Category Archives: Endocannabinoid System

Synaptic Endocannabinoid Signaling in the Anterior Cingulate Cortex: Implications for Alzheimer’s Disease Pathology and Social Behavior

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“Background: Alzheimer’s disease (AD) is a major contributor to neuropsychiatric disorders, exerting profound impacts on individuals and society. Social behavioral impairments associated with AD present significant challenges for both diagnosis and treatment, highlighting the urgent need to unravel their underlying mechanisms. Dysfunction of the anterior cingulate cortex (ACC) has been identified as a key factor driving the emergence of these behavioral deficits. Among its regulatory mechanisms, endocannabinoids play a critical role in modulating short-term synaptic plasticity in the ACC, thereby maintaining synaptic homeostasis. Endocannabinoid signaling is highly sensitive to environmental stimuli, demonstrating dynamic responses to external stressors. Despite these insights, the precise role of synaptic endocannabinoid signaling in the ACC, particularly its contribution to synaptic homeostasis and social behavioral regulation in the context of AD pathology, remains poorly understood.

Method: Using a multifaceted approach-including optogenetic, electrophysiological, pharmacological, and behavioral techniques-we characterized alterations in presynaptic CB1 receptors and endocannabinoid synthesis at excitatory and inhibitory synapses during AD progression.

Result: Our findings reveal a regulatory role of cannabinoid signaling at both pre- and post-synaptic terminals within the ACC, providing insights into its modulation of synaptic transmission in AD. We further examined the impact of disrupted endocannabinoid signaling on synaptic homeostasis, employing calcium signal recording and pharmacological interventions. Alterations in excitatory and inhibitory synaptic function were particularly evident in socially isolated mice, a condition that exacerbates AD-related behavioral deficits. These findings highlight the interplay between endocannabinoid dysregulation, synaptic dysfunction, and behavioral abnormalities in AD. Moreover, we explored therapeutic strategies targeting synaptic endocannabinoid signaling to mitigate AD-induced social behavioral deficits. Using cannabinoid receptor knockout models and pharmacological approaches, we dissected the distinct roles of cannabinoid signaling components in mediating behavioral outcomes. This work underscores the potential of modulating endocannabinoid signaling to alleviate neuropsychiatric symptoms associated with AD.

Conclusion: This comprehensive investigation sheds light on the intricate relationship between AD pathology, synaptic endocannabinoid signaling, and social behavior. By unraveling the molecular, cellular, and behavioral correlates of AD-induced alterations in cannabinoid signaling, our study provides valuable insights into the pathophysiology of AD-related neuropsychiatric disorders. It lays the foundation for innovative therapeutic approaches.”

https://pubmed.ncbi.nlm.nih.gov/41435339

https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz70855_097499

Cannabinoid and cannabinoid related receptors in fibroblasts, inflammatory and endothelial cells of the equine hoof with and without laminitis: novel pharmacological target

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“Background: Evidence suggests that the endocannabinoid system (ECS) is crucial for regulating inflammation, cell proliferation and pain. The ECS is composed of cannabinoid receptors such as type 1 (CBR1), type 2 (CBR2) and GPR55, endocannabinoids and enzymes. Proteins of ECS have previously been localized in the epidermal cells of the horse hooves. Given the physio-pathological role and cellular distribution of the ECS across species, the authors hypothesized that cannabinoid receptors are expressed within the inflammatory cells, fibroblasts and endothelial cells of the equine hoof laminae, going beyond the epidermal cells.

Objectives: To preliminary analyze the gene expression of Cn1r, Cn2r and GPR55 in the hoof laminae and test the specificity of the antibody against GPR55. To characterize the distribution and expression of CBRs in the inflammatory cells and fibroblasts of the laminar junction of equine healthy hooves and with laminitis.

Animals: Animals were divided into 3 groups: healthy, acute laminitis and chronic laminitis. A total of 18 samples were collected and processed from the front limb of animals slaughtered for consumption or euthanized (6 control animals, 4 acute laminitis, 8 chronic laminitis).

Methods: Analysis of CBR1, CBR2 and GPR55 protein expression was made by fluorescence microscopy with co-localization with antibodies against the macrophages marker IBA1, the T cell marker CD3, the neutrophils marker calprotectin (MAC387), the fibroblasts marker vimentin (Clove V9) and the nerve fibers marker Substance P. Preliminary analysis was performed to evaluate gene expression (Cnr1, Cnr2, and Gpr55) using real-time PCR and to verify the specificity of the primary antibody (Gpr55) with Western Blotting (WB).

