Category Archives: Endocannabinoid System

Cannabidiol improves L-DOPA-induced dyskinesia and modulates neuroinflammation and the endocannabinoid, endovanilloid and nitrergic systems

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“Despite the widespread use of L-3,4-dihydroxyphenylalanine (L-DOPA) as the gold standard for dopamine (DA) replacement in Parkinson’s Disease (PD), its prolonged administration frequently leads to L-DOPA-induced dyskinesia (LID), a significant therapeutic challenge.

Modulating the endocannabinoid system has emerged as a promising approach for managing LID.

This study explored whether cannabidiol (CBD), a non-psychoactive compound of Cannabis sativa, and PECS-101, a fluorinated derivative of CBD, could mitigate the onset and progression of LID.

We used unilateral 6-hydroxydopamine-lesioned rats, treated with L-DOPA (10 mg kg – 1) for three weeks to induce severe abnormal involuntary movements (AIMs). Treatments were administered during the final two weeks. CBD (30 mg kg – 1) and PECS-101 (3 and 30 mg kg – 1) significantly reduced AIMs without impairing the motor benefits of L-DOPA.

The antidyskinetic effects of CBD were associated with decreased striatal Fos-B and phospho-ERK expression and were independent of lesion severity. CBD effects were prevented by antagonists of CB1 (1 mg kg – 1) and PPARγ (4 mg kg – 1) receptors. Co-administration of TRPV-1 antagonist capsazepine (5 mg kg – 1) enhanced the antidyskinetic effects of CBD. Combining the capsazepine with the neuronal nitric oxide synthase inhibitor, 7-nitroimidazole (10 mg kg – 1) enhanced these effects. CBD did not alter striatal DA levels but significantly increased the concentrations of anandamide and 2-arachidonoylglycerol in dyskinetic animals.

The antidyskinetic effects of CBD were associated with a reduction of the enhanced striatal glia and peripheral inflammation markers. These findings suggest that CBD alleviates LID by interacting with the nitrergic neurotransmission and TRPV-1, CB1, and PPARγ receptors.”

https://pubmed.ncbi.nlm.nih.gov/40684872/

“Cannabidiol (CBD), the primary non-psychotomimetic compound in Cannabis sativa, has shown promise in PD and LID treatment (Junior et al., 2020; Fernández-Ruiz et al., 2013). Its pharmacological profile includes neuroprotective, anti-inflammatory, and antioxidant properties, as well as interaction (either directly or indirectly) with several receptors associated with LID (Ibeas Bih et al., 2015; Devinsky et al., 2014). CBD also protects neurons from toxic insults by modulating glutamatergic and dopaminergic signaling (Fogaça et al., 2012; Kim et al., 2006).”

https://www.sciencedirect.com/science/article/abs/pii/S0278584625002106?via%3Dihub

Effects of five cannabis oils with different CBD: THC ratios and terpenes on hypertension, dyslipidemia, hepatic steatosis, oxidative stress, and CB1 receptor in an experimental model

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“Background: Non-alcoholic fatty liver disease (NAFLD) is a common liver disorder caused by oxidative stress and dysregulation of lipid metabolism. The endocannabinoid system (ECS), particularly the type 1 cannabinoid (CB1) receptor, plays a crucial role in NAFLD progression. Cannabinoids, such as cannabidiol (CBD) and tetrahydrocannabinol (THC), along with terpenes, such as beta-myrcene and d-limonene, have shown potential therapeutic effects on liver health, particularly in reducing oxidative stress and modulating lipid metabolism.

This study aimed to analyse the effects of five cannabis oils (COs), each with different CBD:THC ratios and terpenes content, on hypertension, dyslipidemia, hepatic steatosis, oxidative stress, and CB1 receptor expression in an experimental model of NAFLD induced by a sucrose-rich diet (SRD) in Wistar rats for 3 weeks.

