Category Archives: Endocannabinoid System

Cannabinoids modulate the microbiota-gut-brain axis in HIV/SIV infection by reducing neuroinflammation and dysbiosis while concurrently elevating endocannabinoid and indole-3-propionate levels

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“Background: Although the advent of combination anti-retroviral therapy (cART) has transformed HIV into a manageable chronic disease, an estimated 30-50% of people living with HIV (PLWH) exhibit cognitive and motor deficits collectively known as HIV-associated neurocognitive disorders (HAND). A key driver of HAND neuropathology is chronic neuroinflammation, where proinflammatory mediators produced by activated microglia and macrophages are thought to inflict neuronal injury and loss. Moreover, the dysregulation of the microbiota-gut-brain axis (MGBA) in PLWH, consequent to gastrointestinal dysfunction and dysbiosis, can lead to neuroinflammation and persistent cognitive impairment, which underscores the need for new interventions.

Methods: We performed RNA-seq and microRNA profiling in basal ganglia (BG), metabolomics (plasma) and shotgun metagenomic sequencing (colon contents) in uninfected and SIV-infected rhesus macaques (RMs) administered vehicle (VEH/SIV) or delta-9-tetrahydrocannabinol (THC) (THC/SIV).

Results: Long-term, low-dose THC reduced neuroinflammation and dysbiosis and significantly increased plasma endocannabinoid, endocannabinoid-like, glycerophospholipid and indole-3-propionate levels in chronically SIV-infected RMs. Chronic THC potently blocked the upregulation of genes associated with type-I interferon responses (NLRC5, CCL2, CXCL10, IRF1, IRF7, STAT2, BST2), excitotoxicity (SLC7A11), and enhanced protein expression of WFS1 (endoplasmic reticulum stress) and CRYM (oxidative stress) in BG. Additionally, THC successfully countered miR-142-3p-mediated suppression of WFS1 protein expression via a cannabinoid receptor-1-mediated mechanism in HCN2 neuronal cells. Most importantly, THC significantly increased the relative abundance of Firmicutes and Clostridia including indole-3-propionate (C. botulinum, C. paraputrificum, and C. cadaveris) and butyrate (C. butyricum, Faecalibacterium prausnitzii and Butyricicoccus pullicaecorum) producers in colonic contents.

Conclusion: This study demonstrates the potential of long-term, low-dose THC to positively modulate the MGBA by reducing neuroinflammation, enhancing endocannabinoid levels and promoting the growth of gut bacterial species that produce neuroprotective metabolites, like indole-3-propionate. The findings from this study may benefit not only PLWH on cART, but also those with no access to cART and more importantly, those who fail to suppress the virus under cART.”

https://pubmed.ncbi.nlm.nih.gov/36890518/

Cannabinoids in traumatic brain injury and related neuropathologies: preclinical and clinical research on endogenous, plant-derived, and synthetic compounds

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Journal of Neuroinflammation | Scholars Portal Journals

“Traumatic brain injury is common, and often results in debilitating consequences. Even mild traumatic brain injury leaves approximately 20% of patients with symptoms that persist for months. Despite great clinical need there are currently no approved pharmaceutical interventions that improve outcomes after traumatic brain injury. Increased understanding of the endocannabinoid system in health and disease has accompanied growing evidence for therapeutic benefits of Cannabis sativa. This has driven research of Cannabis’ active chemical constituents (phytocannabinoids), alongside endogenous and synthetic counterparts, collectively known as cannabinoids. Also of therapeutic interest are other Cannabis constituents, such as terpenes. Cannabinoids interact with neurons, microglia, and astrocytes, and exert anti-inflammatory and neuroprotective effects which are highly desirable for the management of traumatic brain injury. In this review, we comprehensively appraised the relevant scientific literature, where major and minor phytocannabinoids, terpenes, synthetic cannabinoids, and endogenous cannabinoids were assessed in TBI, or other neurological conditions with pathology and symptomology relevant to TBI, as well as recent studies in preclinical TBI models and clinical TBI populations.”

https://pubmed.ncbi.nlm.nih.gov/36935484/

“Diseases with complex, multifaceted pathology, such as TBI, may require treatment that is multi-mechanistic, such as whole plant cannabis extracts.”

https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-023-02734-9

Regulatory role of the endocannabinoid system on glial cells toward cognitive function in Alzheimer’s disease: A systematic review and meta-analysis of animal studies

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“Objective: Over the last decade, researchers have sought to develop novel medications against dementia. One potential agent under investigation is cannabinoids. This review systematically appraised and meta-analyzed published pre-clinical research on the mechanism of endocannabinoid system modulation in glial cells and their effects on cognitive function in animal models of Alzheimer’s disease (AD). 

