Category Archives: Endocannabinoid System

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


Age differences in endocannabinoid tone are ameliorated after recent cannabis use

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“An age-related decline in endocannabinoid system (ECS) activity may contribute to conditions such as chronic pain and Alzheimer’s disease. Although cannabis is increasingly used by older adults to alleviate age-related conditions, it remains unclear how cannabinoids affect ECS activity across the lifespan.

The present study assayed levels of seven endocannabinoids (AEA, 2-AG, DEA, LEA, PEA, SEA, and OEA) in a sample of adults (N = 142; younger 21-24 years, n = 38; midlife 25-54, n = 73; older 55-71, n = 31) assayed before cannabis use (baseline [pre-use]) and ~ 1 h after flower or ~ 2 h after edible cannabis use.

At baseline, older adults exhibited lower AEA and DEA than younger adults, and lower LEA than midlife adults.

Acute cannabis use increased AEA, DEA, LEA, PEA, SEA, and OEA across all age groups (all p < .001). 2-AG showed no increase. For AEA and DEA, increases were larger in older adults (Time×Age).

These findings indicate broad endocannabinoid elevations after cannabis use regardless of age, alongside age-related differences at baseline and in acute responses.”

https://pubmed.ncbi.nlm.nih.gov/41580496

https://www.nature.com/articles/s41598-025-27618-1

Cannabidiol-Ion Channel Interactions Represent a Promising Preventive and Therapeutic Strategy in Hepatocellular Carcinoma

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“Hepatocellular carcinoma (HCC) is the main type of liver cancer and one of the malignancies with the highest mortality rates worldwide. HCC is associated with diverse etiological factors including alcohol use, viral infections, fatty liver disease, and liver cirrhosis (a major risk factor for HCC). Unfortunately, many patients are diagnosed at advanced stages of the disease and receive palliative treatment only. Therefore, early markers of HCC and novel therapeutic approaches are urgently needed.

The endocannabinoid system is involved in various physiological processes such as motor coordination, emotional control, learning and memory, neuronal development, antinociception, and immunological processes. Interestingly, endocannabinoids modulate signaling pathways involved in cell survival, proliferation, apoptosis, autophagy, and immune response.

Consistently, several cannabinoids have demonstrated potential antitumor properties in experimental models.

The participation of metabotropic and ionotropic cannabinoid receptors in the biological effects of cannabinoids has been extensively described. In addition, cannabinoids interact with other targets, including several ion channels. Notably, several ion channels targeted by cannabinoids are involved in inflammation, proliferation, and apoptosis in liver diseases, including HCC.

In this literature review, we describe and discuss both the endocannabinoid system and exogenous phytocannabinoids, such as cannabidiol and Δ9-tetrahydrocannabinol, along with their canonical receptors, as well as the cannabidiol-targeted ion channels and their role in liver cancer and its preceding liver diseases. The cannabidiol-ion channel association is an extraordinary opportunity in liver cancer prevention and therapy, with potential implications for several environments that are for the benefit of cancer patients, including sociocultural, public health, and economic systems.”

https://pubmed.ncbi.nlm.nih.gov/41562849

“The endocannabinoid system (ECS) plays a crucial role in the development and functioning of several biological systems. Classically, the endocannabinoid system comprises receptors, endogenous ligands, and enzymes that synthesize, transport, and degrade such ligands. ECS regulates many biological processes, both in normal conditions like brain function, neurotransmitter release, sleep regulation, appetite, movement, and coordination, as well as pathological states such as neurodegenerative disorders, headaches, chronic pain, anxiety, depression, and cancer, among others.

Accordingly, pharmacological modulation of the endocannabinoid system may be a potential target for preventing disease progression or enhancing symptom relief in multiple conditions, including cancer “

“Dysregulation of voltage-gated sodium channels causes the development of several diseases. CBD is a non-selective Nav1.1–1.7 sodium channel inhibitor and is effective in the treatment of epilepsy.”

“Exploiting the cannabidiol-ion channel-transporters association represents an extraordinary opportunity for liver cancer prevention and therapy, which may help to reduce the high mortality from this malignancy and to involve sociocultural, public health, regulatory, and economic systems.”

“Taken together, preclinical, epidemiological, and clinical data converge to support CBD as a promising candidate for the prevention and management of liver diseases and HCC, with potential implications for sociocultural, public health, and economic systems.”

https://www.mdpi.com/1873-149X/33/1/8

The Evidence for Medical Cannabis in Chronic Musculoskeletal Pain Management

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“Chronic musculoskeletal pain (CMP) is a pervasive condition that can impair daily functioning and quality of life. Traditional pharmaceutical therapies, including non-steroidal anti-inflammatory drugs, gabapentinoids, and opioids, often yield suboptimal results and carry notable risks, such as adverse side effects and dependence.

Increasing interest has turned toward medical cannabis, particularly combined formulations of cannabidiol (CBD) and tetrahydrocannabinol (THC), as a potential alternative or complement to current pain management strategies.

Evidence suggests that cannabinoids interact with the endocannabinoid system to modulate nociception and inflammation, offering meaningful pain relief and possibly reducing opioid requirements.

However, heterogeneity in study designs, product formulations, and regulatory frameworks presents challenges in drawing definitive conclusions. Additionally, while most adverse effects, such as fatigue, dizziness, and mild cognitive changes, are generally reported as tolerable, concerns remain about long-term safety and standardization of dosing.

Taken together, the existing literature points to a promising role for medical cannabis in CMP management, underscoring the need for further high-quality research to establish best practices, clarify patient selection, and guide clinicians in safe and effective cannabinoid therapy.”

“This scoping review highlights the potential role of medical cannabis in managing musculoskeletal pain. Evidence suggests it may reduce pain, enhance well-being, and improve quality of life, particularly as an alternative or adjunct to opioids. Adverse effects are typically mild, supporting its use as a safer long-term option. However, data on long-term efficacy, especially for CBD, remain limited.

Given the risks of opioid dependence, cannabis offers a promising therapeutic alternative.”

https://surgicoll.scholasticahq.com/article/138573-the-evidence-for-medical-cannabis-in-chronic-musculoskeletal-pain-management