Methods: Male Wistar rats were fed either a: (1) reference diet (RD; standard commercial laboratory diet) or a: (2) sucrose-rich diet (SRD) for 3 weeks. 3 to 7 SRD + CO as following: (3) SRD + THC; (4) SRD + CBD; (5) SRD + CBD:THC 1:1; (6) SRD + CBD:THC 2:1; and (7) SRD + CBD:THC 3:1. The COs were administered orally at a dose of 1.5 mg total cannabinoids/kg body weight daily. The cannabinoid and terpenes content of all COs used in the study was determined. The terpenes found in COs were beta-myrcene, d-limonene, terpinolene, linalool, beta-caryophyllene, alpha-humulene, (-)-guaiol, (-)-alpha-bisabolol. During the experimental period, body weight, food intake and blood pressure were measured. Serum glucose, triglyceride, total cholesterol, uric acid, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (AP) levels were evaluated. Liver tissue histology, NAFLD activity score (NAS), triglyceride and cholesterol content, lipogenic enzyme activities, enzyme related to mitochondrial fatty acid oxidation, reactive oxygen species (ROS), thiobarbituric acid reactive substance (TBARS), and antioxidant enzyme activities were also evaluated. The CB1 receptor expression was also determined.

Results: The results showed that SRD-fed rats developed hypertension, dyslipidemia, liver damage, hepatic steatosis, lipid peroxidation, and oxidative stress. This was accompanied by upregulation of liver CB1 receptor expression. CBD-rich CO, CBD:THC 1:1 ratio CO; CBD:THC 2:1 ratio CO and CBD:THC 3:1 ratio CO showed antihypertensive properties. THC-rich CO, CBD:THC 1:1 ratio CO; CBD:THC 2:1 ratio CO showed the greatest beneficial effects against hepatic steatosis and liver damage. All COs exhibited antioxidant effects in liver tissue. This was associated with normal liver CB1 receptor expression.

Conclusions: This study demonstrated that COs, particularly THC-rich CO, CBD:THC ratio 1:1 CO, CBD:THC ratio 2:1 CO and terpenes, can effectively reduce dyslipidemia, liver damage and hepatic steatosis in SRD-induced NAFLD. COs with a higher proportion of CBD in their composition showed antihypertensive properties. All the COs exhibited antioxidant properties. These findings suggest that COs, especially those with CBD:THC ratios of 1:1 and 2:1 and terpenes, may represent a promising therapeutic approach for managing NAFLD and preventing its progression to more severe liver disease.”

https://pubmed.ncbi.nlm.nih.gov/40660358/

“This study demonstrated that COs, particularly THC-rich formulations, and those with CBD:THC ratios of 1:1 and 2:1, effectively reduced dyslipidemia, hepatic steatosis, and liver damage in SRD-induced NAFLD. All COs exhibited significant antioxidant properties, which contributed to the attenuation of oxidative stress. Notably, oils containing CBD also displayed antihypertensive effects, likely due to their vasodilatory properties. The modulation of CB1 receptor is closely linked to the improvement in hepatic steatosis and oxidative stress. These results underscore the synergistic role of cannabinoids and terpenes in targeting key mechanisms involved in NAFLD pathophysiology.”

“These findings suggest that COs, especially those with balanced CBD: THC ratios (1:1 and 2:1) and with meaningful terpenes content, represent a promising therapeutic approach for managing NAFLD and preventing its progression to more severe liver diseases.”

https://jcannabisresearch.biomedcentral.com/articles/10.1186/s42238-025-00286-8

The Role of the Endocannabinoid System in the Mechanism of Action of Nonopioid Analgesics

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“The endocannabinoid system (eCBS) plays a crucial role in pain modulation through its components, including endocannabinoids, cannabinoid receptors (CB1 and CB2), and metabolic enzymes.

Recent research highlights the interaction between the eCBS and non-opioid analgesics, including nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, and pyrazolones. These agents may enhance endogenous endocannabinoid levels or influence eCBS signaling pathways, providing a multifaceted approach to pain relief.

This review examines the pharmacological mechanisms underlying these interactions, focusing on the potential of non-opioid eCBS interactions, detailing synergistic effects that could improve analgesic efficacy while minimizing side effects. Additionally, we explore the therapeutic implications of co-administering non-opioid analgesics with eCBS modulators to create more effective pain management strategies.