Methods: A systematic review complying with PRISMA guidelines was conducted. Six databases were searched: EBSCOHost, Scopus, PubMed, CINAHL, Cochrane, and Web of Science, using the keywords AD, cannabinoid, glial cells, and cognition. The methodological quality of each selected pre-clinical study was evaluated using the SYRCLE risk of bias tool. A random-effects model was applied to analyze the data and calculate the effect size, while I2 and p-values were used to assess heterogeneity. 

Results: The analysis included 26 original articles describing (1050 rodents) with AD-like symptoms. Rodents treated with cannabinoid agonists showed significant reductions in escape latency (standard mean difference [SMD] = -1.26; 95% confidence interval [CI]: -1.77 to -0.76, p < 0.00001) and ability to discriminate novel objects (SMD = 1.40; 95% CI: 1.04 to 1.76, p < 0.00001) compared to the control group. Furthermore, a significant decrease in Aβ plaques (SMD = -0.91; 95% CI: -1.55 to -0.27, p = 0.006) was observed in the endocannabinoid-treated group compared to the control group. Trends were observed toward neuroprotection, as represented by decreased levels of glial cell markers including glial fibrillary acid protein (SMD = -1.47; 95% CI: -2.56 to -0.38, p = 0.008) and Iba1 (SMD = -1.67; 95% CI: -2.56 to -0.79, p = 0.0002). Studies on the wild-type mice demonstrated significantly decreased levels of pro-inflammatory markers TNF-α, IL-1, and IL-6 (SMD = -2.28; 95% CI: -3.15 to -1.41, p = 0.00001). Despite the non-significant decrease in pro-inflammatory marker levels in transgenic mice (SMD = -0.47; 95% CI: -1.03 to 0.08, p = 0.09), the result favored the endocannabinoid-treated group over the control group. 

Conclusion: The revised data suggested that endocannabinoid stimulation promotes cognitive function via modulation of glial cells by decreasing pro-inflammatory markers in AD-like rodent models. Thus, cannabinoid agents may be required to modulate the downstream chain of effect to enhance cognitive stability against concurrent neuroinflammation in AD. Population-based studies and well-designed clinical trials are required to characterize the acceptability and real-world effectiveness of cannabinoid agents.”

https://pubmed.ncbi.nlm.nih.gov/36959856/

“Numerous traditional medical applications of cannabis have already been established and are now accepted practices in medicine.”

https://www.frontiersin.org/articles/10.3389/fphar.2023.1053680/full

The protective effect of cannabinoids against colorectal cancer cachexia through modulation of inflammation and immune responses

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Biomedicine & Pharmacotherapy

“Cancer cachexia is a multifactorial disorder characterized by weight loss and muscle wasting, and there are currently no FDA-approved medications. In the present study, upregulation of six cytokines was observed in serum samples from patients with colorectal cancer (CRC) and in mouse models. A negative correlation between the levels of the six cytokines and body mass index in CRC patients was seen. Gene Ontology analysis revealed that these cytokines were involved in regulating T cell proliferation. The infiltration of CD8+ T cells was found to be associated with muscle atrophy in mice with CRC. Adoptive transfer of CD8+ T cells isolated from CRC mice resulted in muscle wasting in recipients.

The Genotype-Tissue Expression database showed that negative correlations between the expression of cachexia markers and cannabinoid receptor 2 (CB2) in human skeletal muscle tissues. Pharmacological treatment with Δ9-tetrahydrocannabinol (Δ9-THC), a selective CB2 agonist or overexpression of CB2 attenuated CRC-associated muscle atrophy. In contrast, knockout of CB2 with a CRISPR/Cas9-based strategy or depletion of CD8+ T cells in CRC mice abolished the Δ9-THC-mediated effects.

