Category Archives: Endocannabinoid System

The dual roles of natural cannabidiol in combating oxidative stress and inflammation: A potential intestinal guardian

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“Cannabidiol (CBD), a non-psychoactive and non-addictive phytocannabinoid derived from Cannabis sativa L., has attracted increasing attention for its therapeutic potential in intestinal diseases.

Accumulating evidence indicates that CBD exerts prominent antioxidant and anti-inflammatory effects within the gastrointestinal tract. Oxidative stress and redox imbalance are key drivers of epithelial barrier dysfunction, chronic inflammation, and disease progression in disorders such as inflammatory bowel disease (IBD) and colorectal cancer (CRC).

This review focuses on the redox-related mechanisms underlying CBD’s intestinal protective actions, highlighting its ability to regulate reactive oxygen species (ROS) production, activate the Nrf2-Keap1 antioxidant pathway, and modulate redox-sensitive inflammatory signaling, including NF-κB and the NLRP3 inflammasome.

In parallel, CBD engages the endocannabinoid system (ECS) and related receptors to preserve epithelial barrier integrity, regulate gut microbiota composition, and modulate intestinal oxidative stress and inflammation. We further discuss emerging evidence linking CBD’s regulation in the gut to systemic effects along the gut-organ axis, including the gut-brain and gut-liver axes.

Overall, this review synthesizes current evidence on how CBD integrates redox modulation, inflammation control, and intestinal barrier protection, providing a mechanistic framework for its potential application in intestinal disease and health.”

https://pubmed.ncbi.nlm.nih.gov/41713221

“CBD, as a non-psychoactive phyto-CB, has demonstrated substantial therapeutic potential for gastrointestinal health. By modulating the ECS, CBD enhances intestinal barrier integrity, regulates GM composition, and mitigates oxidative stress and inflammation. These effects contribute to its promising role in treating oxidative stress-related gastrointestinal conditions and maintaining intestinal homeostasis.”

https://www.sciencedirect.com/science/article/pii/S2213231726000492?via%3Dihub

Altered endocannabinoid system gene expression in inflammatory bowel disease mucosa: New perspectives in inflammatory bowel disease management

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“Background: Inflammatory bowel disease (IBD) is a broad classification including various chronic inflammatory gastrointestinal conditions that comprises two main disorders: Crohn’s disease (CD) and ulcerative colitis (UC). The key components of the endocannabinoid system (ECS) are highly expressed within the gastrointestinal tract, playing a crucial role in maintaining homeostasis and providing protection against intestinal inflammation.

Aim: To investigate possible impairment of the genes belonging to ECS by analyzing their expression levels in IBD patients and controls.

Methods: The paired biopsies of endoscopically inflamed (IM) and noninflamed (NIM) colonic mucosa from 30 IBD-diagnosed patients (17 UC and 13 CD), and the colonic mucosa from 17 non-IBD controls, were collected and analyzed. The messenger RNA expression level of cannabinoid receptor (CNR) 1, CNR 2, diacylglycerol lipase alpha, diacylglycerol lipase beta, fatty acid amide hydrolase (FAAH), G protein-coupled receptor (GPR) 18, GPR55, monoglyceride lipase, peroxisome proliferator-activated receptor gamma (PPARG), and transient receptor potential cation channel, subfamily V, member 1 (TRPV1) was determined by quantitative polymerase chain reaction.

Results: Six out of the 10 investigated genes were found to be dysregulated in at least one comparison. Specifically, in IBD patients, FAAH, PPARG, and TRPV1 were significantly downregulated in IM compared to NIM (FAAH, P = 0.012; PPARG, P = 0.001; TRPV1, P = 0.032) and in IM compared to controls (FAAH, P < 0.001; PPARG, P < 0.001; TRPV1, P = 0.002). An opposite trend was reported for CNR2 and GPR55, which showed an upregulation in IM compared to NIM (CNR2, P = 0.005; GPR55, P = 0.001).

