Category Archives: Endocannabinoid System

Cannabidiol reshapes the gut microbiome to promote endurance exercise in mice

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“Cannabidiol (CBD), a nonpsychoactive compound from Cannabis, has various bioactive functions in humans and animals.

Evidence suggests that CBD promotes muscle injury recovery in athletes, but whether and how CBD improves endurance performance remains unclear.

Here we investigated the effects of CBD treatment on exercise performance in mice and assessed whether this effect involves the gut microbiome.

CBD administration significantly increased treadmill running performance in mice, accompanied by an increase in oxidative myofiber composition. CBD also increased mitochondrial biogenesis and the expression of associated genes such as PGC-1α, phosphorylated CREB and AMPK in muscle tissue. Interestingly, CBD altered the composition of the gut microbiome, and antibiotic treatment reduced the muscle endurance-enhancing effects of CBD and mitochondrial biogenesis.

We isolated Bifidobacterium animalis, a microbe increased by CBD administration, and named it KBP-1. Treatment with B. animalis KBP-1 in mice resulted in improved running performance. Whole-genome analysis revealed that B. animalis KBP-1 presented high expression of genes involved in branched-chain amino acid biosynthesis, expression of branched-chain amino acid release pumps and metabolism of lactic acid.

In summary, our study identified CBD and B. animalis KBP-1 as potential endurance exercise-promoting agents.”

https://pubmed.ncbi.nlm.nih.gov/39966566/

“In summary, we propose that both CBD and the gut bacteria B. animalis KBP-1, which is increased by CBD treatment, could be used in strategies to promote endurance exercise performance.”

https://www.nature.com/articles/s12276-025-01404-5

The Endocannabinoid System as a Target for Ischemic Stroke Therapy

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“Introduction: Cannabinoids are increasingly being explored as a potential treatment for neurodegenerative diseases. This article aims to provide a narrative review of available data on the treatment of neurological disorders with cannabis constituents, focusing on ischemic stroke. 

Methods: Selected articles are summarized to describe design, results, limitations, conclusions, and implications about this theme. 

Results: The growing understanding of the endocannabinoid system and the cannabinoid receptors distribution in all human body systems and organs and particularly in brain structures importantly involved in myelination processes, suggests potential benefits for stroke symptoms and overall patient improvement. However, the variety of studied compounds, the different administration routes, dosages, and timing complicates data comparison, especially due to limited studies about these compounds, peculiarly in stroke patients. Thereat, this review to showcase disparities in findings and to summarize current advancements in cannabinoid use for potential future treatments. 

Conclusion: This article offers a review of the current literature in the field and discuss a pragmatic approach to the clinical use of cannabinoids in patients with ischemic stroke.”

https://pubmed.ncbi.nlm.nih.gov/39951358/

The cannabinoid CB2 receptor mediates the analgesic effects of Cannabis sativa extract in a rat model of neuropathic pain

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“Neuropathic pain (NP) is a complex and debilitating condition that is often refractory to currently available analgesic medications.

Cannabis sativa extract (CSE) has been reported to exhibit analgesic properties across various pain models; however, the underlying mechanisms of action are not fully understood.

This study aimed to investigate the involvement of the cannabinoid CB2 receptor in mediating the analgesic effects of CSE in a rat model of NP, where NP was induced in male Wistar rats through chronic constriction injury (CCI) of the sciatic nerve.

Rats were randomly allocated into four groups: (1) Sham + vehicle, (2) CCI + vehicle, (3) CCI + CSE, and (4) CCI + CSE + AM630 (a CB2 receptor antagonist). CSE was administered intraperitoneally at a dosage of 30mg/kg once daily for 7 days, starting from day 7 to day 13 post-CCI surgery. To assess the involvement of the CB2 receptor, 7µg of AM630 was administered intrathecally to the rats in group 4, 30minutes before the CSE injections. Mechanical allodynia and thermal hyperalgesia were assessed using the von Frey filament and hot plate tests, respectively, at baseline (day 0) and on days 3, 7, 10, and 14 after surgery. Additionally, at the end of the study period (day 14), the expression level of Iba1 and GFAP genes was quantified in the lumbar enlargement tissues using real-time PCR.

