Category Archives: Endocannabinoid System

The endocannabinoidome-gut microbiome-brain axis as a novel therapeutic target for autism spectrum disorder

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“Introduction: Autism spectrum disorder (ASD) is characterized by disruption of the gut-brain axis, which leads to behavioral, psychiatric, metabolic and gastrointestinal symptoms. Effective ASD treatments are limited. Research highlights the roles of the endocannabinoidome (eCBome) and gut microbiome (GM), both crucial for brain and gut function. This review summarizes research on therapeutic targets within the eCBome-GM-brain axis for ASD and related comorbidities.

Discussion: Evidence suggests that reduced levels of eCBome mediators, like oleoylethanolamide and anandamide, and altered cannabinoid type 1 and type 2 (CB1 and CB2) receptors activity may contribute to ASD symptoms, making them promising targets. Modulating the eCBome-GM-brain axis with inhibitors of fatty acid amide hydrolase (FAAH), transient receptor potential vanilloid 1, and monoacylglycerol lipase (MAGL) may improve repetitive, stereotypical, and sensory behaviors, and alleviate sociability impairments, depression and anxiety. However, inhibition of FAAH and MAGL may also induce ADHD-like behaviors, which can be reversed by CB1 inverse agonists. Targeting metabotropic glutamate receptor 5 to increase levels of the eCBome mediator 2-arachidonoylglycerol (2-AG) may benefit ASD-related behaviors. eCBome mediators such as 2-AG, 1/2-palmitoylglycerol and palmitoylethanolamide may also help manage ASD- and GI-related symptoms, and systemic inflammation. Other potential therapeutic targets that deserve further investigation are eCBome-related receptors G-protein-coupled receptor 55 and peroxisome proliferator-activated receptors-alpha and -gamma, and the cyclooxygenase-2/prostaglandin E2 pathway, which may address hyperactivity and repetitive behaviors. Additionally, mucin-degrading genera like Akkermansia and Ruminococcus may improve ASD-related GI symptoms such as hypersensitivity and inflammation. Selective antibiotics against specific Clostridium strains may improve irritability and aggression. In ASD with ADHD and OCD, treatments may involve modulating the CB1 and CB2 receptor, and bacterial families like Ruminococcaceae and Lachnospiraceae. Lastly, modulating the abundance of anti-inflammatory genera like Prevotella and Anaeroplasma, and taxa associated with gut health such as Roseburia may also offer therapeutic value.

Conclusion: The eCBome-GM-brain axis is a promising target for ASD treatment, meriting further clinical and preclinical research.”

https://pubmed.ncbi.nlm.nih.gov/40605060/

“In conclusion, the eCBome–GM–brain axis represents a promising, multifaceted therapeutic target for ASD and its comorbidities, warranting further clinical and preclinical research to clarify its therapeutic potential and refine targeted interventions.”

https://jbiomedsci.biomedcentral.com/articles/10.1186/s12929-025-01145-7

Cannabinoid receptor ligands with potential therapeutic applications and mechanisms of action: a versatile natural therapeutic agent

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“The endocannabinoid system (ECS) is a complex signaling network essential for regulating various physiological processes in the body. Selective cannabinoid receptor ligands have been developed to modulate specific ECS signaling pathways, offering potential therapeutic benefits. These ligands, with high selectivity and affinity for cannabinoid receptors, demonstrate potential in managing diverse medical conditions. Standardizing dosing is crucial to ensure reliable therapeutic effects, as cannabinoids may exhibit biphasic effects. Combination strategies involving both CB1 and CB2 receptor modulation show promise in managing complex conditions, including chronic pain, autoimmune disorders, and neurodegenerative diseases.”

https://pubmed.ncbi.nlm.nih.gov/40600897/

https://www.tandfonline.com/doi/full/10.1080/10286020.2025.2522396

Neutrophil extracellular traps and cannabinoids: potential in cancer metastasis

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“Cancer is the second leading cause of global mortality after cardiovascular diseases, with breast, lung, colon, and prostate cancers being the most common. WHO projects around 30 million new cancer cases worldwide by 2045, with breast cancer being the most common in women and lung cancer in men.

Metastasis is responsible for nearly 90% of cancer-related deaths. Breast and lung cancers tend to metastasize to the bones, lymph nodes, lungs, liver, and brain. Lungs remains one of the most common organs to which various forms of cancer metastasize.

