Category Archives: Endocannabinoid System

The role of cannabinoid ligands in neurodegenerative diseases: emerging anti-inflammatory, immunomodulation and disease-modifying perspectives

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“Neurodegenerative diseases (NDs) constitute a growing global health burden driven by population aging and remain without disease-modifying therapies. Although chronic neuroinflammation and aberrant protein aggregation are widely recognized as shared pathological hallmarks of major NDs – including Alzheimer’s, Parkinson’s, Huntington’s diseases and multiple sclerosis – the causal relationships linking immunoinflammatory signaling to neurodegenerative progression remain contentious. Therapeutic strategies targeting neuroinflammation have thus far yielded limited clinical success, underscoring the need for mechanistically grounded and context-specific interventions.

The endocannabinoid system (ECS) is a key regulator of synaptic function, glial activity, and immune homeostasis in the central nervous system (CNS), and its dysregulation has been consistently reported in neurodegenerative settings. However, ECS alterations across NDs are heterogeneous and often disease- and stage-dependent, with conflicting findings regarding cannabinoid receptor expression, endocannabinoid tone, and functional outcomes.

Moreover, while preclinical studies demonstrate robust anti-inflammatory and neuroprotective effects of cannabinoid ligands, clinical translation has been constrained by issues of receptor specificity, psychoactive side effects, limited brain penetration, and an incomplete understanding of long-term ECS modulation.

In this Review, we critically evaluate current evidence linking ECS signaling to neuroinflammatory mechanisms in neurodegeneration, highlighting both convergent pathways and unresolved controversies. We discuss the translational implications of ECS-targeted strategies, including the development of selective receptor modulators, allosteric and/or bitopic/dualsteric ligands, and enzyme inhibitors, as well as emerging approaches to mitigate adverse effects and improve therapeutic precision.

By integrating mechanistic insights with clinical challenges, this Review delineates key obstacles and opportunities for advancing ECS-based interventions toward disease-modifying therapies for neurodegenerative disorders.”

https://pubmed.ncbi.nlm.nih.gov/41937092

“These findings are particularly relevant for the development of next-generation cannabinoid therapeutics designed to selectively engage beneficial signaling pathways while minimizing adverse effects.”

https://www.sciencedirect.com/science/article/pii/S1043661826001003?via%3Dihub


Radical Revelations: The Interplay of Nitrosative Stress, the Endocannabinoid System, and Treatment of Age-Related Disorders

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“The crosstalk between the endocannabinoid system (ECS) and reactive nitrogen species (RNS) has emerged as an important area of investigation in recent years.

Although many aspects of this interaction remain elusive, accumulating evidence demonstrates that the ECS plays a critical role in regulating RNS-mediated signaling under physiological conditions. This modulation can be either inhibitory or stimulatory, depending on the specific receptor subtype, cell type, and tissue location involved.

While ECS-RNS interactions support normal cellular homeostasis, their dysregulation contributes to various disease states, particularly neurodegenerative disorders. Studies in both rodent models and human subjects show that ECS modulation can reduce anxiety, attenuate neuroinflammatory responses, and slow disease progression in neurodegenerative conditions.

This review examines how cannabinoid-based interventions modulate nitrosative stress and neuroinflammation in Alzheimer’s disease (AD) and Parkinson’s disease (PD), highlighting their potential as targeted therapeutics that address multiple pathological mechanisms simultaneously and may offer advantages over conventional treatment approaches.”

https://pubmed.ncbi.nlm.nih.gov/41898672

“cannabinoid treatment offers a promising alternative to conventional treatments by addressing symptomology and the underlying molecular mechanisms of these diseases. Cannabinoid treatment uniquely addresses AD and PD pathology via crosstalk between the RNS and ECS, which provides hope for disease modification as an alternative to/supplement to conventional treatments.”

https://www.mdpi.com/1422-0067/27/6/2813


The Diminished Availability of 2-AG in Aged Synaptic Terminals is Ameliorated by a Full-Spectrum Cannabis Extract with a High THC Content

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“We have previously demonstrated that the endocannabinoid system is dysregulated in the synaptic terminals of the cerebral cortex in aged rats. Specifically, the availability of the neuroprotective endocannabinoid 2-arachidonoylglycerol (2-AG) is reduced due to impairments in the enzymes involved in its metabolism, a deficit only partially compensated by the binding of cannabinoid receptor ligands.

