Category Archives: Endocannabinoid System

Efficacy of a Neuroimmune Therapy Including Pineal Methoxyindoles, Angiotensin 1-7, and Endocannabinoids in Cancer, Autoimmune, and Neurodegenerative Diseases

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“Purpose: Recent advancements in psycho-neuro-endocrine-immunology indicate that numerous noncommunicable diseases (NCDs) originate from disruptions in the cytokine immune network, resulting in chronic inflammatory responses. This persistent low-degree inflammation is attributed to deficiencies in crucial endogenous anti-inflammatory neuroendocrine systems, including the pineal gland, the endocannabinoid system, and the angiotensin-converting enzyme 2 / angiotensin 1-7 axis.

The administration of pineal methoxyindoles (melatonin, 5-methoxytryptamine), cannabinoids, and angiotensin 1-7 may entail potential therapeutic benefits for NCDs, particularly for patients who do not respond to conventional treatments.

Patients and methods: This study evaluates the safety and efficacy of a neuroimmune regimen comprising melatonin (100 mg/day at night), 5-methoxytryptamine (30 mg in the early afternoon), angiotensin 1-7 (0.5 mg twice daily), and cannabidiol (20 mg twice daily) in 306 patients with NCDs, including advanced cancer, autoimmune diseases, neurodegenerative disorders, depression, and cardiovascular disease.

Results: The neuroimmune regimen successfully halted cancer progression in 68% of cancer patients, who also reported improvements in mood, sleep, and relief from anxiety, pain, and fatigue. In patients with autoimmune diseases, the treatment effectively controlled the disease process, remarkable in cases of multiple sclerosis. Additionally, positive outcomes were observed in patients with Parkinson’s disease, Alzheimer’s disease, and depression.

Conclusion: Randomized controlled trials are required to assess this therapeutic approach for NCDs that includes endogenous neuroendocrine molecules regulating immune responses in an anti-inflammatory manner.”

https://pubmed.ncbi.nlm.nih.gov/40330271/

“This study highlights the potential of leveraging endogenous molecules to treat NCDs by modulating cell proliferation, inflammation, immune responses, metabolism, and neurological functions. The findings suggest that a neuroimmune regimen incorporating melatonin, angiotensin 1–7, and other bioactive compounds could offer a low-cost, minimally toxic therapeutic approach.”

https://www.dovepress.com/efficacy-of-a-neuroimmune-therapy-including-pineal-methoxyindoles-angi-peer-reviewed-fulltext-article-CIA

Cannabigerol and Cannabinoid Receptors in Major Depressive Disorder: Network Pharmacology, Molecular Docking, and In-vivo Analysis

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“Introduction: Cannabigerol (CBG), being one of the non-psychotropic phyto-cannabinoid, has been labelled and recognized to be antioxidant and neuroprotective; it may conceivably hold depression-relieving activity. Consequently, the objective of the present research procedure was to explore the depression-alleviating competence of cannabigerol in both stressed and unstressed mice using computational/in-silico modelling, followed by in-vivo analysis.

Method: Target genes for Major Depressive Disorder (MDD) were identified using GeneCards and Swiss Target Prediction, with common targets screened via Venny software. STRING database anal-ysis established protein-protein interactions (PPI), identifying CNR2 (CB2 receptor) as a key target. Molecular docking of CBG with CB2 (PDB ID: 8GUR) showed strong binding, prompting in vivo evaluation. ADME profiling via Schrödinger Maestro v10.5 confirmed CBG’s high oral absorption and favorable pharmacokinetics. Male Swiss albino mice underwent chronic unpredictable mild stress (CUMS) for three successive weeks, with CBG (10, 20, 40 mg/kg) and imipramine (15 mg/kg) administered and various behavioral and biochemical parameters being analyzed.