An important factor in metastasis is NETosis – it can initially help to eliminate cancer cells, but it can also promote metastasis. Phytocannabinoids, compounds derived from Cannabis sativa, and the endocannabinoid system (ECS) offer promising therapeutic potential to inhibit NETosis and consequently cancer development and metastasis.

Although the precise effects of phytocannabinoids on neutrophil functions and NETosis are not fully understood and require further research in the context of cancer, preliminary studies suggest their potential to inhibit NET release in various disease models.

This review consolidates current knowledge and provides new insights into how phytocannabinoids and the ECS may serve as effective therapeutic tools to limit cancer metastasis.”

https://pubmed.ncbi.nlm.nih.gov/40599866/

“Research indicates that metastatic progression is responsible for most deaths caused by breast cancer, with metastatic processes accounting for nearly 90% of cancer-related mortality.”

“Phytocannabinoids, together with the endocannabinoid system (ECS), represent a highly promising therapeutic avenue for attenuating neutrophil effector functions, particularly the process of NETosis.

We believe that these compounds have significant potential as agents capable of effectively inhibiting metastatic progression.

Phytocannabinoids, derived primarily from the Cannabis sativa plant, are a group of organic compounds that interact with the endocannabinoid system (ECS) in the human body.”

“Both phytocannabinoids and the endocannabinoid system (ECS) show significant therapeutic potential in cancer treatment. Research indicates that these agents affect the proliferation, apoptosis, migration, and invasiveness of cancer cells. In addition, they modulate the tumor microenvironment, particularly the cells of the immune system.”

https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2025.1595913/full

Differential metabolic pathways underlie THC- and CBD-mediated inhibition of B-cell activation in both young and aged mice

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“Objective: B lymphocytes play a crucial role in immunity but also contribute to the pathogenesis of various diseases. Cannabis plants produce numerous biologically active compounds, including cannabinoids. The two most studied phytocannabinoids are Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD). These cannabinoids exert diverse and potent biological effects primarily through the endocannabinoid system (ECS), which also plays a key role in mature B-cell function. Both the immune system and the ECS undergo age-related changes that lead to a clinically significant decline in function.

Methods: This study compares the effects of THC and CBD on B-cell activity in young and aged mice. Murine B lymphocytes were activated using lipopolysaccharide (LPS) and interleukin-4 (IL-4), and the impact of cannabinoid treatments was assessed in terms of cell phenotype, proliferation, antibody secretion, tumor necrosis factor-alpha (TNFα) secretion, extracellular signal-regulated kinase (ERK) phosphorylation, and the cellular metabolome.

Results: Both THC and CBD exhibited dose-dependent inhibitory effects on B-cell activation in young and aged mice. However, we show here, for the first time, that the treatments induce distinct metabolic profiles. Although some metabolites, such as glucose-6-phosphate, pentose phosphate pathway (PPP) and nucleotide metabolites, were reduced by both cannabinoids, THC selectively reduced the levels of a distinct set of amino acids, while only CBD increased the levels of Citrulline and Allantoin. Additionally, the effects of THC and CBD differed between young and aged B cells, suggesting that age-related changes in the ECS may influence cannabinoid sensitivity.

Conclusions: These findings provide insights into the distinct mechanisms by which THC and CBD regulate immune activation and may open the door for investigating the mechanisms behind cannabinoids effects on the immune system. They also highlight the need for further research into phytocannabinoid-based therapies, particularly in age-specific contexts. Given the immunoregulatory properties of cannabinoids, especially CBD, tailored therapeutic strategies may enhance their clinical applications.”

https://pubmed.ncbi.nlm.nih.gov/40599768/

“These findings emphasize the need for further investigation into phytocannabinoid-based therapies, particularly for age-specific applications. Given the immunoregulatory properties of cannabinoids, especially CBD, tailored therapeutic strategies may be developed to optimize their clinical use.”

https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1605474/full

Cannabidiol attenuates methamphetamine-induced oxidative neurotoxicity via regulating transient receptor potential vanilloid type 1

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“Background: The prevalence of methamphetamine (METH) abuse has significantly escalated in many regions worldwide. Despite this increase, the complexity of neurotoxicity associated with METH is inadequately understood. Cannabidiol (CBD), a non-addictive plant ingredient in cannabis, has been used in preclinical and clinical studies for treating various neuropsychiatric disorders, but the mechanism by which CBD exerts therapeutic effects is still unclear.