Given that ∆9-tetrahydrocannabinol (THC) acts as a ligand for cannabinoid receptors (CBR), we designed the present study to investigate the effects of a full-spectrum cannabis extract with a high THC content, the THC-free fraction of this cannabis extract, and pure THC on the previously mentioned aging model. Thus, 2-AG metabolic enzymes were assayed incubating synaptosomes from aged and adult rat cerebral cortex, with ethanolic cannabis extract, the THC-free fraction of this cannabis extract or pure THC, and the corresponding radiolabeled substrates.

Our key findings indicate that the age-related decline in 2-AG bioavailability: (a) is exacerbated in the presence of either the THC-free fraction from the cannabis extract or pure THC, primarily due to a significant decrease in 2-AG synthesis; and (b) is partially mitigated by the inhibition of 2-AG hydrolysis when the extract contains THC.

These results provide compelling evidence for the regulation of 2-AG metabolism by a full-spectrum cannabis extract with high THC content, supporting the theory of the entourage effect among cannabis phytochemicals.

This highlights the potential of high THC content extracts as therapeutic agents for restoring the decreased 2-AG levels observed in the aging brain.”

https://pubmed.ncbi.nlm.nih.gov/41880097

https://link.springer.com/article/10.1007/s11064-026-04739-1

Cannabis oil modulates liver alterations and endocannabinoid system changes in a female rat model of diet-induced MASLD

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“Introduction: Metabolic dysfunction-associated steatotic liver disease (MASLD) is closely linked to alterations in liver lipid metabolism, oxidative stress, fibrosis, and dysregulation of the endocannabinoid system (ECS). Although increasing evidence supports a role for cannabinoids in metabolic disorders, most preclinical studies have been conducted in male models, leaving female-specific responses largely unexplored.

Methods: This study evaluated the effects of oral administration of a full-spectrum cannabis oil (CBD:THC 2:1) on MASLD-related alterations and ECS regulation in female Wistar rats fed a sucrose-rich diet (SRD). Rats were assigned to reference diet (RD), SRD, or SRD plus cannabis oil (1 mg/kg/day) for 3 weeks.

Results: SRD-fed rats developed liver steatosis and increased NAFLD activity score (NAS), accompanied by enhanced de novo lipogenesis, reduced mitochondrial fatty acid oxidation, increased oxidative stress, early fibrotic changes, and ECS overactivation. Cannabis oil administration improved liver lipid metabolism, reduced NAS and fibrosis markers, attenuated lipid peroxidation and oxidative stress, increased NrF2 and decreased NF-κB p65 expression, and normalized hepatic CB1 expression and circulating endocannabinoid levels.

Discussion: These findings demonstrate that full-spectrum cannabis oil is associated with improved MASLD-related outcomes and modulation of ECS tone in a female-specific model of diet-induced metabolic liver disease.”

https://pubmed.ncbi.nlm.nih.gov/41883411

“For millions of years, medicinal plants have been employed in the treatment and handling of liver diseases”

 “Our results indicate that cannabis oil with this particular CBD:THC ratio may serve as a natural nutraceutical to help prevent metabolic disorders linked to hepatic steatosis, oxidative stress, liver fibrosis, and MASLD.”

https://www.frontiersin.org/journals/nutrition/articles/10.3389/fnut.2026.1770150/full

A sesquiterpene-rich essential oil from Cannabis sativa L. attenuates symptoms and neuroinflammation in experimental autoimmune encephalomyelitis model through a CB2-mediated signalling

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“Background: The efficacy of cannabinoid-based medication as analgesic and neuroprotective in multiple sclerosis (MS) has been described, but little is known on other cannabis active compounds, such as terpenes.