Results: Cannabigerol demonstrated maximum oral absorption in ADME predictions using Schrö-dinger’s Maestro (v10.5). Wayne diagram illustrated MDD-related targets, with CB2 (CNR2) rank-ings in top targets, based on SwissADME and Venny software analysis. Docking analysis revealed a high binding affinity (-10.53) for CB2, outperforming cannabidiol (-9.56) and comparable to Δ9-THC (-10.11). During in vivo evaluation, CBG (40 mg/kg) and Imipramine 15mg/kg significantly reduced CUMS-induced exalted plasma corticosterone, nitrite quantities, and monoamine oxidase-A action in the brain of stressed mice. Additionally, both treatments substantially reversed the unpre-dictable chronic stress-induced decline in catalase action, demonstrating CBG’s possible potential in alleviating depression-like symptoms in mice.

Conclusion: Cannabigerol has shown significant depressive alleviating potential in mice exposed to chronic and unpredictable stress regimes, possibly via interaction with cannabinoid receptors as in-dicated by in-silico modelling, which has been validated by our findings of the in-vivo protocol.”

https://pubmed.ncbi.nlm.nih.gov/40326034/

https://www.eurekaselect.com/article/148152

Targeting the Endocannabinoidome: A Novel Approach to Managing Extraintestinal Complications in Inflammatory Bowel Disease

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“Background: Inflammatory bowel disease (IBD) is a chronic inflammatory disorder marked by persistent gastrointestinal inflammation and a spectrum of systemic effects, including extraintestinal manifestations (EIMs) that impact the joints, skin, liver, and eyes. Conventional therapies primarily target intestinal inflammation, yet they frequently fail to ameliorate these systemic complications. Recent investigations have highlighted the complex interplay among the immune system, gut, and nervous system in IBD pathogenesis, thereby underscoring the need for innovative therapeutic approaches. 

Methods: We conducted a comprehensive literature search using databases such as PubMed, Scopus, Web of Science, Science Direct, and Google Scholar. Keywords including “cannabinoids”, “endocannabinoid system”, “endocannabinoidome”, “inflammatory bowel disease”, and “extraintestinal manifestations” were used to identify peer-reviewed original research and review articles that explore the role of the endocannabinoidome (eCBome) in IBD. 

Results: Emerging evidence suggests that eCBome-a network comprising lipid mediators, receptors (e.g., CB1, CB2, GPR55, GPR35, PPARα, TRPV1), and metabolic enzymes-plays a critical role in modulating immune responses, maintaining gut barrier integrity, and regulating systemic inflammation. Targeting eCBome not only improves intestinal inflammation but also appears to mitigate metabolic, neurological, and extraintestinal complications such as arthritis, liver dysfunction, and dermatological disorders. 

Conclusions: Modulation of eCBome represents a promising strategy for comprehensive IBD management by addressing both local and systemic disease components. These findings advocate for further mechanistic studies to develop targeted interventions that leverage eCBome as a novel therapeutic avenue in IBD.”

https://pubmed.ncbi.nlm.nih.gov/40283915/

“Extraintestinal manifestations of IBD pose a significant and diverse array of clinical challenges, significantly impacting patients’ lives and healthcare utilization. While conventional therapies primarily target gut inflammation, the endocannabinoidome emerges as a promising and versatile target for managing inflammatory, metabolic, and extraintestinal complications of IBD. Preliminary evidence highlights its therapeutic potential, but further research is essential to optimize clinical applications and ensure safety.”

https://www.mdpi.com/1424-8247/18/4/478

The Role of Endocannabinoids in Physiological Processes and Disease Pathology: A Comprehensive Review

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“The endocannabinoid system is a complex communication system involved in maintaining homeostasis in various physiological processes, including metabolism, immune response, pain modulation, and neuroprotection. Endocannabinoids, mainly anandamide and 2-arachidonoylglycerol, are natural ligands of the cannabinoid receptors CB1 and CB2, which are widely distributed throughout the central nervous system and peripheral tissues. Their biosynthesis, degradation, and interaction with other signaling pathways play crucial roles in both health and disease. This article provides a comprehensive overview of the physiological and pathological roles of endocannabinoids, discusses their potential as therapeutic targets, and highlights recent advances in endocannabinoid-based treatments.”