Results: The resident pool of inflammatory cells in the normal laminae and the inflammatory infiltrate cells of the affected equine laminae showed protein expression of CB2R and GPR55; no CB1R staining was seen at the inflammatory cells. Equine dermal fibroblast and endothelial cells exhibited protein expressions of CB1R, CBR2 and GPR55. Substance P positive nerve fibers were positive for CB1R.

Conclusions and clinical importance: Cannabinoid receptors are expressed in different immune cell types of the hoof laminae, pointing to the role of the ECS in modulating inflammatory outburst, tissue degeneration and pain. Our results serve as a foundation for the development of new veterinary pharmacotherapies that target the ECS during laminitis.”

https://pubmed.ncbi.nlm.nih.gov/41394912

“The present findings highlight the presence of cannabinoid receptors CB1, CB2, and GPR55 in the inflammatory cells, fibroblasts and endothelial cells of healthy and pathological hoof lamellar epithelial tissue. The modulation of CB1R, CB2R, and GPR55 signaling pathways could offer novel therapeutic approaches for managing hoof diseases.”

https://www.frontiersin.org/journals/veterinary-science/articles/10.3389/fvets.2025.1723160/full

The Endocannabinoid System: Scientific Insight and Biblical Reflection

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“The endocannabinoid system (ECS) is typically associated with using cannabis or cannabinoids. However, the ECS is a complex regulatory network within the human body that plays a vital role in maintaining physiological homeostasis. The ECS can become dysregulated through various mechanisms.

This article describes the physiology of the ECS using a biblical worldview. Nurses who understand the causes of ECS dysfunction can help lead patients toward lifestyle habits that reflect God’s design for balance, resilience, and wholeness.”

https://pubmed.ncbi.nlm.nih.gov/41359460

“The endocannabinoid system (ECS) is a crucial regulatory network in the human body, often linked to cannabis use but primarily responsible for maintaining physiological balance. This article explores the ECS from a biblical perspective, emphasizing its role in health and homeostasis.

Dysregulation of the ECS can occur through various mechanisms, and nurses who grasp these causes can guide patients towards lifestyle choices that align with a holistic approach to health, reflecting a divine design for balance and resilience.

Understanding the ECS can empower healthcare professionals to support patients in achieving overall well-being.”

https://journals.lww.com/journalofchristiannursing/abstract/2026/01000/the_endocannabinoid_system__scientific_insight_and.11.aspx

“Natural and synthetic cannabinoids finely regulate the endogenous cannabinoid system.”

https://www.sciencedirect.com/science/article/pii/S1043661825004475

Evaluation of long-term safety profile of an EU-GMP certified Cannabis sativa L. strain in a naturally aging preclinical model

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“Aging is characterized in part by chronic, low-grade inflammation, a major driver of cognitive decline, metabolic imbalance and organ dysfunction. Despite its central role in age-related morbidity, pharmacological strategies with well-defined long-term safety profiles remain limited.

Phytocannabinoids have been proposed as modulators of neuroinflammatory and metabolic pathways, but their chronic safety during natural aging is poorly characterized.

Our team has previously reported the acute and 28-day repeated-dose toxicity profile of an EU-GMP certified Cannabis sativa L. strain (Cannabixir® Medium Flos). Here, we extend this work by assessing its long-term safety in a naturally aging preclinical model. Mature to older mice received chronic, intermittent administration of Cannabixir® Medium Flos (2.5, 5, and 10 mg/kg), defined as daily weekday dosing for 3 or 6 months. Clinical and histopathological evaluations were conducted with a focus on systemic and central nervous system safety.

Chronic administration was well tolerated across all doses and durations.

Body weight remained stable despite increased food intake. Respiratory quotient values were preserved and close to 1 across all groups. Histological analyses confirmed preserved neuronal and glial architecture with no evidence of central nervous system injury or other organ-level toxicity. Long-term, intermittent Cannabixir® Medium Flos administration was well tolerated in naturally aged mice, with no adverse effects on systemic physiology or central nervous system integrity.

Together with prior acute and sub-chronic toxicity data, these findings provide robust evidence supporting the long-term safety of EU-GMP certified Cannabis sativa L. strain in the context of aging.”

https://pubmed.ncbi.nlm.nih.gov/41357885

“Importantly, the endocannabinoid system itself undergoes profound remodeling with aging, including reduced endocannabinoid tone, altered receptor expression and impaired signaling efficiency, changes that correlate with increased vulnerability to inflammation, metabolic imbalance, and neurodegeneration. These age-related alterations highlight the importance of evaluating the long-term safety of cannabinoid-based interventions in naturally aging bodies.”