Purpose: This work aims to explore the mechanism of transient receptor potential vanilloid type 1 (TRPV1) mediates oxidative neurotoxicity in the context of METH exposure and reveal the therapeutic target of CBD for METH-induced oxidative neurotoxicity.

Results: In the hippocampus and medial prefrontal cortex of METH users, overactivation of TRPV1, intracellular Ca2+ overload, increased oxidative stress, and elevated apoptosis were observed compared to control individuals. Molecular docking and surface plasmon resonance (SPR) detection results indicated that CBD binds to human TRPV1. In addition, METH induced Ca2+ influx, oxidative stress, cell damage, and TRPV1 activation in HT-22 cells, which were mitigated by TRPV1 knockdown or CBD pretreatment. CBD pretreatment also blocked TRPV1 agonist capsaicin-induced Ca2+ influx, oxidative stress, cell damage, and TRPV1 activation in HT-22 cells. Furthermore, METH triggered stereotyped behavior, spatial memory impairment, TRPV1 activation, Ca2+ overload, apoptosis, and oxidative stress in the hippocampus, which were attenuated by CBD pretreatment in mice. Finally, hippocampal TRPV1 knockdown reduced METH-induced stereotyped behavior and spatial memory impairment in mice, blocked METH-induced apoptosis and oxidative stress in the hippocampus of mice.

Conclusion: METH induces oxidative neurotoxicity via activating TRPV1-dependent Ca2+ influx, oxidative stress, and apoptosis, while CBD inhibits METH-induced oxidative neurotoxicity by regulating TRPV1. This study establishes CBD as a therapeutic intervention for METH use disorders.”

https://pubmed.ncbi.nlm.nih.gov/40582208/

“In summary, our results suggest that METH induced oxidative neurotoxicity by activating TRPV1-dependent Ca2+ influx, oxidative stress, and apoptosis, while CBD pretreatment inhibited METH-induced oxidative neurotoxicity by regulating TRPV1.”

https://www.sciencedirect.com/science/article/abs/pii/S0944711325006543?via%3Dihub

Real-Time Optical Control of CB1 Receptor Signaling In Vitro with Tethered Photoswitchable (-)- trans-Δ9-Tetrahydrocannabinol Derivatives

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“Understanding the intricacies of the endocannabinoid system is hindered by the lack of tools to target specific pools of CB1 receptors (CB1Rs) across diverse neural circuits associated with mood, motor function, cognition, and other physiological processes.

Herein, we introduce the first photoswitchable, orthogonal remotely tethered cannabinoid ligand, PORTL-THC24, designed to achieve cell-specific and reversible control of CB1R signaling with high spatial and temporal resolution, thereby overcoming the limitations of conventional freely diffusible ligands.

PORTL-THC24 was selectively tethered to membrane-anchored SNAP-tags expressed in live cells, and provided reversible optical control of CB1R signaling when photoswitched by UV-A irradiation. We validated the functionality of PORTL-THC24 in live Neuro2a cells using a novel real-time cAMP imaging assay, demonstrating light-dependent and reversible modulation of endogenously expressed CB1R activity. Additionally, we demonstrated that SNAP-tethered PORTL-THC24 does not induce CB1R internalization, distinguishing it from conventional, freely diffusible agonists.

Our results establish PORTL-THC24 as a powerful tool for optical control of CB1R in a spatially restricted manner, setting the stage for dissecting CB1R function in complex settings and advancing the study of cannabinoid signaling across various physiological and pathological contexts.”

https://pubmed.ncbi.nlm.nih.gov/40586440/

https://pubs.acs.org/doi/10.1021/jacs.4c18379

Omega-3 Fatty Acids Mitigate Long-Lasting Disruption of the Endocannabinoid System in the Adult Mouse Hippocampus Following Adolescent Binge Drinking

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“Adolescent binge drinking has lasting behavioral consequences by disrupting the endocannabinoid system (ECS) and depleting brain omega-3.