https://pubmed.ncbi.nlm.nih.gov/40283681/

https://www.mdpi.com/2077-0383/14/8/2851

“The endocannabinoid system plays a crucial role in maintaining physiological balance and regulating functions such as pain perception, immune response, metabolism, and neurological processes . Due to the multifaceted biological actions of the components of the ECS, researchers are seeking agonists/antagonists of cannabinoid receptors or other kinds of compounds with potential applications in targeted pharmacotherapy aimed at the endocannabinoid system. Although plant-derived cannabinoids have long been used in medicine, there are increasing attempts to use synthetic compounds as ligands for cannabinoid receptors or modulators of enzymes involved in endocannabinoid metabolism. Rimonabant, a selective CB1 receptor antagonist, was registered in Europe for the treatment of obesity from 2006 to 2008, particularly in patients with type 2 diabetes or metabolic syndrome. However, the European Medicines Agency determined that the risks of using the drug outweighed its benefits due to the serious psychiatric side effects, including depression and suicidal thoughts. Several novel drugs targeting ECS are under investigation. Notable examples include endocannabinoid reuptake inhibitors (eCBRIs) such as SYT-510 (currently under development), which are designed to treat anxiety, mood, and traumatic stress disorders, and AM404, an active metabolite of paracetamol, which inhibits AEA uptake. The other group consists of inhibitors of enzymes degrading AEA (fatty acid amide hydrolase—FAAH) and 2-AG (monoacyloglycerol lipase—MAGL) being explored for their potential in treating anxiety and pain. Drugs that modulate ECS hold promise for a variety of therapeutic applications, including glucose metabolism, obesity, neuroprotection, psychiatric disorders, pain management, and inflammation control, also in the context of chronic diseases. Further studies are needed to fully understand the complexities of this system and develop safe, effective treatments.”

Cannabinoids and the endocannabinoid system in liver diseases

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“Cannabinoids are biologically active substances acting via feedback-coupled CB1 and CB2 receptors. Their expression in myofibroblasts and liver endothelial cells is reported to be elevated in chronic liver diseases. The effect of CB1 receptor stimulation is to increase fibrosis and inflammatory activity in the liver by stimulating stellate cells, while activation of the CB2 receptor results in inhibition of fibrosis. Stimulation of the CB1 receptor may also lead to progression of liver steatosis and carcinogenesis. In end-stage liver disease, the endocannabinoid system plays an important role in the pathogenesis of encephalopathy and vascular effects, such as portal hypertension, splanchnic vasodilatation and cirrhotic cardiomyopathy. It seems that interference in endocannabinoid transmission may serve as an attractive target for the development of hepatological drugs.”

https://pubmed.ncbi.nlm.nih.gov/40290527/

https://www.termedia.pl/Cannabinoids-and-the-endocannabinoid-system-in-liver-diseases,80,55209,0,1.html

The Endocannabinoid System in Cancer Biology: A Mini-Review of Mechanisms and Therapeutic Potential

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“The Endocannabinoid System (ECS) plays a critical role in maintaining physiological homeostasis, influencing a range of processes such as neuroprotection, inflammation, energy metabolism, and immune responses.

Comprising cannabinoid receptors (CB1 and CB2), endogenous ligands (endocannabinoids), and the enzymes responsible for their synthesis and degradation, the ECS has attracted increasing attention in cancer research. Cannabinoid receptor activation has been associated with the regulation of cancer-related processes, including cell proliferation, apoptosis, and angiogenesis, suggesting that the ECS may have a role in tumor progression and cancer treatment.

Preclinical studies have shown that cannabinoids, through their interaction with CB1 and CB2 receptors, can inhibit tumor cell growth, induce programmed cell death, and suppress the formation of new blood vessels in various cancer models.

