Category Archives: Endocannabinoid System

Exploring the impact of chronic intermittent EU-GMP certified Cannabis sativa L. therapy and its relevance in a rat model of aging

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“Background: Aging is a multifaceted process marked by the progressive accumulation of cellular damage in various tissues, resulting in a decline in physiological functions. The primary aim of aging research is to identify compounds that can delay or mitigate these detrimental changes. As cannabis legalization becomes more widespread and with limited empirical studies on its effects in the aging human population, there is a pressing need for research into the impact of Cannabis and cannabinoids on healthy aging and age-related diseases.

Methods: Our study aims to evaluate the effects of chronic, intermittent exposure, defined as 6 weeks of use of EU-GMP certified Cannabis sativa L. (Cannabixir® Medium Flos) administration, dosed at 6.25 and 25 mg/kg on neurobiological changes in naturally aged rats and its potential efficacy in mitigating age-related alterations. The impact of the Cannabixir® Medium Flos was assessed through clinical, histopathological, immunohistochemical, and behavioral evaluations.

Results: Cannabixir® Medium Flos was found to be generally safe, with no significant effects on motor performance and a neutral effect on anxiety-like behavior. Histological analysis revealed that the hippocampus of aged rats treated with this compound-an area known for its abundance of endocannabinoids and cannabinoid receptor type 1-exhibited characteristics similar to those observed in young adult rats. Additionally, the study suggests that chronic, intermittent treatment with Cannabixir® Medium Flos may modulate astrocyte function, reduce neuroinflammation, and potentially influence cell proliferation and neuronal apoptosis in a dose-dependent manner. However, these preliminary findings should be interpreted with caution, as the study’s exploratory nature.

Conclusions: These preliminary findings suggest that cannabinoid therapy targeting the endocannabinoid system may offer potential neuroprotective benefits in aging.

While the study offers valuable preclinical insights into the effects of an EU-GMP-certified cannabinoid receptor ligand in reducing age-related cognitive decline, these effects are likely mediated by a combination of mechanisms. Given the complex phytochemical composition, the observed outcomes cannot be attributed exclusively to cannabinoid receptor activation. Accordingly, these findings should be interpreted with caution, and further studies employing more targeted methodologies are needed to elucidate the underlying mechanisms.”

https://pubmed.ncbi.nlm.nih.gov/40770774/

“Targeting the ECS could be a promising strategy for developing therapies aimed at promoting healthy aging and longevity.”

https://jcannabisresearch.biomedcentral.com/articles/10.1186/s42238-025-00313-8

Transient CB2 receptor activation triggers irreversible luminal differentiation via chromatin remodeling in breast cancer

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bioRxiv

“Cellular plasticity enables cancer cells to escape therapy by adopting stem-like or alternate lineage states. Here, we identify a mechanism by which cannabinoid receptor 2 (CB2R) activation promotes irreversible lineage commitment in breast cancer. Using patient-derived and murine organoids, we show that brief, low-dose exposure to CB2R agonists—either phytogenic or synthetic—induces a basal-to-luminal transition, accompanied by reduced self-renewal, invasiveness, and tumor-initiating potential. These changes are retained under conditions that normally promote dedifferentiation, including fibroblast co-culture, immune pressure, and mechanical shear stress.

Mechanistically, CB2R engagement initiates a transient chromatin remodeling program, marked by early expression of pluripotency-associated genes followed by silencing and differentiation commitment. This epigenetically stabilized state renders tumor cells more responsive to tamoxifen and limits the emergence of resistant clones.

Our findings uncover a previously unrecognized role for CB2R in modulating cancer cell identity and suggest new opportunities to constrain tumor plasticity by directing differentiation through a drug-responsive pathway.”

https://www.biorxiv.org/content/10.1101/2025.07.29.667375v2

CB2R-induced differentiation epigenetically restrains cancer plasticity enabling adaptive therapy

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“Tumor adaptability relies on the ability of cancer cells to dedifferentiate and acquire stem-like features, fueling therapeutic resistance and metastasis. Differentiation therapy aims to reprogram tumor cells into more mature, less aggressive states to counteract this plasticity.

Here, we identify cannabinoid receptor 2 (CB2R) as a novel therapeutic target that promotes sustained differentiation in breast cancer. Using tumor-derived organoids from both mouse models and patient biopsies, we show that brief, low-dose exposure to phytogenic or synthetic CB2R ligands induces a basal-to-luminal switch, suppresses stemness, and reduces invasiveness and self-renewal. These phenotypic changes are associated with decreased tumor initiation and aggressiveness in vivo .

