Category Archives: Endocannabinoid System

Plant-Derived Compounds: A Potential Treasure for Development of Analgesic and Antinociceptive Therapeutics

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“Pain is one of the most pervasive health problems associated with a negative impact on thinking, mood, psychological, and social communication.

The medicinal plants and their derived compounds have recently attracted great interest as potential candidates for defeating pain because of their worldwide safety, availability, and affordability.

This review was constructed to summarize all in vitro and in vivo studies and clinical trials regarding plant-derived compounds’ analgesic and antinociceptive effects. Further, we focus on structural aspects, molecular mechanisms, and pharmacological effects. A literature survey was performed in “PubMed,” “Science Direct,” and “Google Scholar,” using the keywords “Pain, Analgesic activity, Flavonoids, Phenolics, Medicinal plants, Volatile oils, Tannins, Saponins, Alkaloids” to assess the activities of each compound.

The main natural compounds studied were flavonoids, alkaloids, phenolic acids, lignans, anthraquinones, and volatile oils. Different in vitro studies utilized nucleus pulposus cells, VK2/E6E7, End1/E6E7, and LPS-stimulated RAW264.7 cells to assess analgesic effects. The frequently defined animal models of analgesic activity included acetic acid-induced abdominal constrictions, hot-plate test, tail-flick test, formalin test, complete Freund’s adjuvant-induced pain, and hind paw incisional surgery.

For the natural compounds described, the opioids, serotonergic, and cannabinoid receptors appeared to be the most promising targets for pain management. This review suggested a wealthy resource of natural compounds as analgesic and antinociceptive candidates for pharmacists and drug researchers to launch a new drug with promising efficacy and safety.”

https://pubmed.ncbi.nlm.nih.gov/41126401/

https://onlinelibrary.wiley.com/doi/10.1002/ptr.70113

The Cannabinoid System as a Potential Novel Target for Alcohol-Associated Liver Disease: A Propensity-Matched Cohort Study

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“Background: Alcohol-associated liver disease (ALD) is a leading cause of liver-related morbidity and mortality, yet effective therapeutic options remain limited. Preclinical data suggest that modulation of the hepatic endocannabinoid system, particularly via cannabidiol (CBD), may reduce alcohol-induced liver injury. Due to CBD’s limited clinical use, we sought to evaluate the association between cannabis use and ALD risk among patients with alcohol use disorder (AUD).

Methods: Using the TriNetX US Collaborative Network, we identified adult patients with AUD between 2010 and 2022. Three cohorts were constructed: cannabis use disorder (CUD), cannabis users without cannabis abuse or dependence (CU) and non-cannabis users (non-CU). Outcomes included ALD, hepatic decompensation and composite all-cause mortality over 3 years. Incidence and hazard ratios were calculated using Kaplan-Meier analysis and Cox regression.

Results: After matching, 33 114 patients were included in each of the CUD and non-CU groups. Compared to non-CU, CUD was associated with a lower risk of ALD (HR 0.60, 95% CI 0.53-0.67; p < 0.001), hepatic decompensation (HR 0.83, 95% CI 0.73-0.95; p =0.005) and all-cause mortality (HR 0.86, 95% CI 0.80-0.94; p < 0.001) among individuals with AUD. Although CU was associated with lower risks of ALD, its risks of hepatic decompensation and all-cause mortality were similar to those of the non-CU cohort with AUD.

Conclusion: In this propensity-matched cohort study of patients with AUD, cannabis use was associated with a reduced risk of ALD, with the greatest risk reduction seen in patients with CUD compared to CU and non-CU. Our findings suggest that modulation of cannabinoid receptors may offer a new target for the development of pharmacological therapies for ALD.”

https://pubmed.ncbi.nlm.nih.gov/41117396/

  • “Cannabis use was linked to lower risks of ALD, liver-related complications and death compared to non-cannabis users.
  • These findings suggest the cannabinoid system may represent a promising therapeutic target for ALD.”

https://onlinelibrary.wiley.com/doi/10.1111/liv.70401

The endocannabinoid system as a therapeutic target in intestinal fibrosis

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“Intestinal fibrosis is a common and serious complication of inflammatory bowel diseases, often leading to strictures that require endoscopic or surgical intervention.