Despite these encouraging findings, the clinical translation of ECS-targeted therapies remains in its early stages. The complexity of tumor heterogeneity, the variability in patient responses, and the challenges associated with the pharmacokinetics of cannabinoids are significant obstacles to the broader application of these findings in clinical settings.

This review provides an overview of the current understanding of the ECS’s involvement in cancer biology, focusing on key mechanisms by which it may influence carcinogenesis. Additionally, we discuss the therapeutic potential of targeting the ECS in cancer treatment, while highlighting the limitations and uncertainties that need to be addressed through ongoing research.”

https://www.frontiersin.org/journals/oncology-reviews/articles/10.3389/or.2025.1573797/abstract

The endocannabinoid and paracannabinoid systems in natural reward processes: possible pharmacological targets?

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“Natural rewards such as food, mating, and social interaction are essential for survival and species preservation, and their regulation involves a complex interplay of motivational, cognitive, and emotional processes.

Over the past two decades, increasing attention has been directed toward the endocannabinoid system and its paracannabinoid counterpart as key modulators of these behaviors.

This review aims to provide an integrated overview of the roles played by the endocannabinoid and paracannabinoid systems in regulating natural reward-driven behaviors, focusing on feeding, reproductive behavior, and social interaction.

We highlight how the endocannabinoid system – mainly through CB1 receptor signaling – modulates central and peripheral circuits involved in energy homeostasis, reward processing, and emotional regulation. In parallel, we explore the role of paracannabinoids, such as oleoylethanolamide (OEA), palmitoylethanolamide (PEA), and stearoylethanolamide (SEA), which act primarily via non-cannabinoid receptors and contribute to the regulation of appetite, sexual motivation, and social behavior.

Special attention is given to the relevance of these systems in the pathophysiology of obesity, eating disorders, sexual dysfunctions, and social impairments, as well as their potential as pharmacological targets.

Overall, the evidence discussed supports a broader conceptualization of endocannabinoid and paracannabinoid signaling as pivotal regulators of natural rewards and opens new avenues for the development of targeted interventions for motivational and reward-related disorders.”

https://pubmed.ncbi.nlm.nih.gov/40274041/

“Endocannabinoid/paracannabinoid therapies offer promising innovative drug development.”

https://www.sciencedirect.com/science/article/pii/S0031938425001301?via%3Dihub

Impaired mnemonic pattern separation associated with PTSD symptoms paradoxically improves with regular cannabis use

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“Posttraumatic stress disorder (PTSD) is associated with poor hippocampal function and disrupted pattern recognition. Cannabis use is highly prevalent in individuals with PTSD, yet the impact on these cognitive functions is poorly understood. Participants (n = 111) with a range of PTSD symptoms with and without regular cannabis use completed the mnemonic similarity task. We hypothesized that regular use would be associated with alterations in pattern separation ability in individuals with PTSD symptoms. High PTSD symptoms were associated with reduced pattern separation performance in minimal users. Regular users with high PTSD symptoms showed greater pattern separation, but reduced pattern separation with low PTSD symptoms. These results suggest that regular cannabis use may disrupt pattern separation and similar hippocampal-dependent processes, while it may improve pattern separation in individuals with high PTSD symptoms. These cross-sectional results require longitudinal follow-up studies to evaluate the causal effects of regular cannabis use on cognitive function in PTSD.”

https://pubmed.ncbi.nlm.nih.gov/40274935/

“The finding that regular cannabis use was associated with improved pattern separation ability in those reporting more severe PTSD symptoms was unexpected. One possible explanation for this observation is that the endocannabinoid system is altered by trauma exposure and in PTSD.”

https://www.nature.com/articles/s44184-025-00126-w

Cannabinoid Receptors Reduced Early Brain Damage by Regulating NOX-2 and the NLRP3 Inflammasome in an Animal Model of Intracerebral Hemorrhage

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“Background: Intracerebral hemorrhage (ICH) is a leading cause of death and disability worldwide. Following the initial mechanical injury caused by hematoma expansion, a secondary injury occurs, characterized by the production of reactive oxygen species (ROS) generated by NOX-2 and neuroinflammation, which is exacerbated by the upregulation of the NLRP3 inflammasome. These conditions collectively aggravate brain damage.