Purpose: To investigate the therapeutic potential and molecular mechanism of non-psychotropic Cannabis sativa L. essential oil (EO) in an animal model of MS.

Methods: Chemical composition of EO was analyzed using GC-MS and GC-FID. Mouse model of experimental autoimmune encephalomyelitis (EAE) was employed to evaluate EO efficacy on pain (hot and cold plate test, von Frey test), motor disability (clinical score, rotarod), emotional alterations (sucrose splash test, tail suspension test, open field, light-dark box test) (n = 11). Tissues and LPS-stimulated BV2 cells were analyzed by Western blot, immunofluorescence, Luxol Fast Blue (LFB), hematoxylin and eosin (H&E) staining, UHPLCHRMS analysis.

Results: β-caryophyllene, α-humulene, and caryophyllene oxide were the most abundant EO constituents. Intranasal administration of EO attenuated thermal and mechanical hypersensitivity, promoted motor function recovery, and induced antidepressant- and anxiolytic-like effects in EAE mice. EO increased LFB staining and MBP content while reducing H&E staining. In spinal cord and hippocampal tissues, EO reduced proinflammatory microglia (CD11b/IBA-1 ratio), restored the IL-17/IL-10 balance, and promoted a shift of microglia toward an anti-inflammatory phenotype by increasing CD206 and FoxP3 expression. Mechanistically, EO markedly upregulated CB2 receptor expression in both EAE mice and LPS-stimulated BV2 cells. The protective effect of EO was abolished by a CB2 antagonist (AM630) but not by CB1 blockade (AM251).

Conclusion: Intranasal EO alleviates EAE symptoms and comorbidities through a CB2-mediated attenuation of neuroinflammation and demyelination.”

https://pubmed.ncbi.nlm.nih.gov/41875735

“Studies on the use of medical cannabis in the treatment of MS suggest a reduction in pain and spasticity and most clinical trials have shown symptom improvement with cannabis-based drugs administration”

“Present findings provide the first evidence that a sesquiterpene-rich EO obtained from non-psychoactive C. sativa mitigates EAE neurological symptoms, alleviating pain hypersensitivity, motor disability and mood-related comorbidities through a CB2-mediated anti-neuroinflammatory mechanism.”

https://www.sciencedirect.com/science/article/pii/S0944711326003041?via%3Dihub

Bridging reward and resilience: the endocannabinoid system as a unifying mechanism in exercise-induced protection against major depressive disorder

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“Major depressive disorder (MDD) refers to a complex mental disorder defined by hindered reward system and hindered stress resilience. The limitations of traditional monoamine antidepressants have prompted the academic community to study new pathological processes and intervention strategies. Major depressive disorder arises from a complex interplay of psychological, social, and biological factors.

Among the latter, dysfunction of the endocannabinoid system (ECS) has emerged as a critical pathological mechanism contributing to the core symptoms.

This review demonstrates the key idea that exercise as a powerful non-pharmacological intervention can increase stress resilience and exert antidepressant effects by positively activating the ECS.

Exercise, especially moderate intensity aerobic exercise, can significantly increase the levels of major endogenous cannabinoids AEA and 2-AG, and exert effects at multiple levels by activating CB1 receptors: at the acute level, it can immediately promote mood, generate analgesic effects and improve the termination of the stress response; At the long-term level, it can drive synaptic plasticity, facilitate hippocampal neurogenesis, and regulate neuroimmunity, thereby obtaining lasting structural improvement of emotional and stress neural circuits.

These processes work together to reshape the brain’s reward function and establish internal resilience against stress. In comparison to drug therapy, ECS-regulated exercise interventions have the unique benefits of high safety, systemic advantages, and endogenous reward reinforcement.