Despite advances in anti-inflammatory therapies, effective antifibrotic treatments is currently not available. Therefore, new treatment methods for intestinal fibrosis are sought with the endocannabinoid system (ECS) as a potential therapeutic target.

Cannabinoid receptors 1 and 2 (CB1/2) are classic receptors of the ES involved in the modulation of intestinal inflammation and permeability of the mucosal barrier. Experimental evidence from liver and lung models suggests that CB1 receptor activation promotes fibrosis through enhancement of the TGF-β/Smad pathway, interaction with the renin-angiotensin system, and upregulation of profibrotic markers, such as collagen and α-SMA.

In contrast, CB2 receptor signaling appears to exert protective effects by limiting inflammation, fibroblast activation, and extracellular matrix deposition. Recent findings also suggest cross-talk between cannabinoid signaling and platelet-derived growth factor pathways, which are key drivers of myofibroblast proliferation and fibrogenesis. Although these mechanisms are well-established in hepatic, pulmonary and skin fibrosis, data from small and large intestine is scarce. However, direct evidence in intestinal fibrosis is scarce, representing a major knowledge gap.

Elucidating ECS mechanisms in the alimentary tract could enable targeted antifibrotic strategies, complement current therapies, and reduce progression to fibrostenotic disease.”

https://pubmed.ncbi.nlm.nih.gov/41111512/

“The ECS is widespread in the human body, which proves its many functions in the body. Due to its presence in the digestive system and immune cells, it can influence the modulation of inflammation and the process of fibrosis in IBD. Numerous studies, both in animal models, cell cultures and in human tissue, show that the activation or inhibition of individual elements of the ECS can affect the process of intestinal fibrosis. Hence, the ECS may be a potential target aiming at the fibrosis reduction.”

https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2025.1669951/full

The Endocannabinoid System in the Development and Treatment of Obesity: Searching for New Ideas

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“Obesity is a complex, multifactorial disease and a growing global health challenge associated with type 2 diabetes, cardiovascular disorders, cancer, and reduced quality of life. The existing pharmacological therapies are characterized by their limited number and efficacy, and safety concerns further restrict their utilization.

This review synthesizes extensive knowledge regarding the role of the endocannabinoid system (ECS) in the pathogenesis of obesity, as well as its potential as a therapeutic target. A thorough evaluation of preclinical and clinical data concerning endocannabinoid ligands, cannabinoid receptors (CB1, CB2), their genetic variants, and pharmacological interventions targeting the ECS was conducted.

Literature data suggests that the overactivation of the ECS may play a role in the pathophysiology of excessive food intake, dysregulated energy balance, adiposity, and metabolic disturbances.

The pharmacological modulation of ECS components, by means of CB1 receptor antagonists/inverse agonists, CB2 receptor agonists, enzyme inhibitors, and hybrid or allosteric ligands, has demonstrated promising anti-obesity effects in animal models. However, the translation of these findings into clinical practice remains challenging due to safety concerns, particularly neuropsychiatric adverse events.

The development of novel strategies, including peripherally restricted compounds, hybrid dual-target agents, dietary modulation of endocannabinoid tone, and non-pharmacological interventions, promises to advance the field of obesity management.”

https://pubmed.ncbi.nlm.nih.gov/41096816/

“Taken together, the growing body of evidence suggests that targeting the ECS, either pharmacologically or through lifestyle interventions, may open a new chapter in the prevention and treatment of obesity.”

https://www.mdpi.com/1422-0067/26/19/9549

Cardiovascular Effects of Cannabidiol: From Molecular Mechanisms to Clinical Implementation

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“Cannabidiol (CBD) and other phytocannabinoids are gaining attention for their therapeutic potential in cardiovascular disease (CVD), the world’s leading cause of death.

This review highlights advances in understanding the endocannabinoid system, including CB1 and CB2 receptors, and the mechanisms by which CBD exerts anti-inflammatory, antioxidative, vasoprotective, and immunomodulatory effects.

