here, we explored the role of the cannabinoid system in muscle plasticity through the expression of muscle cannabinoid receptors (CBs) in young and old humans.

The CB1 expression was higher (+ 25%; p = 0.04) in muscle of old (≥ 65 years) vs. young adults (20-27 years), whereas CB2 was not differently expressed. Furthermore, resistance exercise tended to increase the CB1 (+ 11%; p = 0.055) and CB2 (+ 37%; p = 0.066) expression in muscle of older adults. Interestingly, increases in the expression of CB2 following resistance exercise positively correlated with changes in key mechanisms of muscle homeostasis, such as catabolism (FOXO3a) and regenerative capacity (Pax7, MyoD).

This study for the first time shows that CB1 is differentially expressed with aging and that changes in CB2 expression upon resistance exercise training correlate with changes in mediators that play a central role in muscle plasticity.

These data confirm earlier work in cells and mice showing that the cannabinoid system might orchestrate muscle growth, which is an incentive to further explore CB-based strategies that might counteract sarcopenia.”

https://pubmed.ncbi.nlm.nih.gov/34526596/

“In conclusion, cell culture and murine experiments suggested that CBs can be a promising target to treat cachexia and sarcopenia through modulation of the metabolism and muscle regenerative capacity. These data imply that CB modulation might be a promising tool to combat muscle degeneration. ”

https://www.nature.com/articles/s41598-021-97859-3

Endocannabinoid Levels in Ulcerative Colitis Patients Correlate With Clinical Parameters and Are Affected by Cannabis Consumption

Logo of frontendo“Inflammatory bowel diseases (IBDs) are chronic, idiopathic, inflammatory, gastrointestinal disorders.

The endocannabinoid system may have a role in the pathogenesis of IBD.

We aimed to assess whether cannabis treatment influences endocannabinoids (eCBs) level and clinical symptoms of IBD patients.

Conclusion

Our study supports the notion that cannabis use affects eCB “tone” in UC patients and may have beneficial effects on disease symptoms in UC patients.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8438407/

“In conclusion, our study suggests that cannabis use may affect eCBs tone in UC patients. This affect has a beneficial effect on UC symptoms.”

https://www.frontiersin.org/articles/10.3389/fendo.2021.685289/full

Cannabinoids and Cancer

cancers-logo“Cannabinoids, active components of the plant Cannabis sativa, had been used for centuries in ancient medicine as therapeutic remedies for a variety of conditions, before becoming stigmatized due to their psychoactive effects.

In the second half of the 19th century, phyto-cannabinoids have been re-evaluated after the discovery of the chemical structure and isolation of different substances, and the subsequent development of cannabinoid-based drugs that have been FDA approved mainly to treat chemotherapy-induced nausea, insomnia and appetite, epilepsy, spasticity, and pain management.

Then, the elucidation of the endocannabinoid system, from the initial type 1 and type 2 (CB1 and CB2) cannabinoid receptors and their endogenous ligands (especially N-arachidonoylethanolamine, or anandamide, and 2-arachidonoylglycerol) to the emerging complexity of a wider system made up of additional putative receptors, ligands and enzymes, altogether termed endocannabinoidome, has further boosted research into the therapeutic potential of phyto-, endo- and even syntho-(synthetic) cannabinoids, cancer treatment included.”

https://pubmed.ncbi.nlm.nih.gov/34503268/

https://www.mdpi.com/2072-6694/13/17/4458/htm

Cannabinoids and Endocannabinoid System Changes in Intestinal Inflammation and Colorectal Cancer

cancers-logo“Despite the multiple preventive measures and treatment options, colorectal cancer holds a significant place in the world’s disease and mortality rates. The development of novel therapy is in critical need, and based on recent experimental data, cannabinoids could become excellent candidates. This review covered known experimental studies regarding the effects of cannabinoids on intestinal inflammation and colorectal cancer. In our opinion, because colorectal cancer is a heterogeneous disease with different genomic landscapes, the choice of cannabinoids for tumor prevention and treatment depends on the type of the disease, its etiology, driver mutations, and the expression levels of cannabinoid receptors. In this review, we describe the molecular changes of the endocannabinoid system in the pathologies of the large intestine, focusing on inflammation and cancer.”

https://pubmed.ncbi.nlm.nih.gov/34503163/

“In recent years, multiple preclinical studies have shown that changes in endocannabinoid system signaling may have various effects on intestinal inflammation and colorectal cancer. However, not all tumors can respond to cannabinoid therapy in the same manner. Given that colorectal cancer is a heterogeneous disease with different genomic landscapes, experiments with cannabinoids should involve different molecular subtypes, emerging mutations, and various stages of the disease. We hope that this review can help researchers form a comprehensive understanding of cannabinoid interactions in colorectal cancer and intestinal bowel diseases. We believe that selecting a particular experimental model based on the disease’s genetic landscape is a crucial step in the drug discovery, which eventually may tremendously benefit patient’s treatment outcomes and bring us one step closer to individualized medicine.”

https://www.mdpi.com/2072-6694/13/17/4353

The Endocannabinoid System: A Potential Target for the Treatment of Various Diseases

ijms-logo“The Endocannabinoid System (ECS) is primarily responsible for maintaining homeostasis, a balance in internal environment (temperature, mood, and immune system) and energy input and output in living, biological systems.

In addition to regulating physiological processes, the ECS directly influences anxiety, feeding behaviour/appetite, emotional behaviour, depression, nervous functions, neurogenesis, neuroprotection, reward, cognition, learning, memory, pain sensation, fertility, pregnancy, and pre-and post-natal development.

The ECS is also involved in several pathophysiological diseases such as cancer, cardiovascular diseases, and neurodegenerative diseases. In recent years, genetic and pharmacological manipulation of the ECS has gained significant interest in medicine, research, and drug discovery and development.

The distribution of the components of the ECS system throughout the body, and the physiological/pathophysiological role of the ECS-signalling pathways in many diseases, all offer promising opportunities for the development of novel cannabinergic, cannabimimetic, and cannabinoid-based therapeutic drugs that genetically or pharmacologically modulate the ECS via inhibition of metabolic pathways and/or agonism or antagonism of the receptors of the ECS. This modulation results in the differential expression/activity of the components of the ECS that may be beneficial in the treatment of a number of diseases.

This manuscript in-depth review will investigate the potential of the ECS in the treatment of various diseases, and to put forth the suggestion that many of these secondary metabolites of Cannabis sativa L. (hereafter referred to as “C. sativa L.” or “medical cannabis”), may also have potential as lead compounds in the development of cannabinoid-based pharmaceuticals for a variety of diseases.”

https://pubmed.ncbi.nlm.nih.gov/34502379/

https://www.mdpi.com/1422-0067/22/17/9472