Conclusion: We found a significant impairment of the ECS in IBD patients. Further analyses on larger cohorts are needed for a better understanding of the potential of cannabinoids in managing IBD.”

https://pubmed.ncbi.nlm.nih.gov/41700170

“The role of ECS in gastrointestinal physiology and the exact involvement of this system in IBD are still under investigation. Given this, our preliminary findings of the impairment of analyzed ECS genes in the IBD mucosa may serve as a basis for more in-depth research in larger cohorts to better understand the potential of cannabinoids in the management of IBD. After the introduction of artificial intelligence in the multi-omics drug delivery pipeline, future therapeutic targets should emerge, allowing for an even more personalized approach to IBD patients.”

https://www.wjgnet.com/1948-5190/full/v18/i2/113576.htm?appgw_azwaf_jsc=pjmb6U0PmJ8Jhw6KK0wkG7dIIANmqb_h-_TRqMyZe5S0n2nN12xjj6IEXzXltFiMGkrPy5gdVTqeL9FpqEwxg2IRdQtlxGphrdrCTC-8UB5iTS-53eOUekwL8V6ddoD3rUPUEsVlA14gjfLy8jmezIuYPV2vjfZ-Qoy-hEGym4pY7k9iS4yH7a1n8E6oEldBMV5stbazp3UctrqNhXMRb1bGo8NvE8b14zuvRdlvOI8MhNFNMTV-JysZCgnImMJg1XC1kSYNzlziNr4LuxGaowrDxyFS9KaRq_rQ_cNEf6ip8MXlhXSmgIWPhdPyy1s0xQclW9zOboCaV9pRBR83KQ

Activation of Cannabinoid Receptor 1 Enhances Wound Healing by Promoting the Proliferative Phase

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“The mechanisms underlying wound healing mediated by cannabinoid receptor 1 (CB1)-known for its neuromodulatory functions-remain incompletely understood. Therefore, we investigated the impact of activating CB1 using specific agonists, both in vitro and in vivo, with a focus on wound healing.

In the in vitro study, fibroblasts were isolated and cultured from the dermis of human skin and treated with a CB1 agonist, 2-arachidonyl glyceryl ether (2-AGE). In the in vivo study, a mouse acute wound model was created using a skin biopsy punch and treated with the CB1 agonist arachidonoyl 2′-chloroethylamide (ACEA).

The in vitro study revealed that 2-AGE increased cell proliferation and differentiation, upregulated the expression of alpha-smooth muscle actin (α-SMA), N-cadherin, and vimentin, and enhanced cell migration as well as the synthesis of type I and III collagen and fibronectin in normal human dermal fibroblasts. The CB1 antagonist AM251 abolished 2-AGE-induced expression of α-SMA, type I collagen, and fibronectin. In vivo, ACEA treatment accelerated wound closure, increased expression of α-SMA, type I collagen, and fibronectin, and ultimately increased epidermal and dermal thickness.

Overall, these findings suggest that the activation of CB1 promotes wound healing and provides evidence for the therapeutic potential of CB1 agonists in wound treatment.”

https://pubmed.ncbi.nlm.nih.gov/41683598

“Recent research has highlighted the role of the endocannabinoid system (ECS) in skin physiology and repair.”

“Clinical evidence indicates that the topical application of Cannabis-Based Medicines (TCBMs) facilitates tissue repair and promotes complete wound closure in previously refractory wounds.”

“In conclusion, our findings support the hypothesis that CB1 receptor activation facilitates wound healing through both cellular and molecular mechanisms.”

“Thus, these findings strongly support the therapeutic potential of targeting specific agonists as a viable strategy to accelerate the proliferative or contractile phases and thereby enhance the rate of wound healing.”

https://www.mdpi.com/1422-0067/27/3/1171


Role of Endocannabinoid System Perturbation in Organophosphate-Mediated Metabolic Impairment and Neuroinflammation

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“Organophosphates have been used for decades as pesticides, insecticides and herbicides, both in agricultural and industrial settings. However, their toxic effects on multiple body systems limit their safety. The clinical presentation of organophosphate toxicity varies depending on the route and duration of exposure. Although most research is focused on their cholinergic toxicity, emerging evidence points to their crucial contribution to metabolic dysfunction, including Type 2 diabetes and neuroinflammation.