Preclinical and translational studies indicate that selective activation of CB2 receptors may attenuate atherogenesis, limit infarct size in ischemia-reperfusion injury, decrease oxidative stress, and lessen chronic inflammation, while avoiding the psychotropic effects linked to CB1.

CBD also acts on multiple molecular targets beyond the CB receptors, affecting redox-sensitive transcription factors, vascular tone, immune function, and endothelial integrity.

Early clinical trials and observational studies suggest that CBD may lower blood pressure, improve endothelial function, and reduce sympatho-excitatory peptides such as catestatin, with a favorable safety profile. However, limited bioavailability, small sample sizes, short study durations, and uncertainty about long-term safety present challenges to its clinical use. Further research is needed to standardize dosing, refine receptor targeting, and clarify the role of the endocannabinoid system in cardiovascular health.

Overall, current evidence supports CBD’s promise as an adjunct in CVD treatment, but broader clinical use requires more rigorous, large-scale studies.”

https://pubmed.ncbi.nlm.nih.gov/41096874/

“In summary, although cannabinoids have not yet reached clinical maturity for broad implementation in cardiovascular therapeutics, the underlying scientific evidence is promising, and preliminary findings are encouraging. Bridging the translational gap prudently will demand methodologically rigorous, multidisciplinary research efforts, ensuring that any future clinical claims are grounded in robust human evidence.”

https://www.mdpi.com/1422-0067/26/19/9610

Antiviral and Anti-inflammatory Effects of Cannabidiol in HIV/SIV Infection

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“Persistent reservoirs and chronic immune activation are hallmarks of HIV, despite the effectiveness of antiretroviral therapy (ART) in suppressing viral replication. Here, we use rhesus macaques and primary and induced pluripotent stem cell (iPSC)-derived human immune cells to evaluate the virologic and immunologic consequences of cannabidiol (CBD) exposure during HIV/SIV infection.

We show that CBD, in the absence of ART, suppresses viral replication and establishment of the viral reservoir to levels comparable with first-line therapies during acute SIV infection of rhesus macaques.

This antiviral effect of CBD extended to in vitro HIV infection of human macrophages, T cells, and microglia. Immunologically, we observe CBD slowed CD4+ T cell decline and polarization, decreased CD14+CD16+ monocyte expansion, and reduced interferon-inducible cytokine release in rhesus macaques. We identify comparable effects on cytokine production with in vitro CBD treatment of human macrophages, T cells, and microglia.

Importantly, we find CBD inhibits cytokines only when an immune response is elicited by HIV, suggesting it is not broadly immunosuppressive. Finally, we determine CBD regulates endocannabinoid receptors, modulators, and transporters and inhibits NF-κb and STAT1 activation when mediating its antiviral and anti-inflammatory effects.

These findings show beneficial effects of CBD in laboratory models of untreated HIV, thus placebo-controlled clinical trials to evaluate the safety and effectiveness of adjunctive CBD use with ART is warranted.”

https://pubmed.ncbi.nlm.nih.gov/41040324/

https://www.biorxiv.org/content/10.1101/2025.09.25.678534v1

Optimal Cannabinoid-Terpene Combination Ratios Suppress Mutagenicity of Gastric Reflux in Normal and Metaplastic Esophageal Cells

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“Background: Esophageal adenocarcinoma (EAC) frequently arises from chronic exposure to acid and bile reflux, with secondary bile acids, such as deoxycholic acid (DCA), contributing to its pathogenesis through mechanisms involving reactive oxygen species (ROS), oxidative DNA damage, and resistance to apoptosis. The human endocannabinoid system (ECS) regulates diverse anti-inflammatory, antioxidant, and analgesic pathways implicated in disease modulation. Despite its therapeutic promise, effective pharmacological activation of the ECS remains challenging.

Objectives: This study aimed to evaluate whether specific cannabinoid-terpene combinations targeting the ECS could attenuate the mutagenic and cytotoxic effects of bile acid-induced stress in esophageal cell models. Additionally, we assessed the clinical significance of ECS-related protein receptors in the progression of EAC.

Design: In vitro experimental models combined with clinical samples analyses.