The combined modulation of non-opioid pathways and the eCBS represents a promising treatment for acute and chronic pain, warranting further clinical investigation and translational research in this evolving field.”

https://pubmed.ncbi.nlm.nih.gov/40659176/

“Emerging Therapeutic Strategies: The integration of non-opioid medications with eCBS modulators represents a novel approach in pain management strategies, aiming to minimize opioid use while maximizing therapeutic efficacy and safety profiles during chronic pain management.”

https://www.sciencedirect.com/science/article/abs/pii/S0014299925007009?via%3Dihub

Dysregulation of the Cannabinoid System in Childhood Epilepsy: From Mechanisms to Therapy

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“Epilepsy affects over 12 million children worldwide, with approximately 30% classified as having drug-resistant epilepsy (DRE), often accompanied by neuropsychiatric comorbidities that severely impact quality of life.

The endocannabinoid system (ECS) functions as a multifaceted neuromodulatory network regulating neuronal excitability, synaptic plasticity, and immune homeostasis from early life through adolescence and into aging. In pediatric epilepsies, alterations in ECS components, particularly CB1 receptor expression and endocannabinoid levels, reveal disorder-specific vulnerabilities and therapeutic opportunities.

Cannabidiol (CBD), a non-psychoactive compound from Cannabis sativa, has shown strong preclinical and clinical efficacy in treating DRE and is approved for Dravet syndrome, Lennox-Gastaut syndrome, and Tuberous Sclerosis Complex. Other ECS-based strategies, such as the use of CB1 receptor-positive allosteric modulators, can selectively enhance endogenous cannabinoid signaling where and when it is active, potentially reducing seizures in conditions like Dravet and absence epilepsy. Similarly, FAAH and MAGL inhibitors may help restore ECS tone without directly activating CB1 receptors.

Precision targeting of ECS components based on regional expression and syndrome-specific pathophysiology may optimize seizure control and associated comorbidities. Nonetheless, long-term pediatric use must be approached with caution, given the critical role of the ECS in brain development.”

https://pubmed.ncbi.nlm.nih.gov/40650012/

“In conclusion, alterations in the ECS are likely involved in the pathophysiology of childhood epilepsy. Precision targeting of ECS components, considering regional CB1R density, fluctuating eCB levels, and syndrome-specific ECS pathophysiology, may offer a more rational and safer strategy for pediatric epilepsy cases with multifactorial etiologies. “

https://www.mdpi.com/1422-0067/26/13/6234

Long-term cannabinoid therapy can ameliorate chronic sleep deprivation-induced behavioral and neuroinflammatory changes in mice

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“Endocannabinoid system is an important contributor to body’s immune responses which are significantly impaired by chronic sleep deprivation (cSD). Although cannabinoids can modulate the endocannabinoid system, most are understudied, especially regarding cSD.

To investigate the therapeutic potential of CBD, CBG, CBC and their combinations, current study analyzed cSD-induced memory impairment, depression, microglial responses, cytokine profile and therapeutic effects of cannabinoid treatments using behavioral test and ELISA. Furthermore, molecular docking of these cannabinoids was performed to deduce the binding affinity with cannabinoid receptors and possible entrouge effects.

The results showed that memory impairment and depression were more evident in cSD groups. Moreover, microglial activation and pro-inflammatory polarization was also more evident and was supported by increased pro-inflammatory cytokine concentrations in cSD groups.

These changes were significantly reversed the cannabinoid groups but the combination of CBD + CBC was more effective than other treatments in reversing these cSD-induced behavioral and neuroinflammatory changes. Whereas, the molecular docking results also corroborated with the neuroimmunological changes observed in the current study, pointing towards the possible therapeutic role.

SIGNIFICANCE STATEMENT: Chronic SD employs microglial activation/polarization, to exert behavioral impairments and neuroinflammation.

This study signifies the therapeutic potential of proper sleep and cannabinoid intake.”

https://pubmed.ncbi.nlm.nih.gov/40628367/

“This study demonstrates the therapeutic efficacy of cannabinoid treatments in ameliorating cSD-induced behavioral and neuroinflammatory alterations. Notably, a multiple-compound treatment of CBD and CBC exhibited superior effectiveness compared to single-compound treatments. These findings suggest potential avenues for developing effective interventions against cSD-induced detrimental changes.”

https://www.sciencedirect.com/science/article/abs/pii/S0304394025002022?via%3Dihub

Treatment of Migraine With Phytocannabinoids, the Involvement of Endocannabinoids in Migraine, and Potential Mechanisms of Action