This study demonstrates that cannabinoids ameliorate CD8+ T cell infiltration in CRC-associated skeletal muscle atrophy via a CB2-mediated pathway. Serum levels of the six-cytokine signature might serve as a potential biomarker to detect the therapeutic effects of cannabinoids in CRC-associated cachexia.”

https://pubmed.ncbi.nlm.nih.gov/36871538/

“In recent years, researchers have gradually found that marijuana, in addition to recreational use, has potential applications as a supportive therapy or palliative medicine.

In conclusion, our findings indicate that the infiltration of CD8+ T cells in skeletal muscle plays a vital role in CRC-associated muscle atrophy. Treatment with Δ9-THC or CB65 can ameliorate CRC-associated cachexia and muscle atrophy by activating CB2 in CD8+ T cells. Targeting the CB2 receptor in CD8+ T cells should be evaluated as a therapeutic option for CRC patients who develop cachexia, and the six-cytokine signature in serum might serve as a potential biomarker for the therapeutic effects of cannabinoids in CRC-associated cachexia.”

https://www.sciencedirect.com/science/article/pii/S075333222300255X?via%3Dihub

The Anti-Tumorigenic Role of Cannabinoid Receptor 2 in Colon Cancer: A Study in Mice and Humans

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“The endocannabinoid system, particularly cannabinoid receptor 2 (CB2 in mice and CNR2 in humans), has controversial pathophysiological implications in colon cancer.

Here, we investigate the role of CB2 in potentiating the immune response in colon cancer in mice and determine the influence of CNR2 variants in humans. Comparing wild-type (WT) mice to CB2 knockout (CB2-/-) mice, we performed a spontaneous cancer study in aging mice and subsequently used the AOM/DSS model of colitis-associated colorectal cancer and a model for hereditary colon cancer (ApcMin/+). Additionally, we analyzed genomic data in a large human population to determine the relationship between CNR2 variants and colon cancer incidence.

Aging CB2-/- mice exhibited a higher incidence of spontaneous precancerous lesions in the colon compared to WT controls. The AOM/DSS-treated CB2-/- and ApcMin/+CB2-/- mice experienced aggravated tumorigenesis and enhanced splenic populations of immunosuppressive myeloid-derived suppressor cells along with abated anti-tumor CD8+ T cells. Importantly, corroborative genomic data reveal a significant association between non-synonymous variants of CNR2 and the incidence of colon cancer in humans.

Taken together, the results suggest that endogenous CB2 activation suppresses colon tumorigenesis by shifting the balance towards anti-tumor immune cells in mice and thus portray the prognostic value of CNR2 variants for colon cancer patients.”

https://pubmed.ncbi.nlm.nih.gov/36835468/

https://www.mdpi.com/1422-0067/24/4/4060

The Endocannabinoid System and Physical Exercise

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“The endocannabinoid system (ECS) is involved in various processes, including brain plasticity, learning and memory, neuronal development, nociception, inflammation, appetite regulation, digestion, metabolism, energy balance, motility, and regulation of stress and emotions.

Physical exercise (PE) is considered a valuable non-pharmacological therapy that is an immediately available and cost-effective method with a lot of health benefits, one of them being the activation of the endogenous cannabinoids.

Endocannabinoids (eCBs) are generated as a response to high-intensity activities and can act as short-term circuit breakers, generating antinociceptive responses for a short and variable period of time.

A runner’s high is an ephemeral feeling some sport practitioners experience during endurance activities, such as running. The release of eCBs during sustained physical exercise appears to be involved in triggering this phenomenon.

The last decades have been characterized by an increased interest in this emotional state induced by exercise, as it is believed to alleviate pain, induce mild sedation, increase euphoric levels, and have anxiolytic effects.