Beyond acetylcholinesterase inhibition, recent research highlights the potential role of organophosphates in disrupting endocannabinoid signalling, particularly by affecting endogenous ligands that modulate G protein-coupled receptors. This dysregulation may contribute to organophosphate-induced metabolic disturbances and inflammation.

This review aims to explore how chronic subtoxic exposure to organophosphates contributes to metabolic syndrome and neuroinflammation through disruption of insulin and endocannabinoid signalling. It highlights the role of the endocannabinoid system in mediating these effects and evaluates its potential as a therapeutic target in organophosphate-induced toxicity.”

https://pubmed.ncbi.nlm.nih.gov/41668464

Plain language summary

“Organophosphates (OPs), commonly used as pesticides, have been shown to adversely affect both metabolism and brain health by disrupting the endocannabinoid system (ECS), a critical regulatory network involved in inflammation, energy balance, and neural function. Chronic, low‐dose exposure to OPs can alter ECS enzymes and signalling pathways, contributing to insulin resistance, obesity and neuroinflammation. These metabolic disturbances may play a key role in the development of neurodegenerative outcomes associated with OP toxicity. This review aims to examine the interplay between OPs exposure and ECS disruption, emphasizing the ECS role in pathogenesis and its potential as a therapeutic target.”

https://onlinelibrary.wiley.com/doi/10.1111/bcpt.70198

The relationship between the cannabinoids and cardiac remodelling: A comprehensive review of pivotal mechanisms and emerging evidence

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“Cardiac remodelling and fibrosis after myocardial infarction or during chronic diseases, such as arterial and pulmonary hypertension or diabetes mellitus, continue to be the more important prognostic factors in determining survival, and so the search for effective anti-fibrotic interventions is an important target for research and therapy in cardiology.

It has been suggested that compounds with anti-inflammatory and antioxidant properties (such as cannabinoids) may represent interesting therapeutic alternatives, due to their ability to influence pro-fibrotic signalling and inhibit pathological extracellular matrix deposition in the heart.

This review describes the more important signalling pathways involved in cardiac fibrosis and some new concepts regarding the utility of cannabinoids and modulation of the endocannabinoid system (ESC) as therapeutic interventions against cardiac fibrosis.

The studies presented in this review suggest that specific cannabinoid type 2 receptor activation and peripheral cannabinoid Type 1 receptor blockade appear particularly promising.

The potential for the cardioprotective anti-fibrotic effects of cannabinoids and ECS modulators appears to lie in their high antioxidant and anti-inflammatory efficacy, which limits the progression of fibrotic lesions and restores normal regulation of molecular signalling pathways.”

https://pubmed.ncbi.nlm.nih.gov/41662725

“The studies presented in this review confirm that cannabinoids (especially CBD and β-CP) and modulating the activity of the ECS may be useful therapeutically in states of pathological cardiac remodelling and fibrosis; specific activation of CB2 receptors and peripheral blockade of CB1 receptors seems particularly promising as an adjuvant therapies.

In addition to their anti-fibrotic effects in the course of various diseases, it appears that cannabinoids may improve cardiac regeneration after MI and reduce infarct size, which, given the minimal ability of cardiomyocytes to proliferate after ischaemic damage, may represent a promising direction for modern regenerative medicine to restore the structural and functional integrity of the myocardium.

The greatest potential for the cardioprotective anti-fibrotic effect of cannabinoids and ECS modulators appears to lie in their high antioxidant and anti-inflammatory efficacy, which limits the progression of fibrotic changes and restores the normal regulation of molecular signalling pathways.”

https://bpspubs.onlinelibrary.wiley.com/doi/10.1111/bph.70347

Cannabinoids and skin cancer: Mechanistic insights, therapeutic potential, and translational perspectives

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“Skin cancer represents a significant global healthcare challenge, with rising incidence and persistent gaps in effective long-term management.

