Category Archives: Endocannabinoid System

Cannabis sativa Root Extract Exerts Anti-Nociceptive and Anti-Inflammatory Effects via Endocannabinoid Pathway Modulation In Vivo and In Vitro

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“Cannabis sativa root has traditionally been used to relieve pain and inflammation, but its pharmacological properties remain underexplored due to low levels of psychoactive cannabinoids.

This study aimed to investigate the anti-inflammatory and antinociceptive effects of the ethyl acetate fraction of Cannabis sativa root (CSREA) using in vivo rodent pain models. Mice were subjected to formalin and acetic acid-induced nociceptive tests, while rats were evaluated using a carrageenan-induced paw edema model.

CSREA significantly reduced pain-related behaviors in both early (0-10 min) and late phases (15-30 min) of the formalin test and decreased writhing responses in the acetic acid model. Notably, CSREA also improved survival rates following acetic acid injection. Inflammatory markers, including IL-6 and IL-1β, were significantly lowered in serum.

Furthermore, CSREA suppressed paw edema and redness in the carrageenan-induced rat model, demonstrating dose-dependent anti-inflammatory efficacy comparable to diclofenac. CSREA also downregulated pain-related gene expression (SCN9A, ASIC1A, TACR1) and regulated key enzymes involved in endocannabinoid metabolism (FAAH, MAGL, DAGL), suggesting its role in the molecular modulation of pain pathways.

These effects are likely mediated via modulation of the endocannabinoid system, particularly by rebalancing the CB1R/CB2R ratio. The findings suggest that CSREA holds promise as a natural therapeutic agent for managing pain and inflammation and warrants further investigation into its molecular mechanisms and long-term effects.”

https://pubmed.ncbi.nlm.nih.gov/41009431/

“This study provides evidence for the in vivo analgesic and anti-inflammatory effects and underlying mechanism of CSREA in vitro. Our results from the formalin and writhing tests demonstrate that CSREA significantly reduced nociceptive pain-related behaviors and inflammatory cytokine levels indicating strong anti-nociceptive properties in a dose-dependent manner. In addition, CSREA markedly reduced paw edema in the carrageenan-induced rat model, suggesting its potential as a natural product with anti-inflammatory activity. These effects are likely mediated through modulation of the endocannabinoid system, particularly by altering cannabinoid levels as demonstrated in the in vitro model.”

https://www.mdpi.com/1422-0067/26/18/8863

Putative Effects of Lead on the Endocannabinoid System: A Literature Review and Summary

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“Lead is a naturally occurring metal found in numerous compounds used in everyday life. Toxicity from lead is a well-known public health problem. Its effects are implicated in multiple tissues, encompassing the gastrointestinal, renal, cardiovascular, and neurological systems.

Endocannabinoid receptors are involved in each of these systems, but the effects of lead on the receptors themselves are not well elucidated. In the neurological system, lead has varying interactions with neurotransmitters and downstream regulators implicated in neuronal transmissions influenced by endocannabinoid receptor function.

Lead’s effect is likely indirect on endocannabinoid receptor function; however, its influence on neuronal function is likely inhibitory to the receptor’s functioning. Lead has also been implicated in oxidative stress states, which would influence endocannabinoid receptors’ function.

The literature clearly supports lead having a negative impact on the overall function of endocannabinoid receptors, setting the stage for pathological states related to diminished neurosynaptic function and, in embryology, altered neuronal development, especially of the neural tube.”

https://pubmed.ncbi.nlm.nih.gov/41009561/

https://www.mdpi.com/1422-0067/26/18/8994

Tetrahydrocannabivarin (THCV) Dose Dependently Blocks or Substitutes for Tetrahydrocannabinol (THC) in a Drug Discrimination Task in Rats

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“Delta-9-Tetrahydrocannabivarin (THCV), a naturally occurring cannabinoid and structural analog of THC, exhibits a dual pharmacological profile as a CB1 receptor agonist/antagonist and a partial CB2 agonist. This study evaluated the effects of THCV in a THC discrimination model in rats. Male Sprague-Dawley rats (n = 16, 300-340 g, PND60) were trained under a fixed ratio 20 (FR20) schedule to discriminate THC (3 mg/kg) from vehicle. Substitution tests were conducted with THC (0.325-3 mg/kg), THCV (0.75-6 mg/kg), and THC-THCV combinations. THCV produced an inverted U-shaped substitution curve, significantly differing from vehicle (p = 0.008). At 3 mg/kg, THCV partially substituted for THC (54.6% ± 17.82, p = 0.003). Response rate significantly increased during the substitution test with 3 mg/kg of THCV (p = 0.042). THCV (6 mg/kg) reversed THC (0.75 mg/kg)-induced responding (p = 0.040), with no significant change in response rate (p = 0.247). However, THCV combined with THC (1.5 mg/kg) affected response rates (p = 0.012), with 6 mg/kg significantly reducing rates vs. 3 mg/kg (p = 0.013). Blood THC and 11-OH-THC levels remained unchanged when THC was combined with THCV. The findings suggest THCV can partially mimic or block THC’s discriminative effects in a dose-dependent manner, possibly acting as a partial CB1 agonist.”