This review provides information about the current state of knowledge about endocannabinoids and physical effort and also an overview of the studies published in the specialized literature about this subject.”

https://pubmed.ncbi.nlm.nih.gov/36768332/

“PE is considered a valuable non-pharmacological therapy that is an immediately available and cost-effective method with many health benefits, one of them being the activation of endogenous cannabinoids to reduce stress and anxiety and improve wellness.”

https://www.mdpi.com/1422-0067/24/3/1989

“Exercise activates the endocannabinoid system”

https://pubmed.ncbi.nlm.nih.gov/14625449/

Endocannabinoids are potential inhibitors of glioblastoma multiforme proliferation

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Journal of Integrative Medicine

“Globally, it is evident that glioblastoma multiforme (GBM) is an aggressive malignant cancer with a high mortality rate and no effective treatment options. Glioblastoma is classified as the stage-four progression of a glioma tumor, and its diagnosis results in a shortened life expectancy. Treatment options for GBM include chemotherapy, immunotherapy, surgical intervention, and conventional pharmacotherapy; however, at best, they extend the patient’s life by a maximum of 5 years. GBMs are considered incurable due to their high recurrence rate, despite various aggressive therapeutic approaches which can have many serious adverse effects.

Ceramides, classified as endocannabinoids, offer a promising novel therapeutic approach for GBM. Endocannabinoids may enhance the apoptosis of GBM cells but have no effect on normal healthy neural cells. Cannabinoids promote atypical protein kinase C, deactivate fatty acid amide hydrolase enzymes, and activate transient receptor potential vanilloid 1 (TRPV1) and TRPV2 to induce pro-apoptotic signaling pathways without increasing endogenous cannabinoids. In previous in vivo studies, endocannabinoids, chemically classified as amide formations of oleic and palmitic acids, have been shown to increase the pro-apoptotic activity of human cancer cells and inhibit cell migration and angiogenesis.

This review focuses on the biological synthesis and pharmacology of endogenous cannabinoids for the enhancement of cancer cell apoptosis, which have potential as a novel therapy for GBM.”

https://pubmed.ncbi.nlm.nih.gov/36805391/

“As discussed above, endocannabinoids could prove to be a viable alternative treatment for GBM.”

https://www.sciencedirect.com/science/article/abs/pii/S2095496423000055?via%3Dihub

A Retrospective Cohort Study That Examined the Impact of Cannabis Consumption on Long-Term Kidney Outcomes

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“Background: Cannabis consumption for recreational and medical use is increasing worldwide. However, the long-term effects on kidney health and disease are largely unknown. 

Materials and Methods: Post hoc analysis of cannabis use as a risk factor for kidney disease was performed using data from the Assessment, Serial Evaluation, and Subsequent Sequelae of Acute Kidney Injury (ASSESS-AKI) study that enrolled hospitalized adults with and without acute kidney injury from four U.S. centers during 2009-2015. Associations between self-reported cannabis consumption and the categorical and continuous outcomes were determined using multivariable Cox regression and linear mixed models, respectively. 

Results: Over a mean follow-up of 4.5±1.8 years, 94 participants without chronic kidney disease (CKD) (estimated glomerular filtration rate [eGFR] >60 mL/min/1.73 m2) who consumed cannabis had similar rates of annual eGFR decline versus 889 nonconsumers (mean difference=-0.02 mL/min/1.73 m2/year, p=0.9) and incident CKD (≥25% reduction in eGFR compared with the 3-month post-hospitalization measured eGFR and achieving CKD stage 3 or higher) (adjusted hazard ratio [aHR]=1.2; 95% confidence interval [CI]=0.7-2.0). Nineteen participants with CKD (eGFR <60 mL/min/1.73 m2) who consumed cannabis had more rapid eGFR decline versus 597 nonconsumers (mean difference=-1.3 mL/min/1.73 m2/year; p=0.02) that was not independently associated with an increased risk of CKD progression (≥50% reduction in eGFR compared with the 3-month post-hospitalization eGFR, reaching CKD stage 5, or receiving kidney replacement therapy) (aHR=1.6; 95% CI=0.7-3.5). Cannabis consumption was not associated with the rate of change in urine albumin to creatinine ratio (UACR) over time among those with (p=0.7) or without CKD (p=0.4). 