“These findings suggest the potential for phytocannabinoid-mediated neuroprotection via modulation of the endocannabinoid system, although the precise molecular pathways remain to be elucidated.”

https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2025.1716366/full

Anti-Cancer Potential of Cannabinoids, Terpenes, and Flavonoids Present in Cannabis

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“In recent years, and even more since its legalization in several jurisdictions, cannabis and the endocannabinoid system have received an increasing amount of interest related to their potential exploitation in clinical settings.

Cannabinoids have been suggested and shown to be effective in the treatment of various conditions.

In cancer, the endocannabinoid system is altered in numerous types of tumours and can relate to cancer prognosis and disease outcome. Additionally, cannabinoids display anticancer effects in several models by suppressing the proliferation, migration and/or invasion of cancer cells, as well as tumour angiogenesis.

Along with cannabinoids, cannabis contains several other compounds that have also been shown to exert anti-tumorigenic actions.”

https://pubmed.ncbi.nlm.nih.gov/32708138

“Dysregulation of the endocannabinoid system has been implicated in several diseases, including cancer.”

“Based on the preliminary evidence in various models, it appears that cannabinoids target key signaling pathways involved in all the hallmarks of cancer. Additionally to the cannabinoids, a large number of terpenes and flavonoids, some of them also present in cannabis, exhibit cytotoxicity against a variety of cancers.”

“Considering all the available literature at this time, much stronger experimental evidence (obtained in vitro, in vivo and even in a few clinical trials) support that THC and cannabidiol (CBD) have better anticancer activity than for the other cannabinoids.”

https://www.mdpi.com/2072-6694/12/7/1985

Computational GWAS Meta Meta Analysis Revealing Cross Talk Between Cannabis CNR1 and DRD2 Receptors Optimizing Long-Term Outcomes for Cannabis Use Disorder (CUD) By Enhancing Dopamine Homeostasis Promoting High-Quality Cannabis Medicinals

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“This paper presents a shared perspective from scientists and clinicians seeking to harness the therapeutic potential of cannabis while addressing Cannabis Use Disorder (CUD) through reproducible scientific findings.

Rather than blocking CNR1 receptors, which may induce hypodopaminergia, we propose a pro-dopaminergic strategy using a natural nutraceutical formulation designed to enhance dopamine release and upregulate D2 receptor mRNA, thereby increasing D2 receptor density.

Given the failure of CNR1 antagonists such as Rimonabant, we argue for an opposite approach: restoring dopamine balance through CNR1 stimulation rather than inhibition.”

https://pubmed.ncbi.nlm.nih.gov/41333412

https://www.researchsquare.com/article/rs-8140327/v1


Endocannabinoid system and mood responses to acute aerobic exercise in adult cancer patients versus healthy controls: a pilot study

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“Purpose: To investigate the endocannabinoid system (ECS) and affective state responses to acute aerobic exercise in adult cancer patients versus their healthy peers.

Methods: Participants engaged in 30 min of quiet rest followed by 30 min of exercise. Exercise involved 5-min warm-up/cool-down procedures and 20 min of moderate-intensity training (64-76% of age-predicted maximal heart rate) on a treadmill or cycle. Blood samples and 10 Visual Analog Scales (VAS) were collected before and after each condition. Participants were also asked after exercise: ‘Did you experience a Runner’s high’. Blood samples were analysed for endocannabinoids: N-arachidonoylethanolamine (AEA; anandamide), 2-arachidonoylglycerol (2-AG) and 1-arachidonoylglycerol (1-AG), and endocannabinoid-like lipid mediators: palmitoylethanolamide (PEA), oleoylethanolamide (OEA) and stearoylethanolamide (SEA).

Results: Cancer patients had lower circulating AEA, OEA and log SEA versus controls across all timepoints (all p < 0.06). In the total cohort, exercise increased AEA, log 1-AG, OEA, PEA and log SEA (all p = 0.05) while log 2-AG did not change. Of 10 VAS, only Happiness increased with exercise in the total cohort (p = 0.02). There were no group x time effects or associations between ECS and VAS responses to exercise. Five patients per group (50%) reported experiencing a Runner’s high.

Conclusions: Exercise increased endocannabinoids and endocannabinoid-like lipid mediators in the total cohort. However, cancer patients exhibited lower AEA, OEA and SEA concentrations versus their peers, indicating potential ECS dysfunction.