Thus, individualized exercise therapy for ECS represents a promising mechanism-induced non-pharmacological intervention approach offering a new aspect and perspective for the prevention and rehabilitation of depression.”

https://pubmed.ncbi.nlm.nih.gov/41877874

https://www.frontiersin.org/journals/psychiatry/articles/10.3389/fpsyt.2026.1766980/full

“Exercise activates the endocannabinoid system”

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

Enhancing the endocannabinoid system to treat residual disease in relapse-free multiple sclerosis

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“The recent introduction of High-Efficacy Therapies (HETs) in clinical practice has drastically reduced the frequency of acute inflammatory episodes and relapses, in patients with Multiple Sclerosis (MS), gradually shifting the interest of clinicians toward preventing disease progression and treating symptoms associated with the residual disease. This article summarizes the output of a recent meeting (June 2025, in Rome) among an Italian group of neurologists, who discussed about published evidence supporting the involvement of the endocannabinoid system (ECS) in MS spasticity and its associated symptoms. Sharing their clinical experiences about the silent progression of the disease, in patients with Relapse-Free Multiple Sclerosis (RFMS), treated with HETs, authors propose a new algorithm to treat residual disease in RFMS, by enhancing ECS with both cannabinoid agents and lifestyle interventions (diet and physical activity).”

https://pubmed.ncbi.nlm.nih.gov/41859417

“authors developed a treatment algorithm, emphasizing the importance of timely intervention both with an increase in endogenous cannabinoids, through diet and physical activity, and with the use of an exogenous cannabinoid agent such as nabiximols.”

https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2026.1747131/full

“Nabiximols (brand name Sativex) is a pharmaceutical-grade, oromucosal spray containing a 1:1 ratio of cannabinoids THC and CBD derived from Cannabis sativa.”

Cannabinoids and cognition in Parkinson’s disease: Insights from animal models and emerging clinical evidence

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“Parkinson’s disease (PD) is a progressive, multisystem neurodegenerative disorder characterized not only by motor impairments but also by a broad spectrum of debilitating non-motor symptoms, including cognitive decline. The cognitive function depends on neuronal plasticity, which is tightly regulated by multiple signaling systems, among which the endocannabinoid system (ECS) plays a significant role.

Over the past three decades, substantial evidence has accumulated regarding how endogenous cannabinoids, plant-derived cannabinoids, and pharmacological modulators of ECS signaling influence synaptic plasticity, neuronal excitability, and neuroinflammation – processes that are critical in PD pathophysiology.

This narrative review synthesizes experimental and clinical evidence on the effects of cannabinoid compounds on cognition in preclinical PD models and patients. Available clinical data are limited, heterogeneous, and often underpowered, with cognition frequently assessed as a secondary outcome. Observed variability in cognitive effects likely reflects differences in cannabinoid formulation, dose and treatment duration, study design, patient characteristics, and the use of heterogeneous cognitive endpoints across studies.

Cannabinoid-based interventions hold promise for preserving neural circuits and modulating cognitive function in PD; however, well-designed, mechanism-informed trials with standardized, domain-specific cognitive endpoints are essential before clinical recommendations can be made.”

https://pubmed.ncbi.nlm.nih.gov/41864320

“Endocannabinoid system participates in cognitive modulation in Parkinson’s disease.”

https://www.ibroneuroscience.org/article/S0306-4522(26)00197-1/abstract

Therapeutic relevance of an EU-GMP certified Cannabis sativa L. strain in a dual in vivo model of cognitive impairment and chronic neuropathic pain

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“Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and frequently co-occurs with chronic pain. Worldwide, over 55 million people are affected by AD, with nearly half experiencing persistent pain. Chronic pain has been linked to accelerated memory deterioration and an increased risk of dementia, but the interplay between these conditions remains poorly understood. Existing therapies for AD and chronic pain are limited in efficacy, highlighting the need for interventions targeting multiple pathological pathways. The endocannabinoid system, which is altered in both AD and chronic pain, represents a potential therapeutic target, though its role in AD patients with comorbid pain remains unexplored.

Methods: The study evaluated the effects of an EU-GMP certified Cannabis sativa L. strain (5 mg/kg, Cannabixir® Medium Flos) on neurobiological alterations in a rat model designed to explore mechanistic interactions between scopolamine-induced transient cognitive impairment and chronic neuropathic pain induced by unilateral sciatic nerve ligation. Treatment outcomes were assessed through nociceptive tests, clinical monitoring and tissue analyses to examine cognitive and pain-related effects.