Transcriptomic profiling reveals that CB2R activation initiates transient chromatin remodeling and epigenetic reprogramming, resulting in a stably differentiated state. Importantly, CB2R-driven differentiation sensitizes tumor cells to tamoxifen, enabling lower therapeutic doses with improved efficacy-supporting the principles of adaptive therapy aimed at long-term disease control.

Our findings position CB2R modulation as a promising non-cytotoxic strategy to restrict cancer plasticity and enhance the effectiveness of existing breast cancer treatments.”

https://pubmed.ncbi.nlm.nih.gov/40766353/

Anti-Inflammatory Effects of Cannabinoids in Therapy of Neurodegenerative Disorders and Inflammatory Diseases of the CNS

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“Many neurodegenerative diseases are associated with immune system disorders, while neurodegenerative processes often occur in inflammatory conditions of the Central Nervous System (CNS).

Cannabinoids exhibit significant therapeutic potential due to their dual ability to modulate both neural and immune functions. These compounds have a broad spectrum of action, allowing them to target multiple pathological mechanisms underlying neurodegenerative and inflammatory CNS diseases.

The present review outlines the therapeutic potential of cannabinoids, with a focus on their anti-inflammatory properties, in the treatment of neurodegenerative conditions, including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and Huntington’s disease, as well as inflammatory CNS disorders like multiple sclerosis and HIV-associated dementia.”

https://pubmed.ncbi.nlm.nih.gov/40724820/

“Cannabinoids, the active compounds derived from Cannabis sativa, are attracting increasing interest for their therapeutic potential in neurodegenerative disorders (Parkinson’s disease, Alzheimer’s disease, and Huntington’s disease) and inflammatory CNS conditions (multiple sclerosis and HIV-associated dementia).

Their multimodal mechanisms of action include the following: (1) modulating pathological protein aggregation and mitochondrial dysfunction, and (2) exerting neuroprotective and anti-inflammatory effects which are mediated through microglial regulation.

The neurodegenerative diseases and inflammatory CNS disorders discussed in this work represent a serious challenge for healthcare systems due to their complex etiology or pathophysiology, severe symptoms, and the limited effectiveness of existing treatments. Consequently, improving therapeutic strategies for these disorders remains a priority.

Many studies suggest that pharmacological modulation of the endocannabinoid system could influence neurodegenerative processes, providing a basis for further research into cannabinoid-based therapies. In particular, the inhibition of FAAH in the endocannabinoid system has emerged as a potential therapeutic approach to control neuroinflammatory processes.”

https://www.mdpi.com/1422-0067/26/14/6570

Cannabinoid Receptor Modulation in Focal Ischemic Stroke: A Systematic Review and Meta-Analysis of Infarct Volume and Behavioral Deficits in Animal Models

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“Introduction: Stroke is a leading cause of morbidity and mortality worldwide, with ischemic stroke accounting for the majority of cases. The endocannabinoid system (ECS), comprising cannabinoid receptors CB1 and CB2, has been implicated in regulating physiological processes and has shown potential neuroprotective effects in preclinical studies. However, the precise impact of cannabinoid receptor modulation on stroke outcomes remains unclear. This systematic review and meta-analysis aimed to evaluate the impact of cannabinoid receptor modulation on infarct volume and behavioral deficits in animal models of focal ischemic stroke, with a primary focus on infarct outcomes.

Method: A comprehensive literature search was conducted following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, yielding 29 eligible studies for inclusion.

Results: The analysis revealed significant reductions in infarct volume with cannabinoid agonists, particularly CB1 and CB2 agonists, indicating their potential as neuroprotective agents. Subgroup analyses further highlighted specific agonists, such as ACEA and KN38-72717, as particularly effective in reducing infarct volume. Additionally, CB antagonists, particularly CB1 antagonists, such as SR141716, showed promising results in reducing infarct volume. Although improvements in neurological scores were observed with both agonists and antagonists, statistical significance was not reached, indicating the need for further investigation.

Conclusion: These results highlight the potential of cannabinoid receptor modulation as a neuroprotective strategy in ischemic strokes and underscore the need for further research to elucidate the underlying mechanisms and optimize therapeutic approaches.”

https://pubmed.ncbi.nlm.nih.gov/40706582/

https://karger.com/mpp/article/doi/10.1159/000547277/930925/Cannabinoid-Receptor-Modulation-in-Focal-Ischemic

Ageing, Neurodegeneration and the Endocannabinoid System

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“Numerous studies carried out in the last 30-40 years have strongly demonstrated that the endocannabinoid system exerts important modulatory functions in the central nervous system (CNS). These neuromodulatory functions encompass the whole life of animals, with specific activities during neurodevelopment (prenatal, postnatal and adolescent periods), adulthood and possibly senescence too. However, this is the life stage less investigated in relation with the endocannabinoid system to date.