Additional research is required to investigate the effect of various modalities and dosages of exercise on ECS markers and the clinical interpretation of these adaptations across a range of cancer populations.”

https://pubmed.ncbi.nlm.nih.gov/41331388

https://link.springer.com/article/10.1007/s00520-025-10221-5

“Exercise activates the endocannabinoid system”

https://pubmed.ncbi.nlm.nih.gov/14625449

“The Endocannabinoid System: A Target for Cancer Treatment.”

https://pmc.ncbi.nlm.nih.gov/articles/PMC7037210

The endocannabinoid system as a therapeutic target in prodromal psychosis: From molecular mechanisms to clinical applications

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“This systematic review explores the role of the endocannabinoid system (ECS) in prodromal psychosis and its potential as a therapeutic target.

Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, 22 studies published between 2000 and 2025 were analyzed, comprising preclinical research, genetic studies, neuroimaging investigations, and clinical trials.

Converging evidence suggests that ECS alterations precede and potentially contribute to the development of psychotic symptoms, with CB1 receptor modifications and endocannabinoid levels correlating with symptom severity and transition risk to full-blown psychosis.

Neuroimaging studies revealed reduced CB1 receptor availability in key brain regions in high-risk subjects, and intervention studies, particularly with cannabidiol-though its therapeutic mechanisms likely extend beyond ECS modulation to include dopaminergic and other neurotransmitter pathways-have shown promising results.

Proposed mechanisms of action include stress response attenuation, neuroinflammatory modulation, neurodevelopmental stabilization, and normalization of the dopamine-glutamate interface.

Despite limitations of existing studies, primarily small size and short duration, this review provides a solid foundation for developing ECS-targeted interventions as a promising approach to modify disease trajectory during the prodromal phase, potentially offering safer and more effective therapeutic options for individuals at clinical high risk for psychosis.”

https://pubmed.ncbi.nlm.nih.gov/41328544

https://journals.sagepub.com/doi/10.1177/02698811251389574

Cannabis Use in Central Disorders of Hypersomnolence in the Netherlands

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“Introduction: The endocannabinoid system plays a role in sleep-wake regulation. In clinical practice, people with central disorders of hypersomnolence (CDH) frequently report use of cannabis.

Methods: We compared lifetime and current use of cannabis of people with CDH to the Dutch general population. Additionally, we assessed cannabis use in relation to hypersomnolence symptoms.

Results: In total, 76 (out of 88) patients completed the online questionnaire. Lifetime cannabis use (42% vs. 23%, p < 0.001) and current use (18% vs. 4%, p < 0.001) were higher in people with CDH compared to the Dutch general population. For 57% of patients currently using cannabis, improvements of at least one CDH symptom were the motivation for use. Additionally, 79% of current cannabis users reported cannabis-related effects on a symptom, which were mostly positive (43%), some negative (7%), or mixed effects (29%). Patients that stopped using mostly started using cannabis before symptom onset and for recreational purposes. The most reported reasons to stop using were disadvantages of using or changes in the social environment.

Conclusion: This study provides a rationale for future research on the potential benefits of cannabis in CDH.”

https://pubmed.ncbi.nlm.nih.gov/41321442

https://karger.com/mca/article/8/1/181/935204/Cannabis-Use-in-Central-Disorders-of

Structural and dynamic mechanisms of cannabinoid receptors

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“Cannabinoids and their G protein-coupled receptors (GPCRs) within the endocannabinoidome are pivotal regulators of neuromodulation, inflammation, and metabolic homeostasis.

Dysregulation of this system has been associated with a wide spectrum of pathological conditions, including neuropsychiatric disorders, chronic pain, and immune dysfunction.

In this review, we summarize recent structural advances in cannabinoid receptors that have deepened our understanding of receptor activation, allosteric modulation, transducer coupling selectivity, and dynamic conformational mechanisms.

These structural insights will facilitate cannabinoid receptor-targeted drug discovery, enabling the development of therapeutics with improved subtype selectivity, enhanced signaling precision, and reduced off-target effects.”

https://pubmed.ncbi.nlm.nih.gov/41319927

“The medicinal use of phytocannabinoids has been documented for millennia, with applications across diverse cultures in the treatment of insomnia, pain, epilepsy, headaches, and inflammation. Modern scientific investigation into cannabis began in the 1930 s, culminating in the isolation and structural characterization of its major constituents.”

“Taken together, these findings highlight cannabinoid receptors as multifaceted and dynamic therapeutic targets positioned at the intersection of neurology, immunology, and metabolism. A deeper understanding of its structural and signaling mechanisms will be critical for the rational design of next-generation cannabinoid-based therapies that harness its extensive regulatory potential with precision.”

https://www.sciencedirect.com/science/article/abs/pii/S0006295225008330?via%3Dihub