Methods: We utilized in vitro models, including human esophageal epithelial cell lines exposed to DCA and a Barrett’s esophagus gastroesophageal reflux (GER) model subjected to low pH and a bile acid cocktail. Patient-derived samples were analyzed to investigate the clinical association of ECS pathway markers with EAC progression. Experimental models were treated with varying ratios of phyto-cannabinoids and terpenes. Endpoints included assessment of DNA damage, mitochondrial membrane potential, and ROS production to identify optimal compound combinations. Expression of ECS-related protein receptors was evaluated in clinical samples to elucidate their role in EAC development.

Results: A 1:5 ratio of cannabigerol (CBG) to Phytol (Phy) was found to significantly reduce DCA-induced DNA damage, preserve mitochondrial membrane potential, and decrease ROS levels. This combination also enhanced apoptosis in damaged cells and diminished mutagenicity. Analysis of patient samples revealed that the expression of the ECS-associated receptor protein CB1 correlated with EAC progression, suggesting a broader clinical role for ECS modulation in cancer prevention.

Conclusion: Modulation of the ECS through carefully selected cannabinoid-terpene ratios can mitigate bile acid-induced esophageal damage and may reduce carcinogenic progression. These findings support further in vivo investigations and raise the possibility of expanding cannabinoid-terpene therapeutics to other conditions involving similar pathogenic processes.”

https://pubmed.ncbi.nlm.nih.gov/41040236/

https://www.biorxiv.org/content/10.1101/2025.09.23.678062v1

New insights into the crosstalk between endocannabinoids and sphingosine-1-phosphate

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“This review aims at highlighting the interplay between the endocannabinoids (eCBs) anandamide and 2-arachidonoylglycerol, and sphingosine-1-phosphate (S1P) signaling. The eCBs and S1P are bioactive compounds that exemplify a paradigm of crosstalk among lipid signals, with profound implications for physiological processes and disease pathogenesis.

Cross-communication between eCBs and S1P occurs through multiple mechanisms: (i) receptor heterodimerization and co-regulation, (ii) mutual metabolic modulation, and (iii) integrated regulation of downstream effectors. The latter emerged as a key mechanism underlying the bidirectional interactions between eCBs and S1P, with functional overlaps that regulate several processes including inflammation, vascular function, and neuronal activity.

In addition, cannabis-derived compounds (such as cannabidiol) can influence eCBs and S1P signaling, calling for further research into their therapeutic exploitation.

Overall, the dynamic interplay between endogenous eCBs and S1P – as well as with exogenous cannabidiol – described here offers a compelling example of the complexity of interactions among bioactive lipids. A deeper mechanistic understanding of these relationships could pave the way to novel strategies in drug design and development, emphasizing the importance of integrated approaches in the study of bioactive lipid biochemistry.”

https://pubmed.ncbi.nlm.nih.gov/41033556/

“In conclusion, it seems apparent that eCB and S1P signaling pathways operate through interconnected networks of remarkable complexity. As yet, the biochemical crosstalk between these bioactive lipids remains incompletely understood, potentially limiting the therapeutic exploitation of these signals. Future strategies targeting the spatiotemporal dynamics of lipid transport – from intracellular trafficking to extracellular distribution – combined with selective receptor engagement, may unlock novel therapeutic opportunities that current approaches have not fully realized.”

https://www.jbc.org/article/S0021-9258(25)02633-X/fulltext

Cannabidiol attenuates diet-induced metabolic endotoxemia, neuroinflammation, and anxiety-like behaviors in male aged rats

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“Obesity and aging synergistically reinforce neuroinflammation and disruption of homeostatic mechanisms, triggering pathological behaviors such as increased anxiety.

Cannabidiol (CBD) has been reported to exert anxiolytic, anti-inflammatory, and neuroprotective effects, supporting the hypothesis that it may attenuate the detrimental consequences of obesity, even in aged animals.