The natural accumulation of omega-3 fatty acids in cell membranes is crucial for maintaining the membrane structure, supporting interactions with the ECS, and restoring synaptic plasticity and cognition impaired by prenatal ethanol (EtOH) exposure. However, it remains unclear whether omega-3 supplementation can mitigate the long-term effects on the ECS, endocannabinoid-dependent synaptic plasticity, and cognition following adolescent binge drinking.

Here, we demonstrated that omega-3 supplementation during EtOH withdrawal increases CB1 receptors in hippocampal presynaptic terminals of male mice, along with the recovery of receptor-stimulated [35S]GTPγS binding to Gαi/o proteins. These changes are associated with long-term potentiation (LTP) at excitatory medial perforant path (MPP) synapses in the dentate gyrus (DG), which depends on anandamide (AEA), transient receptor potential vanilloid 1 (TRPV1), and N-methyl-D-aspartate (NMDA) receptors. Finally, omega-3 intake following binge drinking reduced the time and number of errors required to locate the escape box in the Barnes maze test.

Collectively, these findings suggest that omega-3 supplementation restores Barnes maze performance to levels comparable to those of control mice after adolescent binge drinking. This recovery is likely mediated by modulation of the hippocampal ECS, enhancing endocannabinoid-dependent excitatory synaptic plasticity.”

https://pubmed.ncbi.nlm.nih.gov/40564971/

“In summary, omega-3 intake mitigates some of the adverse effects of adolescent binge drinking on Barnes maze performance.”

“Omega-3 supplementation has also been shown to reverse synaptic plasticity impairments caused by prenatal EtOH exposure.”

https://www.mdpi.com/1422-0067/26/12/5507

“Hemp (Cannabis sativa L.) is a valuable source of omega-3 fatty acids.”

Recent Preclinical Evidence on Phytocannabinoids in Neurodegenerative Disorders: A Focus on Parkinson’s and Alzheimer’s Disease

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“The endocannabinoid system (ECS) is a vital biological network essential for maintaining homeostasis and supporting various physiological functions. It comprises cannabinoid receptors, endogenous lipid-based ligands, known as endocannabinoids, as well as metabolic enzymes and associated proteins responsible for regulating their levels within tissues. The ECS plays a central role in modulating processes involving the central nervous system (CNS). Recent studies have highlighted its antioxidant, anti-inflammatory, and neuroprotective properties.

The therapeutic potential of cannabinoids, particularly phytocannabinoids derived from plants, has attracted significant attention in medical and pharmaceutical research. This interest has grown in parallel with the increasing availability of cannabinoid-based food supplements on the pharmaceutical market. Given the complexity of the ECS and its broad range of interactions, the discovery of this system has spurred extensive investigations into the use of cannabinoids for various health conditions.

In this review, we examine recent preclinical evidence supporting the use of phytocannabinoids in the context of neurodegenerative diseases, particularly in Alzheimer’s disease and Parkinson’s disease. Targeting the ECS through phytocannabinoid-based pharmacological modulation offers a promising therapeutic strategy for these neurological disorders. Among these compounds, cannabidiol has emerged as a key focus of research due to its multifaceted effects and favorable safety profile. Nonetheless, continued investigation is necessary to clarify its mechanisms of action, and to develop effective, evidence-based clinical applications.”

https://pubmed.ncbi.nlm.nih.gov/40573285/

“Recent advances in cannabinoid research have shed light on the considerable therapeutic potential of phytocannabinoids, particularly CBD, in the treatment of neurodegenerative diseases.

The preclinical studies presented in this review demonstrate consistent neuroprotective, anti-inflammatory, antioxidant, and neuromodulator effects in models of AD, PD, or HD.

These effects are largely mediated through the complex interplay of phytocannabinoids with the ECS, as well as their interactions with non-cannabinoid targets, such as TRPV1, 5-HT1A receptors, and PPARs.The ECS emerges as a crucial modulator of CNS homeostasis, and its dysregulation appears to be closely linked with the pathophysiology of major neurodegenerative diseases.

Phytocannabinoid-mediated modulation of ECS activity has shown promising outcomes in various animal models, including reductions in neuroinflammation, attenuation of excitotoxicity, and preservation of cognitive and motor function.The evidence suggests that phytocannabinoids may contribute to neuronal preservation, attenuation of neuroinflammatory cascades, and improvement in motor and cognitive performance in disease models. Moreover, their favorable safety profile and ability to act on multiple molecular pathways position them as promising candidates for disease-modifying interventions.