In the aged brain, the activity of this system appears to be altered, which contributes to subtle impairments that typically occur during ageing in learning and memory, motor behaviour, social behaviour and other neurobiological functions. Some of the changes in endocannabinoid activity may represent a process to attenuate ageing-related impairment in the brain function, which is consistent with its role as a pro-homeostatic system.

An important observation is that these alterations become extreme when normal brain ageing acquires pathological characteristics, as happens in chronic neurodegenerative disorders. This includes the cannabinoid type-1 (CB1) receptor downregulation or impairment in its signalling and the increase in endocannabinoid-inactivating enzymes, both hypothesised to contribute to pathogenic events. By contrast, elevated levels of endocannabinoids due to a reduced Fatty acid amide hydrolase (FAAH) and monoacyl glycerol lipase (MAGL) expression and the upregulation of cannabinoid type-2 (CB2) receptors may in turn serve as endogenous pro-homeostatic adaptations against brain impairment.

This review synthesises information on: (i) subtle alterations in the endocannabinoid system in the senescent brain in the absence of pathology, with the purpose of demonstrating that these alterations are representative of the extreme changes experienced by this system in the brain pathological ageing; and (ii) the development of neuroprotective therapies based on the pharmacological management of specific endocannabinoid targets to combat neurodegenerative pathologies.

Together, research in this area comes at a critical time as global lifespan is increasing, incidence of age-related neurodegenerative disorders is expanding, and the unmet need for efficacious neuroprotective treatments is a public health necessity.”

https://pubmed.ncbi.nlm.nih.gov/40707697/

https://link.springer.com/chapter/10.1007/7854_2025_597

Role of the Endocannabinoid System in Fibromyalgia

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“Fibromyalgia is a chronic disease marked by extensive musculoskeletal pain, persistent fatigue, and cognitive impairments. Despite its high prevalence, the underlying pathological mechanisms of fibromyalgia are still not fully elucidated.

Emerging research has identified the endocannabinoid system as an essential factor in modulating pain and other symptoms related to fibromyalgia. The endocannabinoid system plays a key role in many physiological processes such as pain perception, mood regulation, and inflammation.

This review provides a powerful analysis of the principal aspects of fibromyalgia and examines the evidence regarding the involvement of the endocannabinoid system in this condition, focusing on its influence on pain modulation. Moreover, the dysregulation of the endocannabinoid system in fibromyalgia patients will be examined, with an assessment of how variations in endocannabinoid levels and receptor activity may contribute to the clinical manifestations of the condition.

A better knowledge of this physiological system could lead to the development of novel strategies for managing fibromyalgia.”

https://pubmed.ncbi.nlm.nih.gov/40699629/

https://www.mdpi.com/1467-3045/47/4/230

Inflammatory bowel disease patients believe cannabis and cannabidiol oil relieve symptoms

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“Background: Patients with Inflammatory bowel disease (IBD) often seek alternative therapies for symptom management. This study investigates the perceptions, consumption patterns, and reported outcomes of cannabis and cannabidiol (CBD) oil use among IBD patients and controls.

Methods: A 37-question survey was administered to 139 participants (IBD patients, n = 93; control/non-IBD participants, n = 33) to assess usage frequency and beliefs regarding cannabis and CBD oil as treatment for IBD. The survey also evaluated the impact of these substances on IBD symptoms, quality of life, and opioid use.

Results: Cannabis consumption was higher in IBD patients (57, 53.8%) than controls (15, 45.5%) with both groups strongly supporting medical cannabis use (IBD; 92, 86.8% vs. controls; 29, 84.9%). Most IBD patients believed cannabis (67, 63.2%), CBD oil (60, 56.6%), corticosteroids (77, 73.3%), and biologics/immunosuppressants (85, 81.0%) had a somewhat-extremely beneficial effect in relieving IBD symptoms. Over 50% of IBD cannabis users reported relief from abdominal pain, other pain, stress, anxiety, depression, and nausea/vomiting, with Crohn’s disease patients experiencing significantly more relief than ulcerative colitis patients for certain symptoms (p < 0.05). Notably, 19.4% of IBD patients reported decreased opioid use, and 14.5% reported induced remission with cannabis or CBD oil.