https://pubmed.ncbi.nlm.nih.gov/41008636/

“Taken together, our findings highlight THCV’s unique pharmacological profile, characterized by partial agonism dose-dependent substitution for THC, and antagonism at higher doses. Importantly, THCV substituted for THC in a graded manner without evidence of pharmacokinetic interactions, and it also produced stimulant-like effects that distinguish it from THC. These results suggest that THCV may act as a dose-dependent modulator of cannabinoid receptor activity, capable of both mimicking and opposing THC’s discriminative stimulus effects. Such bidirectional properties are consistent with its complex receptor pharmacology and underscore the importance of dose in determining behavioral outcomes. Future studies should expand on these findings by examining sex- and strain-dependent variability, assessing the role of CB1 and CB2 receptor mechanisms using antagonist approaches, and exploring THCV’s actions across a broader range of behavioral paradigms, including those related to reward, cognition, and feeding behavior. Together, these efforts will help to clarify the pharmacology of THCV and further delineate its position within the cannabinoid spectrum.”

https://www.mdpi.com/2218-273X/15/9/1329

Cannabinoids in preclinical research of sepsis: a scoping review

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“Background: Sepsis is a global health problem that ends millions of lives and costs billions of dollars in treatment and management every year. This disease is responsible for one in every five deaths worldwide, and is the third leading cause of death in hospitals. Despite decades of research, no current specific treatment or cure are available, only supportive and symptomatic care, and few preclinical studies reach human trials. Since the discovery of the endocannabinoid system (ECS), cannabinoids have been researched as a potential treatment for various diseases, including sepsis. Our review aimed to summarize what is known about the endocannabinoid system research in preclinical sepsis.

Methods: A scoping search was conducted in the databases Pubmed, Scopus and Web of Science. Articles were selected in case they studied a cannabinoid or the ECS in preclinical sepsis or septic shock, with no time limit. Data regarding animals species, model os sepsis, treatments, cannabinoids utilized and main outcomes were analyzed.

Results: We found that the most commonly used animal species was both Mus musculus and Rattus norvegicus, and the most frequently performed sepsis model was the endotoxemia induced by lipopolysaccharide (LPS). The most studied receptor was cannabinoid receptor type 2 (CB2) and among all cannabinoid types, synthetic cannabinoids were researched in the majority of the studies. We also discuss the evaluated outcomes, as well as their involvement with the endocannabinoid system and underlying molecular mechanisms. We highlight the main promising results and explore the limitations and future challenges in the field.

Conclusion: Cannabinoids are promising therapeutic targets in the treatment of sepsis, as they improved survival, and reduced inflammation and organ injury. However, deleterious adverse effects were reported, with the underlying molecular mechanisms still unknown, and further research is needed to evaluate their benefits and future use in clinical research.”

https://pubmed.ncbi.nlm.nih.gov/40956450/

https://link.springer.com/article/10.1007/s00011-025-02090-9

Endocannabinoid signaling in epilepsy

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“Epilepsy, characterized by recurrent abnormal neuronal discharges, can lead to severe manifestations, including prolonged seizures that may become life-threatening. Despite the availability of numerous antiseizure drugs, many patients remain refractory to existing treatments, prompting the urgent search for novel therapeutic strategies.

One pivotal factor driving epileptogenesis is the disruption of the excitatory-inhibitory balance, resulting in excessive neuronal firing and hyperexcitability. In addition, neuroinflammation not only contributes to seizure generation but also exacerbates disease progression, forming a vicious cycle of neuronal damage.

The endocannabinoid (eCB) system, including eCBs, cannabinoid receptors, as well as biosynthetic and catabolic enzymes, has emerged as a crucial regulator of brain homeostasis.

By restoring excitatory-inhibitory balance and alleviating inflammation, eCB signaling influences key processes such as synaptic transmission, neuronal plasticity, and immune responses.