The results demonstrated that CCI surgery induced mechanical allodynia and thermal hyperalgesia, along with the upregulation of Iba1 and GFAP genes in the vehicle-treated CCI group. Treatment with CSE significantly mitigated both allodynia and hyperalgesia and downregulated the expression of Iba1 and GFAP genes compared to the CCI + vehicle group. Furthermore, the administration of the CB2 receptor antagonist AM630 not only robustly blocked the antinociceptive effects of CSE but also reversed the significant downregulation of Iba1 and GFAP gene expression in the lumbar enlargement tissues.

These findings highlight the novel role of the CB2 receptor in mediating the analgesic effects of CSE, providing new insights into the potential therapeutic mechanisms of CSE in neuropathic pain management.”

https://pubmed.ncbi.nlm.nih.gov/39947333/

“In summary, this study provides evidence that CSE exerts analgesic and anti-inflammatory effects in NP through CB2 receptor activation. These findings contribute to the growing body of research supporting cannabinoids as potential therapeutic agents for NP management.”

https://www.sciencedirect.com/science/article/abs/pii/S0166432825000683?via%3Dihub

The Presence of the Endocannabinoid System in an In Vitro Model of Gorham-Stout Disease and Its Possible Role in the Pathogenesis

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“Gorham-Stout syndrome (GSD), also known as disappearing bone disease, is an extremely rare bone disorder, characterized by a huge bone loss, which is followed by a lack of new matrix deposition and an excessive proliferation of both blood vessels and lymphatics. Unfortunately, the biological causes of GSD are still unknown. Recent studies that have tried to understand the etiopathogenesis of GSD have been principally focused on the vascular and osteoclastogenic aspects, not considering the possibility of a lack of osteoblast function. Nowadays, a diagnosis is still difficult, and is often made by exclusion of the presence of other pathologies, as well as on radiological evidence, and finally confirmed by histological examination. Treatment also remains a critical issue for clinicians today, who mostly try to control the progression of the disease.

Over the last two decades, clear evidence has emerged that the endocannabinoid system plays an important role in bone metabolism, leading scientists to hypothesize that it could be involved in physiological and pathological bone processes. In this work, we analyzed the presence of the ES in a primary cell line of human mesenchymal stem cells derived from a GSD patient for the first time, to understand if and how this complex network may play a role in the pathogenesis of the syndrome.

Our preliminary results demonstrated that the ES is also present in the pathological tissue. Moreover, the qRT-PCR analysis showed an altered expression of the different ES components (i.e., CNR1, CNR2, TRPV1, and GPR55). We observed an upregulation of CNR1 and TRPV1 expression, while the opposite trend was noticed for CNR2 and GPR55 expression. Thus, these results could lead us to speculate that possible deregulation of the ES may play an important role in the lack of bone regeneration in GSD patients. However, further studies will be necessary to confirm the role of the ES in the progression of GSD and understand whether the natural components of Cannabis Sativa could play a therapeutic role in the treatment of the disease.”

https://pubmed.ncbi.nlm.nih.gov/39940911/

“In conclusion, this is only a preliminary study, and further future analyses are needed to understand the role of the ES during osteogenic differentiation better and to try to comprehend what the molecular mechanisms involved in GSD pathogenesis are. In addition to this, the demonstration that the ES is present in our GSD in vitro model could pave the way to a study of the effects of the natural components of Cannabis Sativa as possible future new molecules that could be useful in the treatment of GSD and other bone diseases.”

https://www.mdpi.com/1422-0067/26/3/1143

The Endocannabinoid System: Implications in Gastrointestinal Physiology and Pathology

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“The endocannabinoid system (ECS), composed of receptors, endocannabinoids, and enzymes that regulate biosynthesis and degradation, plays a fundamental role in the physiology and pathology of the gastrointestinal tract, particularly in the small and large intestine and liver.

Specifically, cannabinoid receptor type 1 (CB1R) and cannabinoid receptor type 2 (CB2R), located principally in the nervous system and immune cells, orchestrate processes such as intestinal motility, intestinal and hepatic inflammation, and energy metabolism, respectively.