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“The American Migraine Foundation estimates that over 39 million Americans and over 1 billion people worldwide suffer from some form of migraine. Treatment of migraine generally falls into two categories: treatment of attacks once they have begun, and prophylactic prevention, including lifestyle changes. The use of phytocannabinoids to reduce both the frequency and severity of migraine is widely documented in scientific, grey, and popular literature. This review provides descriptions of both preclinical and clinical studies involving the treatment of migraines with phytocannabinoids as well as the involvement of endocannabinoids and endocannabinoid-like compounds in migraine pathology, including the receptors and associated mechanisms. Currently unanswered questions and areas for further exploration are discussed.”

https://pubmed.ncbi.nlm.nih.gov/40630421/

“The clinical studies published to date strongly suggest that phytocannabinoids are useful for mitigating migraine pain and for migraine prophylaxis. Further, studies show the potential for endocannabinoid and endocannabinoid-like compounds in migraine treatment.”

https://onlinelibrary.wiley.com/doi/10.1155/prm/7181066

“Migraine, fibromyalgia, IBS and related conditions display common clinical, biochemical and pathophysiological patterns that suggest an underlying clinical endocannabinoid deficiency that may be suitably treated with cannabinoid medicines.”

https://pubmed.ncbi.nlm.nih.gov/15159679/

A 1:1 combination of cannabidiol and Δ9-tetrahydrocannabinol inhibit toll-like receptor 7- and 8-mediated inflammation in human immune cells

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“Cannabinoid regulation of endosomal signalling via innate immune toll-like receptors (TLRs) is understudied. Endosomal cell signalling via TLR7 and TLR8 governs cellular responses to infection with viral and bacterial single-stranded RNA. TLR7/8 activation is associated with neuroinflammation, with inappropriate activation of TLR7/8 linked to the propagation of autoimmune disease. Following activation, TLR7 and TLR8 control the cellular production of cytokines, chemokines and type I interferons (IFNs).

In this study we focused on two clinically relevant plant-derived (phyto) cannabinoids, cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC), given that cannabinoid-based therapeutics containing these compounds are currently available in the form of sativex® (nabiximols) and epidiolex®. The study aim was to determine the anti-inflammatory effects of CBD and THC, when delivered in isolation and in a sativex-like combination (1:1), on TLR7/8-induced inflammation in immune cells.

We employed the use of CL075 (3M-002), a thiazoloquinolone derivative that acts as an agonist of both TLR7 and TLR8. Using THP-1-derived macrophages and primary peripheral blood mononuclear cells (PBMCs) from healthy control subjects, we demonstrate that TLR7/8 activation promoted the time- and concentration-dependent production of the chemokine CXCL10, cytokine TNFα and type I IFNs in both macrophages and PBMCs. TLR7/8 activation promoted nuclear factor (NF)-κB activation, p38 MAPK phosphorylation and the transcription of interferon regulator factor 7 (IRF7).

We assessed the anti-inflammatory effects of CBD and THC, when delivered alone and in a 1:1 combination, on CL075-stimulated inflammatory mediator production in macrophages/PBMCs. Data presented herein indicate that CBD and THC, particularly when delivered in a 1:1 combination, can act as TLR7/8 immunomodulatory drugs to dampen inflammation in macrophages and PBMCs.

This study provides evidence that phytocannabinoids target TLR7/8-induced viral signalling on endosomal compartments to control inflammation in immune cells.”

https://pubmed.ncbi.nlm.nih.gov/40615103/

“The significant finding is that CBD and THC can differentially ameliorate TLR7/8-induced inflammation in immune cells, depending on whether the cannabinoids are administered alone or in combination. In particular, the 1:1 combination of CBD:THC (at 10 μM) was consistently anti-inflammatory in immune cells stimulated with CL075. The CB1, CB2, PPAR-γ and A2A receptors do not mediate the anti-inflammatory propensity of the phytocannabinoids in our cell models of inflammation.

Overall, data presented herein identifies TLR7/8-mediated inflammation as a phytocannabinoid target, and gives important insight regarding the cellular mechanisms by which CBD and THC regulate inflammation.”

https://www.sciencedirect.com/science/article/pii/S0014299925006326?via%3Dihub

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