Recent evidence has identified the endocannabinoid system as an emerging therapeutic target offering novel pharmacological approaches for the prevention and treatment of various skin cancers.

Cannabinoids, through modulation of the endocannabinoid system, have demonstrated antitumor activity by inhibiting tumor proliferation, angiogenesis, invasion, and metastasis and by inducing apoptosis and autophagy in malignant cells.

This review synthesizes the most recent preclinical evidence on phytocannabinoids, endocannabinoids, and synthetic cannabinoids in melanoma and non-melanoma skin cancers, delineating receptor-dependent and receptor-independent mechanisms. Additionally, emerging cannabinoid-based delivery strategies, particularly cannabidiol formulations designed to enhance skin penetration and therapeutic efficacy, are critically examined. Despite encouraging preclinical findings, clinical translation remains limited by scarce skin-cancer-specific trials, variability in cannabinoid preparations, and uncertainties around dosing and safety. Consequently, robust mechanistic studies and well-designed clinical trials are required to validate cannabinoids’ therapeutic potential and guide their integration into future skin cancer treatment paradigms.”

https://pubmed.ncbi.nlm.nih.gov/41621140

“Cannabinoids show anticancer effects in melanoma and non-melanoma skin cancers.”

https://www.sciencedirect.com/science/article/pii/S0014480026000067?via%3Dihub


Cannabis sativa in the fight against drug-resistant bacteria and fungi

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“Drug resistance in bacteria and fungi is a global threat to public health. The purpose of this publication is to review the latest scientific achievements, mainly from 2020-2025, concerning the use of hemp compounds from Cannabis sativa in combating drug-resistant bacterial and fungal infections.

The literature review confirms that C.sativa, a plant with a documented centuries-old therapeutic history, is a rich source of cannabinoids and terpenes that combat drug-resistant bacteria: Mycobacterium tuberculosis, Pseudomonas aeruginosa, Staphylococcus aureus, Streptococcus pneumoniae, and fungi: Cryptococcus neoformans, as well as species from the Candida and Aspergillus.

The potential of hemp compounds is based on their activity in interacting directly with pathogens by disrupting cell membrane integrity, eradicating biofilm, having a bactericidal effect on bacterial spores, acting synergistically, affecting host inflammatory pathways, and the human endocannabinoid system.”

https://pubmed.ncbi.nlm.nih.gov/41607163

The role of the endocannabinoid system in managing neuropsychiatric symptoms in Alzheimer’s disease

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“The endocannabinoid system comprises cannabinoid receptors (CBRs) 1 & 2, endocannabinoids (eCBs) anandamide (AEA) and 2-arachidonoylglycerol (2-AG), and the enzymes that regulate their production and degradation.

ECS plays a significant role in both health and disease.

It influences neuronal and glial communications, neurotransmitter regulations, neuroinflammation, and behavioral alterations. Neuropsychiatric symptoms (NPS) are commonly seen in neurodegenerative conditions like Alzheimer’s disease (AD), apart from the core clinical diagnosis of dementia.

NPS consists of various disturbing symptoms, including anxiety, agitation, apathy, hallucinations, delusions, sleeping problems, appetite problems, and depression. In AD, up to 97% exhibit one or more NPS.

Emerging evidence from preclinical and clinical studies suggests that ECS is both a contributor to and a potential therapeutic target for managing NPS. This review explores ECS’s role in NPS and its therapeutic implications.”

https://pubmed.ncbi.nlm.nih.gov/41608471

“ECS is essential for regulating a range of behaviors and undergoes notable changes during the progression of AD, particularly through modulation of the CB1R and CB2Rs and their endocannabinoids. Further placebo-controlled, randomized clinical trials are needed to confirm the efficacy of cannabinoid receptor-targeting therapies in managing NPS in AD.”

https://www.frontiersin.org/journals/psychiatry/articles/10.3389/fpsyt.2025.1709266/full


Exploring cannabinoid modulation on autophagy mechanisms in Alzheimer’s disease: a review

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“Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the accumulation of toxic protein aggregates in the brain, leading to brain cell death and cognitive impairment. Central to AD pathogenesis is the autophagy pathway, a crucial cellular self-digestion process.