The main endocannabinoids, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), influence appetite, body weight regulation, and inflammatory states and thus have implications in obesity, non-alcoholic fatty liver disease (NAFLD) and irritable bowel syndrome (IBS).

Recent studies have highlighted the therapeutic potential of targeting the ECS to modulate gastrointestinal and metabolic diseases. In particular, peripheral CB1R antagonists and CB2R agonists have shown efficacy in treating intestinal inflammation, reducing hepatic steatosis, and controlling IBS symptoms. Moreover, the ECS is emerging as a potential target for the treatment of colorectal cancer, acting on cell proliferation and apoptosis.

This review highlights the opportunity to exploit the endocannabinoid system in the search for innovative therapeutic strategies, emphasizing the importance of a targeted approach to optimize treatment efficacy and minimize side effects.”

https://pubmed.ncbi.nlm.nih.gov/39941074/

“In conclusion, these findings suggest that the ECS offers a versatile approach for modulating gastrointestinal physiological aspects and treating conditions such as obesity and its complications, IBS, and CRC. Future research should refine ECS-targeted therapies to maximize their efficacy and minimize adverse effects, unlocking new opportunities for innovative treatments of disordered metabolism, inflammation, and cancer.

Clinical studies show that medical cannabis could be a valuable adjunct to cancer and treatments for inflammation, providing symptom relief and improving patients’ overall quality of life. However, further research is needed to refine treatment protocols and explore their full therapeutic potential.”

https://www.mdpi.com/1422-0067/26/3/1306

Amyotrophic Lateral Sclerosis, the Endocannabinoid System, and Exogenous Cannabinoids: Current State and Clinical Implications

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“A unifying mechanistic cause for amyotrophic lateral sclerosis (ALS) remains uncertain. Multiple pathophysiological processes appear to occur simultaneously.

Cannabinoids, including delta-9-tetrahydrocannabinol (THC), cannabidiol (CBD), cannabigerol (CBG), and others found in cannabis, and cannabis extracts (CEs), appear to have activity in these pathogenic pathways, which have led to increasing interest in cannabinoids as therapeutic agents for ALS.

The use of cannabinoids as a treatment strategy is substantiated by preclinical evidence suggesting a role for the endocannabinoid system (ECS) in ALS and other neurodegenerative disorders.

Preclinical data indicate that cannabis and CEs have powerful antioxidative, anti-inflammatory, and neuroprotective effects in the SOD1G93A mouse model of ALS. The use of CEs in SOD1G93A murine models has been shown to prolong neuronal cell survival, which leads to delayed onset of the disease state, and slows progression of the disease.

Although research in humans remains limited, a few studies suggest that cannabis and CBD, in humans, provide benefits for both motor symptoms, including rigidity, cramps, and fasciculations, and non-motor symptoms including sleep quality, pain, emotional state, quality of life, and depression. There remains a need for further, well-designed clinical trials to validate further the use of an individual cannabinoid, or a combination of cannabinoids, as a disease-modifying therapy for ALS.”

https://pubmed.ncbi.nlm.nih.gov/39936266/

https://onlinelibrary.wiley.com/doi/10.1002/mus.28359

Advances in cannabinoid receptors pharmacology: from receptor structural insights to ligand discovery

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“The medicinal and recreational uses of Cannabis sativa have been recognized for thousands of years.

Today, cannabis-derived medicines are used to treat a variety of conditions, including chronic pain, epilepsy, multiple sclerosis, and chemotherapy-induced nausea. However, cannabis use disorder (CUD) has become the third most prevalent substance use disorder globally.

Cannabinoid receptors are the primary targets that mediate the effects of cannabis and its analogs. Despite their importance, the mechanisms of modulation and the full therapeutic potential of cannabinoid receptors remain unclear, hindering the development of the next generation of cannabinoid-based drugs.

This review summarizes the discovery and medicinal potential of phytocannabinoids and explores the distribution, signaling pathways, and functional roles of cannabinoid receptors. It also discusses classical cannabinoid drugs, as well as agonists, antagonists, and inverse agonists, which serve as key therapeutic agents.