Conclusions: Consumption of cannabis and CBD oil was perceived as beneficial for relieving IBD, with many reporting significant symptom relief from using these substances. The strong support of cannabis and CBD oil as medical treatments and therapeutic effects highlights the potential for cannabis and CBD oil as treatments in IBD.”

https://pubmed.ncbi.nlm.nih.gov/40687272/

“Recent preclinical studies have suggested that cannabinoids, including CBD and THC, may reduce gastrointestinal inflammation and modulate intestinal motility. The presence of cannabinoid receptors in the gut, along with the anti-inflammatory effects of some cannabinoids, has led researchers to explore the potential for therapeutic applications of cannabis in the treatment of IBD.”

“Animal studies of the chemistry and physiology of cannabinoids have shown potential anti-inflammatory, antidiarrheal, and nociceptive-limiting effects, paralleling the growing interest in cannabis as a treatment option for IBD.

Human studies have also indicated that there may be a benefit in controlling IBD symptoms and improving quality of life. Additionally, anecdotal reports and observational studies have highlighted potential benefits in reducing disease activity and managing symptoms like abdominal pain, cramping, joint pain, and diarrhea.”

https://www.academia.edu/2994-435X/2/2/10.20935/AcadMed7773

How THC works: Explaining ligand affinity for, and partial agonism of, cannabinoid receptor 1

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“Interaction with cannabinoid receptor 1 (CB1) partially determines the bioactivity of the phytocannabinoids. Consequently, there has also been significant effort directed toward preparing synthetic cannabinoids with either enhanced agonistic or antagonistic activity against this receptor. The design process of these molecules, and the identification of off-target effects at this receptor for molecules designed to target other proteins, would be aided by a reliable computational tool that can accurately predict binding. Furthermore, although the mechanism of CB1 agonism is understood, the conformational behavior that underlies the molecular mechanism of partial agonism is unclear. In this report, we provide a correction for calculating a ligand’s affinity to the orthosteric site of CB1 to account for their partition into membranes, use this to register the predicted affinity (high and low) of cannabinoids, and discuss how a mechanism for THC partial agonism arises natively from the model consistent with experimental data.”

https://pubmed.ncbi.nlm.nih.gov/40687805/

“We developed a model for predicting binding affinity and activity of cannabinoids which can be used for further drug design efforts in the design of new cannabinoid-based ligands.”

https://www.cell.com/iscience/fulltext/S2589-0042(25)00967-8?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS2589004225009678%3Fshowall%3Dtrue

Integrated multi-omic profiling uncovers endocannabinoid system as a driver of nerve agent-induced cognitive dysfunction in guinea pigs

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“Soman, a highly lethal organophosphorus compound (OP), is notorious for its rapid induction of irreversible acetylcholinesterase binding through accelerated aging. Although subacute soman exposure has been specifically implicated in cognitive deficits, the molecular pathways driving these impairments remain poorly characterized, highlighting a significant research gap.

This study aims to comprehensively elucidate the effects of soman exposure on cognitive impairment by analyzing proteome and lipidome alterations in the hippocampal tissue of guinea pigs administered a sublethal dose (11 µg/kg) of soman. A molecular network based on lipidomic and proteomics data was constructed to investigate the key molecules.

The study demonstrates that subcutaneous exposure to low-dose soman for 14 consecutive days in guinea pigs impairs learning and memory. We further observed that soman exposure induces damage to both the hippocampal neurons and the mitochondrial ultrastructure in the brains of these animals.

The study revealed that subacute soman exposure significantly altered the endocannabinoid system, characterized by disrupted biosynthesis and metabolism of 2-arachidonoylglycerol (2-AG), with a significant down-regulation of 2-AG lipid metabolism pathways, as well as a significant up-regulation of cannabinoid receptor 1 (CB1R) pathways. Notably, the disruption of 2-AG biosynthesis and metabolism is primarily attributed to the upregulation of the activities of three key enzymes, DAGLα, MAGL, and ABHD6. The activation of CB1R negatively feedback-regulate the cAMP/PKA pathway which further leads to dysregulation of mitochondrial homeostasis and reduced energy metabolism. Pharmacodynamic evaluations demonstrated that reversible MAGL inhibitor and ABHD6 inhibitor effectively elevate 2-AG levels in cerebral organoid models, subsequently restoring mitochondrial energy metabolism.

This research expands the current understanding of soman’s systemic neurotoxicity, particularly its capacity to modulate endocannabinoid-mediated cognitive processes. Our results provide mechanistic insights into soman-induced cognitive deficits and associated health risks. Importantly, elevating 2-AG levels may serve as an effective strategy for preventing and treating soman-induced memory impairment.”

https://pubmed.ncbi.nlm.nih.gov/40691673/

https://link.springer.com/article/10.1007/s00204-025-04131-y