Conclusions: Cannabis consumption did not adversely affect the kidney function of participants without CKD but was associated with a faster annual eGFR decline among participants with CKD. Cannabis consumption was not associated with changes in UACR over time, incident CKD, or progressive CKD regardless of baseline kidney function. Additional research is needed to investigate the kidney endocannabinoid system and the impact of cannabis use on kidney disease outcomes.”

https://pubmed.ncbi.nlm.nih.gov/36791309/

https://www.liebertpub.com/doi/10.1089/can.2022.0141

Role of Gut Microbiota in Cannabinoid-Mediated Suppression of Inflammation

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“Cannabinoids and the endocannabinoid system have been well established to play a crucial role in the regulation of the immune response. Also, emerging data from numerous investigations unravel the imperative role of gut microbiota and their metabolites in the maintenance of immune homeostasis and gut barrier integrity. In this review, we concisely report the immunosuppressive mechanisms triggered by cannabinoids, and how they are closely associated with the alterations in the gut microbiome and metabolome following exposure to endogenous or exogenous cannabinoids. We discuss how cannabinoid-mediated induction of microbial secondary bile acids, short chain fatty acids, and indole metabolites, produced in the gut, can suppress inflammation even in distal organs. While clearly, more clinical studies are necessary to establish the cross talk between exo- or endocannabinoid system with the gut microbiome and the immune system, the current evidence opens a new avenue of cannabinoid-gut-microbiota-based therapeutics to regulate immunological disorders.”

https://pubmed.ncbi.nlm.nih.gov/36776218/

“The microbiome-eCB signaling modulation exploiting exo- or endogenous cannabinoids opens a new avenue of cannabinoid-gut microbiota-based therapeutics to curb metabolic and immune-oriented conditions.”

https://www.frontierspartnerships.org/articles/10.3389/adar.2022.10550/full

Rare Phytocannabinoids Exert Anti-Inflammatory Effects on Human Keratinocytes via the Endocannabinoid System and MAPK Signaling Pathway

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“Increasing evidence supports the therapeutic potential of rare cannabis-derived phytocannabinoids (pCBs) in skin disorders such as atopic dermatitis, psoriasis, pruritus, and acne. However, the molecular mechanisms of the biological action of these pCBs remain poorly investigated.

In this study, an experimental model of inflamed human keratinocytes (HaCaT cells) was set up by using lipopolysaccharide (LPS) in order to investigate the anti-inflammatory effects of the rare pCBs cannabigerol (CBG), cannabichromene (CBC), Δ9-tetrahydrocannabivarin (THCV) and cannabigerolic acid (CBGA). To this aim, pro-inflammatory interleukins (IL)-1β, IL-8, IL-12, IL-31, tumor necrosis factor (TNF-β) and anti-inflammatory IL-10 levels were measured through ELISA quantification. In addition, IL-12 and IL-31 levels were measured after treatment of HaCaT cells with THCV and CBGA in the presence of selected modulators of endocannabinoid (eCB) signaling. In the latter cells, the activation of 17 distinct proteins along the mitogen-activated protein kinase (MAPK) pathway was also investigated via Human Phosphorylation Array.

Our results demonstrate that rare pCBs significantly blocked inflammation by reducing the release of all pro-inflammatory ILs tested, except for TNF-β. Moreover, the reduction of IL-31 expression by THCV and CBGA was significantly reverted by blocking the eCB-binding TRPV1 receptor and by inhibiting the eCB-hydrolase MAGL. Remarkably, THCV and CBGA modulated the expression of the phosphorylated forms (and hence of the activity) of the MAPK-related proteins GSK3β, MEK1, MKK6 and CREB also by engaging eCB hydrolases MAGL and FAAH.

Taken together, the ability of rare pCBs to exert an anti-inflammatory effect in human keratinocytes through modifications of eCB and MAPK signaling opens new perspectives for the treatment of inflammation-related skin pathologies.”

https://pubmed.ncbi.nlm.nih.gov/36769042/

“Overall, this proof of concept, which shows that in inflamed human keratinocytes, rare pCBs can indeed interact with specific eCB system elements, opens new perspectives for possible treatments of inflammation-related skin diseases. Incidentally, such interactions between pCBs and eCB system seems to hold therapeutic potential well beyond the skin, such as possible treatments reported for autism spectrum disorders and cancer”

https://www.mdpi.com/1422-0067/24/3/2721

“Effects of Rare Phytocannabinoids on the Endocannabinoid System of Human Keratinocytes”

https://pubmed.ncbi.nlm.nih.gov/35628241/