Recent advancements in the development of allosteric drugs are highlighted, with a focus on positive and negative allosteric modulators (PAMs and NAMs) that target CB1 and CB2 receptors. The identification of multiple allosteric sites on the CB1 receptor and the structural basis for allosteric modulation are emphasized, along with the structure-based discovery of ago-BAMs for CB1.

This review concludes by examining the future potential of allosteric modulators in cannabinoid drug development, noting that ongoing progress in cannabinoid-derived drugs continues to open new avenues for therapeutic use and paves the way for future research into their full medicinal potential.”

https://pubmed.ncbi.nlm.nih.gov/39910211/

https://www.nature.com/articles/s41401-024-01472-9

Cannabidiol attenuates lipid metabolism and induces CB1 receptor-mediated ER stress associated apoptosis in ovarian cancer cells

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“Ovarian cancer (OC) is the most deadly gynecological tumor. OC cells utilize cellular metabolic reprogramming to gain a survival advantage, particularly through aberrant lipid metabolic process.

As the primary ingredient in exogenous cannabinoids, cannabidiol (CBD) has been confirmed to exhibit antitumor activity in preclinical studies. However, it is still unclear whether CBD can disrupt fatty acid metabolism and induce apoptosis in OC cells.

In this study, we have demonstrated that CBD significantly inhibits the proliferation of OCs through a cannabinoid receptor type 1 (CB1R)-mediated manner.

Fatty acid metabolic profiling and flow cytometry analysis revealed that CBD has the ability to decrease fatty acid levels and significantly suppress the transcription of genes involved in fatty acid uptake and synthesis in ES-2 cells. In addition, the analysis from RNA-seq and real-time RT-PCR revealed that CBD activated the endoplasmic reticulum (ER) stress pathway. Conversely, by supplementation with unsaturated fatty acid or blocking CB1R, ER stress or reactive oxygen species (ROS) signals with specific inhibitors could significantly relieve CBD induced, dose-dependent, ER stress associated apoptosis, G0-G1 phase arrest, and mitochondrial dysfunction.

Taken collectively, these data indicate that CBD may disrupt lipid metabolism, and lead to ER stress-related apoptosis in OCs. Our findings may provide a theoretical mechanism for anti-ovarian cancer using CBD.”

https://pubmed.ncbi.nlm.nih.gov/39910152/

“Preclinical studies have demonstrated that CBD, either as a monotherapy or in conjunction with other treatments, holds potential as a novel anti-tumor, anti-inflammatory, and analgesic agent. Our results demonstrated that CBD promoted OC cells apoptosis and G0-G1 phase arrest by disrupting the CBR1-mediated lipid metabolism and ER stress- and mitochondrial dysfunction-associated apoptosis signaling pathways (Fig. 8). Therefore, CBD may serve as a potential candidate for adjuvant therapy in the treatment of ovarian cancer. However, larger-scale clinical studies involving more patient samples and detailed dose-response relationship analyses are still needed to confirm the efficacy of CBD in cancer patients.”

https://www.nature.com/articles/s41598-025-88917-1

Cannabidiol-Induced Autophagy Ameliorates Tau Protein Clearance

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“Tau is a neuronal protein that confers stability to microtubules; however, its hyperphosphorylation and accumulation can lead to an impairment of protein degradation pathways, such as autophagy. Autophagy is a lysosomal catabolic process responsible for degrading cytosolic components, being essential for cellular homeostasis and survival.

In this context, autophagy modulation has been postulated as a possible therapeutic target for the treatment of neurodegenerative diseases.

Studies point to the modulatory and neuroprotective role of the cannabinoid system in neurodegenerative models and here it was investigated the effects of cannabidiol (CBD) on autophagy in a human neuroblastoma strain (SH-SY5Y) that overexpresses the EGFP-Tau WT (Wild Type) protein in an inducible Tet-On system way.

The results demonstrated that CBD (100 nM and 10 µM) decreased the expression of AT8 and total tau proteins, activating autophagy, evidenced by increased expression of light chain 3-II (LC3-II) protein and formation of autophagosomes.

Furthermore, the cannabinoid compounds CBD, ACEA (CB1 agonist) and GW-405,833 (CB2 agonist) decreased the fluorescence intensity of EGFP-Tau WT; and when chloroquine, an autophagic blocker, was used, there was a reversal in the fluorescence intensity of EGFP-Tau WT with CBD (1 and 10 µM) and GW-405,833 (2 µM), demonstrating the possible participation of autophagy in these groups.