To test this hypothesis, 18-month-old male Wistar rats were divided into four experimental groups: control + vehicle (CT + vehicle), CT + CBD, cafeteria diet + vehicle (CAF + vehicle) and CAF + CBD. The animals were fed their diets for 8 weeks. Oral treatment with CBD (15 mg/kg/day) or vehicle began in the 9th week and continued until the end of the experiment, concurrently with the ongoing diet.

We found that the CAF increased anxiety-like behaviors in the open field and elevated plus maze tests, while CBD mitigated these behaviors in the open field. Obesogenic diet also increased circulating levels of lipopolysaccharide, which were reduced by CBD. In the prefrontal cortex, CAF increased levels of interleukin-6 (IL-6), which were decreased by CBD. Additionally, CBD reduced the expression of tumor necrosis factor-α (TNF-α) and toll-like receptor 4 (TLR4). CAF feeding also caused a reduction in the main endocannabinoids, 2-Arachidonoylglycerol (2-AG) and anandamide (AEA). In the prefrontal cortex, CAF increased transcripts of cannabinoid receptor 1 (CB1) and reduced those of cannabinoid receptor 2 (CB2) and serotonin receptor 5-Hydroxytryptamine receptor 1A (5-HT1A). Moreover, levels of triggering receptor expressed on myeloid cells 2 (TREM2) were reduced by the diet.

These findings support the notion that obesity, through its metabolic and inflammatory consequences, exacerbates neuroinflammation and contributes to the dysregulation of the endocannabinoid system in aged animals. Notably, CBD demonstrated the ability to attenuate inflammatory markers and improve anxiety-like behavior, suggesting its potential as a therapeutic strategy to counteract obesity-induced neurobiological alterations in aging.”

https://pubmed.ncbi.nlm.nih.gov/41022293/

“CBD reversed systemic and central inflammatory effects of obesity.”

https://linkinghub.elsevier.com/retrieve/pii/S0889159125003630

Cannabis sativa Root Extract Exerts Anti-Nociceptive and Anti-Inflammatory Effects via Endocannabinoid Pathway Modulation In Vivo and In Vitro

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“Cannabis sativa root has traditionally been used to relieve pain and inflammation, but its pharmacological properties remain underexplored due to low levels of psychoactive cannabinoids.

This study aimed to investigate the anti-inflammatory and antinociceptive effects of the ethyl acetate fraction of Cannabis sativa root (CSREA) using in vivo rodent pain models. Mice were subjected to formalin and acetic acid-induced nociceptive tests, while rats were evaluated using a carrageenan-induced paw edema model.

CSREA significantly reduced pain-related behaviors in both early (0-10 min) and late phases (15-30 min) of the formalin test and decreased writhing responses in the acetic acid model. Notably, CSREA also improved survival rates following acetic acid injection. Inflammatory markers, including IL-6 and IL-1β, were significantly lowered in serum.

Furthermore, CSREA suppressed paw edema and redness in the carrageenan-induced rat model, demonstrating dose-dependent anti-inflammatory efficacy comparable to diclofenac. CSREA also downregulated pain-related gene expression (SCN9A, ASIC1A, TACR1) and regulated key enzymes involved in endocannabinoid metabolism (FAAH, MAGL, DAGL), suggesting its role in the molecular modulation of pain pathways.

These effects are likely mediated via modulation of the endocannabinoid system, particularly by rebalancing the CB1R/CB2R ratio. The findings suggest that CSREA holds promise as a natural therapeutic agent for managing pain and inflammation and warrants further investigation into its molecular mechanisms and long-term effects.”

https://pubmed.ncbi.nlm.nih.gov/41009431/

“This study provides evidence for the in vivo analgesic and anti-inflammatory effects and underlying mechanism of CSREA in vitro. Our results from the formalin and writhing tests demonstrate that CSREA significantly reduced nociceptive pain-related behaviors and inflammatory cytokine levels indicating strong anti-nociceptive properties in a dose-dependent manner. In addition, CSREA markedly reduced paw edema in the carrageenan-induced rat model, suggesting its potential as a natural product with anti-inflammatory activity. These effects are likely mediated through modulation of the endocannabinoid system, particularly by altering cannabinoid levels as demonstrated in the in vitro model.”

https://www.mdpi.com/1422-0067/26/18/8863