Cannabinoids, the fundamental phytochemical compounds derived from the Cannabis sativa plant, have been demonstrated to exhibit neuroprotective qualities when used as a treatment at microdoses.

However, the impact of multi-cannabinoid treatments on autophagy induction and subsequent cell survival in AD in vitro models remains uncertain. This review seeks to explore the potential of a multi-cannabinoid treatment strategy in enhancing neuronal cell survival through autophagy activation within an AD in vitro model.

The proposed approach involves a combination of cannabinoids in their potential to upregulate autophagy mechanisms, potentially supporting neuronal cell resilience. By unravelling the mechanistic link between autophagy, cannabinoid treatment, and neuronal viability, this review aims to elucidate how cannabinoids influence neuronal function and survival at a cellular and molecular level. By offering insights into the exploitation of the endocannabinoid system, this review contributes to the development of novel cannabinoid-based treatment avenues for AD. This pursuit aligns with the broader objective of addressing the debilitating effects of AD on the quality of life for those affected.”

https://pubmed.ncbi.nlm.nih.gov/41601969

“Emerging evidence, including a recent case report, suggests that cannabinoid microdosing may offer a potential strategy for reducing AD-related symptoms while minimizing adverse effects.”

“Pharmacokinetic data further indicate that multi-cannabinoid formulations, particularly those combining THC and CBD, add additional minor cannabinoids, may provide enhanced therapeutic efficacy and improved safety profiles compared to monotherapy.”

https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2025.1748368/full


The Effect of Cannabidiol on Nociceptive Behaviour and the Endocannabinoid System in an Incisional Wound Model

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“Background/Objectives: Wound-related pain is a common, yet inadequately managed condition, and new therapeutic strategies are warranted. Limited data suggests that phytocannabinoids and cannabis may alleviate wound-related pain; however, further studies are required. This study investigated the effects of systemic administration of cannabidiol (CBD) on nociceptive behaviour following dorsum incision and on the endocannabinoid system. 

Methods: Male Sprague-Dawley rats (150-200 g on arrival, n = 9/group) underwent a 1.2 cm incision on the hairy skin of the dorsum or sham procedure. Back and hind paw mechanical withdrawal thresholds were assessed at baseline and post-surgery/sham days (PSDs) 1, 4, 7, and 8 using manual and electronic von Frey tests, respectively. On PSD 8, the effect of a single acute administration of CBD (3, 10, or 30 mg/kg, i.p.) on mechanical hypersensitivity in the dorsum and hind paws was assessed. The levels of endocannabinoids and N-acylethanolamines in the plasma and discrete brain regions following CBD administration were analysed. 

Results: Robust mechanical hypersensitivity was evident in the dorsum and hind paws following the incision. CBD (3 mg/kg) partially attenuated primary mechanical hypersensitivity in the dorsum, in a site- and dose-specific manner. CBD had no effect on secondary mechanical hypersensitivity. CBD did not alter the levels of endocannabinoids or N-acylethanolamines, but in rats that received CBD (3 mg/kg), levels of 2-AG were lower in the contralateral amygdala and levels of AEA were higher in the contralateral lumbar spinal cord, compared to the ipsilateral sides. 

Conclusions: These data provide evidence for antinociceptive effects of CBD in a model of incisional wound-related pain. Further research on CBD’s mechanism(s) of action is warranted. The potential antinociceptive effects of other phytocannabinoids in this model should also be investigated.”

https://pubmed.ncbi.nlm.nih.gov/41599645

“Cannabidiol (CBD) is a phytocannabinoid found in Cannabis sativa L.”

“These results indicate dose- and site-specific antinociceptive effects of CBD in a rat model of incisional wound-related pain, providing preclinical evidence to support the contention that CBD may have therapeutic potential for alleviating incisional wound-related pain.”

“These results also indicate that investigation of the potential antinociceptive effects of other phytocannabinoids in this model of incisional wound-related pain is warranted.”

https://www.mdpi.com/1424-8247/19/1/43