Thus, it was possible to conclude that CBD induced autophagy in EGFP-Tau WT cells which increased tau degradation, showing its possible neuroprotective role. Hence, this study may contribute to a better understanding of how cannabinoids can modulate autophagy and present a potential therapeutic target in a neurodegeneration model.”

https://pubmed.ncbi.nlm.nih.gov/39900844/

“CBD induces autophagy promoting tau clearance in an in vitro model of tauopathy. Moreover, CBD, ACEA and GW-405,833 decreased tau expression, which was reversed by chloroquine indicating that autophagy participates in tau clearance.

Our results support the relevance of cannabinoid compounds in the autophagic process involved in the degradation of accumulated tau, which has been associated with several neuropathies. Therefore, autophagy is a potential therapeutic target of cannabinoids in neurodegenerative diseases.”

https://link.springer.com/article/10.1007/s12640-025-00729-3

GPR55 in the tumor microenvironment of pancreatic cancer controls tumorigenesis

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“Background: The G protein-coupled receptor 55 (GPR55) is part of an expanded endocannabinoid system (ECS), and plays a pro-tumorigenic role in different cancer models, including pancreatic cancer. Next to cancer cells, various cells of the immune tumor microenvironment (TME) express receptors of the ECS that critically determine tumor growth. The role of GPR55 in cancer cells has been widely described, but its role in the immune TME is not well understood.

Methods: We intended to uncover the role of GPR55 in tumor immunity in a model of pancreatic ductal adenocarcinoma (PDAC). To this end, a KPCY tumor cell line or a GPR55-overexpressing KPCY cell line (KPCY55) from murine PDAC were subcutaneously injected into wildtype (WT) and GPR55 knockout (KO) mice, and immune cell populations were evaluated by flow cytometry.

Results: Deficiency of GPR55 in the TME led to reduced tumor weight and volume, and altered the immune cell composition of tumors, favoring an anti-tumorigenic environment by increasing the number of CD3+ T cells, particularly CD8+ T cells, and the expression of PDL1 on macrophages. RNA-seq pathway analysis revealed higher T cell activity in KPCY55 tumors of GPR55 KO vs. WT mice. In addition, tumors from GPR55 KO mice displayed increased levels of T cell chemokines Cxcl9 and Cxcl10. Migration of T cells from GPR55 KO mice towards CXCL9 was increased in comparison to T cells from WT mice, suggesting that a CXCR3/CXCL9 axis was involved in T cell influx into tumors of GPR55 KO mice. Notably, anti-PD-1 immunotherapy increased tumor burden in WT mice, while this effect was absent in the GPR55 KO mice.

Conclusion: Our study indicates that GPR55 in TME cells may drive tumor growth by suppressing T cell functions, such as migration, in a model of PDAC, making it an interesting target for immunotherapies.”

https://pubmed.ncbi.nlm.nih.gov/39885986/

“Our study indicates that GPR55 in TME cells may drive tumor growth by suppressing T cell functions, such as migration, in a model of PDAC, making it an interesting target for immunotherapies.”

https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1513547/full

“GPR55 – a putative “type 3″ cannabinoid receptor in inflammation”

https://pubmed.ncbi.nlm.nih.gov/26669245/

“Therapeutic targeting of the tumor microenvironments with cannabinoids and their analogs: Update on clinical trials”

https://pubmed.ncbi.nlm.nih.gov/37146933/

“Anti-proliferative and apoptotic effect of cannabinoids on human pancreatic ductal adenocarcinoma xenograft in BALB/c nude mice model”

https://pubmed.ncbi.nlm.nih.gov/38499634/

“Antitumor Effects of Cannabinoids in Human Pancreatic Ductal Adenocarcinoma Cell Line (Capan-2)-Derived Xenograft Mouse Model”

https://pubmed.ncbi.nlm.nih.gov/35937289/

“Cannabinoid improves survival rates of mice with pancreatic cancer”

https://medicalxpress.com/news/2018-07-cannabinoid-survival-mice-pancreatic-cancer.html