Results: Cannabixir® Medium Flos induced robust, time-dependent analgesia in thermal nociceptive tests, with the combination of the Cannabis sativa L. strain, donepezil and tramadol producing significantly longer response latencies than tramadol alone. Mechanical sensitivity was minimally affected across treatments. Immunohistochemical analyses revealed that Cannabixir® Medium Flos, either alone or in combination with donepezil or tramadol, produced the most pronounced neuroprotective effects, reducing astrocytic (GFAP) and microglial (Iba1) activation, lowering Caspase-3 and IL-6 expression, and preserving both hippocampal neuronal integrity as well as peripheral nerve structure.

Conclusion: These findings indicate that Cannabixir® Medium Flos, particularly when combined with donepezil and tramadol, provides superior analgesic and neuroprotective effects compared to tramadol alone. Its multi-target action – alleviating thermal nociception, reducing neuroinflammation, limiting apoptosis and preserving neuronal and peripheral nerve integrity-supports its potential as an adjunct therapy in managing dementia with comorbid chronic neuropathic pain. Future studies should explore the molecular mechanisms underlying these effects and assess long-term safety and efficacy across diverse models of neurodegeneration and chronic pain.”

https://pubmed.ncbi.nlm.nih.gov/41800101

https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2026.1761426/full

Peripheral Cannabinoid Receptor Activation Attenuates Frostbite-Induced Chronic Pain via Modulation of TRP Channels, Neuroinflammation, and Autophagy

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“Frostbite injury is a debilitating cold injury encountered in extreme high-altitude and subzero environments, frequently resulting in persistent chronic pain even after tissue healing. Using our previously validated frostbite-induced chronic pain model, we further investigated the contribution of neuroimmune, excitatory mechanisms and evaluated the therapeutic efficacy of peripheral cannabinoid receptor activation.

Frostbite produced significant mechanical allodynia, mechanical hyperalgesia, and cold hypersensitivity, along with increased spontaneous nocifensive behaviors.

Local peripheral administration of CB13, a peripherally acting CB1/CB2 receptor dual agonist, dose-dependently attenuated both mechanical and cold allodynia without impairing locomotor activity, indicating a lack of central nervous system side effects.

At the molecular level, frostbite induced marked peripheral and spinal sensitization, demonstrated by elevated expression of TRPV1, TRPA1, TRPV4, and TRPM8 channels, increased levels of pro-inflammatory cytokines, and enhanced c-Fos expression as an indicator of heightened neuronal activation in pain-relevant regions. These alterations were accompanied by pronounced microglial activation and upregulation of the NLRP3 inflammasome.

CB13 treatment significantly reversed these pathological changes and concurrently restored Beclin-1-associated autophagy signaling, suggesting engagement of both neuroimmune resolution and intracellular homeostasis pathways. Notably, frostbite injury was associated with marked oxidative and nitrosative stress in the sciatic nerve, as evidenced by reduced glutathione depletion and elevated lipid peroxidation and nitrite levels, which were significantly normalized by CB13 treatment.

Collectively, these findings demonstrate that peripheral cannabinoid receptor activation effectively inhibit frostbite induced chronic pain through modulation of nociceptive, neuroinflammatory, redox, and cellular stress pathways.

This work highlights peripherally selective cannabinoid receptor agonists as promising, safer therapeutic strategies for chronic pain associated with cold injuries.”

https://pubmed.ncbi.nlm.nih.gov/41802611

“This study demonstrates that peripheral cannabinoid receptor activation via CB13 effectively alleviates frostbite-induced chronic pain by targeting multiple pathological mechanisms, including nociceptor hyperexcitability, spinal neuronal activation, neuroinflammation, inflammasome signaling, oxidative stress, and impaired autophagy.”

https://www.sciencedirect.com/science/article/abs/pii/S0891584926001565?via%3Dihub