The endocannabinoid system (ECS), through the activation of the cannabinoid receptors, has demonstrated neuroprotective properties in various models of brain injury. However, the role of the ECS during ICH remains poorly understood, particularly regarding the action of the CB1 receptor in the activation of NOX-2 and the inflammasome. The present study investigates the neuroprotective effects of the cannabinoid receptor agonist WIN55,212-2 in an ICH animal model, specifically examining the roles of NLRP3 and NOX-2.

Methods: Male C57BL/6 mice were subjected to ICH through an intracerebral injection of collagenase, followed by intraperitoneal administration of WIN55,212-2 and/or MCC950, a selective NLRP3 inhibitor. Various outcome measures were employed, including assessments of motor activity, hematoma volume, brain water content, and blood-brain barrier (BBB) permeability, which was evaluated using Evans blue assay. Additionally, the activity of NOX and the protein levels of crucial markers such as CB1, gp91phox, NLRP3, AQP4, and caspase-1 were measured via western blot analysis.

Result: The findings demonstrate that ICH induced a significant brain lesion characterized by hematoma formation, edema, BBB disruption, and subsequent motor impairments in the affected mice. Notably, these detrimental effects were markedly reduced in animals treated with WIN55,212-2. The study also revealed an activation of both NOX-2 and NLRP3 in response to ICH, which was reduced by cannabinoid receptor activation. Furthermore, the pharmacological inhibition of NLRP3 using MCC950 also led to a reduction in hematoma size, edema, and motor impairment secondary to ICH.

Conclusions: These results support a neuroprotective role of the cannabinoid receptor activation during ICH and suggest the involvement of NOX-2 and NLRP3.”

https://pubmed.ncbi.nlm.nih.gov/40245261/

Research mapping of cannabinoids and endocannabinoid system in cancer over the past three decades: insights from bibliometric analysis

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“Background: The cannabinoids and endocannabinoid system are thought to play critical roles in multiple signaling pathways in organisms, and extensive evidence from preclinical studies indicated that cannabinoids and endocannabinoids displayed anticancer potential. This study aimed to summarize the research of cannabinoids and endocannabinoid system in cancer through bibliometric analysis.

Methods: Relevant literature in the field of cannabinoids and endocannabinoid system in cancer published during 1995-2024 were collected from the Web of Science Core Collection database. VOSviewer and SCImago Graphica were applied to perform bibliometric analysis of countries, institutions, authors, journals, documents, and keywords.

Results: A total of 3,052 publications were identified, and the global output exhibited a generally upward trend over the past 3 decades. The USA had the greatest number of publications and citations in this research field. Italian National Research Council led in terms of publication, while Complutense University of Madrid had the highest total citations. Vincenzo Di Marzo was the leading author in this field with the greatest number of publications and citations. The co-occurrence of keywords revealed that the research frontiers mainly included “cannabinoids”, “endocannabinoid system”, “cancer”, “anandamide”, “cannabidiol”, “cannabinoid receptor”, “apoptosis”, and “proliferation”.

Conclusion: Our results revealed that the research of cannabinoids and endocannabinoid system in cancer would receive continuous attention. The USA and Italy have made remarkable contributions to this field, supported by their influential institutions and prolific scholars. The research emphasis has evolved from basic functional characterization to mechanistic exploration of disease pathways and translational applications within multidisciplinary framework.”

https://pubmed.ncbi.nlm.nih.gov/40242437/

“In this study, we conducted a comprehensive bibliometric analysis on the research of cannabinoids and endocannabinoid system in cancer over the past 3 decades. Our results would provide referable guidance for the understanding of research emphasis on this topic, offering insights for clinical interventions and scientific inquiries.”

https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2025.1540619/full