As interest in cannabinoid pharmacotherapy continues to grow, phytocannabinoids represent a promising, multifaceted class of compounds with the potential to address unmet therapeutic needs in the field of neurodegeneration.”

https://www.mdpi.com/1424-8247/18/6/890

The endocannabinoidomes: Pharmacological redundancy and promiscuity, and multi-kingdom variety of sources and molecular targets

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“The endocannabinoid system (eCB) is a complex signaling network discovered in mammals during the 1980s-1990s.

It conventionally revolves around two arachidonic acid-derived mediators, N-arachidonoyl-ethanolamine (anandamide) and 2-arachidonoyl-glycerol; their main receptors, the cannabinoid receptors of type 1 (CB1) and type 2 (CB2), and the transient receptor potential vanilloid-1 channels; and the enzymes responsible for their biosynthesis and degradation. However, drawing on these discoveries, numerous eCB-like signaling lipids beyond the classical eCBs, have been unveiled, together with their receptors and metabolic enzymes, thus forming a more complex signaling network known as the endocannabinoidome (eCBome).

This review explores the physiology, pharmacological complexity, and molecular targets of the mammalian eCBome, highlighting its versatility and redundancy in the context of global health. Emerging mediators, metabolic pathways and mechanisms, receptors, and their implications in human physiology and pathology are described, particularly concerning metabolic disorders, pain, inflammation, neurodegenerative diseases, and cancer.

The importance of other “eCBomes” in nonmammalian forms of life that constitute the external and internal environments of mammals is also discussed for the first time in this context. The overarching objective of this article is to gain insights into the potential of eCBome-based therapeutic strategies aimed at enhancing both human and environmental well-being.

SIGNIFICANCE STATEMENT: Lipid-based signaling molecules are ubiquitous in nature, yet their study remains challenging due to intricate regulatory mechanisms. Among lipid signaling pathways, the endocannabinoid (eCB) system and its extended version, the endocannabinoidome (eCBome), are particularly remarkable. Comprising hundreds of mediators, and dozens of receptors and metabolic enzymes, the eCBome regulates critical physiological processes not only in mammals but also across diverse organisms, including plants, fungi, and bacteria. This article examines the evolutionary and functional diversity of eCBomes and highlights their untapped potential as multikingdom therapeutic targets to address pressing challenges in global health.”

https://pubmed.ncbi.nlm.nih.gov/40554266/

https://pharmrev.aspetjournals.org/article/S0031-6997(25)07478-2/abstract

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New cannabidiol structure-related terpene N-acyl-hydrazones with potent antinociceptive and anti-inflammatory activity

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“Inflammation is the organism’s protective mechanism to restore cellular and tissue homeostasis. Cannabidiol has been reported for its ability to bind to diverse receptors related to or not related to the endocannabinoid system, with good safety being one of the most promising phytocannabinoids for therapeutical purposes. CBD has shown in vitro and in vivo ability to significantly reduce the production of cytokines and other inflammatory mediators, with an unclear mechanism of action.

Herein, we report the design and synthesis of a novel series of eight terpene N-acylaryl hydrazone analogues and their pharmacological evaluation for potential antioxidant, antinociceptive, and anti-inflammatory properties.

Our results led to the identification of compounds 5a (PQM-242), with significant peripheral and central antinociceptive effects, 5b (PQM-243), and 5g (PQM-248) with antinociceptive activities probably related to the ability of modulation of TRPV1 receptors, and 5c (PQM-244) that seems to have the most promising peripheral antinociceptive profile, showing significant effects on both neurogenic and inflammatory phases of formalin-induced licking test, coupled to potential antioxidant activity.

Overall, our experimental data suggest that the new CBD-based architecture is capable of ensuring peripheral and central antinociceptive effects by different modes of action, with no in vivo toxicity and adequate predicted ADME properties.”

https://pubmed.ncbi.nlm.nih.gov/40521634/

“Several compounds showed similar antinociceptive and anti-inflammatory effects to those described for CBD.”

https://www.tandfonline.com/doi/full/10.1080/17568919.2025.2515821