This dual capacity to regulate excitability and inflammatory pathways underscores its therapeutic potential for epilepsy.

In this review, we discussed the mechanisms by which eCB signaling regulates neuronal plasticity and inflammatory responses, emphasizing the interplay between these processes in epilepsy. We also discussed preclinical findings that support the therapeutic potential of targeting the eCB system.

By integrating insights from recent studies, we aim to provide a comprehensive overview of eCB-mediated neuroprotection and highlight future directions for epilepsy research and treatment.”

https://pubmed.ncbi.nlm.nih.gov/40886859/

https://www.sciencedirect.com/science/article/pii/S0969996125002918?via%3Dihub

Cannabidiol prevents cognitive and social deficits in a male rat model of Alzheimer’s disease through CB1 activation and inflammation modulation

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“Cognitive decline is a hallmark of Alzheimer’s disease (AD). Cannabidiol (CBD), a non-intoxicating phytocannabinoid with immunomodulatory properties, shows promise in alleviating AD symptoms.

This study examined the effects of chronic CBD treatment in a male rat model of sporadic AD induced by intracerebroventricular streptozotocin (ICV-STZ) and explored its impact on neuroinflammatory genes and cannabinoid signaling.

STZ rats showed impaired performance in object location and recognition tasks, along with reduced social behavior. STZ exposure also affected AD-related hippocampal markers, leading to increased levels of amyloid β-protein (Aβ) and tau phosphorylation (p-Tau) and elevated mRNA levels of triggering receptor expressed on myeloid cells 2 (TREM2) and apolipoprotein E4 (APOEε4). Additionally, STZ increased hippocampal neuroinflammatory markers, including mRNA levels of Tumor Necrosis Factor α (TNF-α), nuclear factor kappa B subunit 1 (NF-κB1), and interleukin (IL)-1β. It also altered cannabinoid receptor expression, with cannabinoid receptor 1 (cnr1) and 2 (cnr2) genes upregulated in the dentate gyrus (DG), whereas in the CA1, cnr2 was upregulated and cnr1 downregulated.

Chronic CBD treatment restored the STZ-induced behavioral deficits, reduced neuroinflammatory marker expression, and mitigated AD-associated changes. Importantly, the CB1 receptor antagonist AM251, but not CB2 antagonist AM630, blocked the beneficial effects of CBD on performance in object location and social tasks in STZ-treated rats, highlighting CB1 receptor activation as a key mechanism.

These findings suggest that CBD holds promise as a therapeutic agent for inflammation-induced AD, with the potential to ameliorate cognitive deficits and prevent disease onset through mechanisms involving CB1 receptor activation and modulation of neuroinflammation.”

https://pubmed.ncbi.nlm.nih.gov/40859005/

“Our findings suggest that CBD protects against STZ-induced cognitive and social deficits, hippocampal neuroinflammation, and AD-related pathology, with CB1r playing a key role in its therapeutic effects. As current AD treatments are limited, our study highlights CBD as a promising candidate, demonstrating for the first time that a low dose can prevent behavioral and molecular deficits in a rodent model of sporadic AD. By targeting neuroinflammation and endocannabinoid pathways, CBD may help prevent cognitive decline and neuropathological changes in AD.”

https://www.nature.com/articles/s41386-025-02213-0

Cannabinoid Receptors CB1 and CB2 Activation Restores Hippocampal Lipid Profiles and Alleviates Autism-Like Behaviors in Valproic Acid-Induced ASD Rats

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“Objective: Emerging evidence suggests lipid metabolism dysregulation contributes to autism spectrum disorders (ASD), with the endocannabinoid system (cannabinoid receptors CB1R/CB2R) implicated in lipid homeostasis. This study investigated whether CB1R/CB2R activation improves hippocampal lipid metabolism and ASD-like behaviors in a valproic acid (VPA)-induced ASD rat model.

Methods: Male offspring from dams exposed to VPA (600 mg/kg, i.p.) received the CB1R agonist ACPA (0.1 mg/kg) or the CB2R agonist AM1241 (3 mg/kg) from postnatal days 21-27. ASD-like behaviors (marble burying, self-grooming, social interaction, open-field tests) and hippocampal lipid profiles (UPLC-MS/MS) were analyzed.

Results: VPA-exposed rats displayed heightened repetitive behaviors, social deficits, and hyperactivity, all significantly alleviated by ACPA and AM1241. Lipidomics revealed marked reductions in hippocampal phosphatidylcholines, lysophosphatidylcholines, fatty acids, sphingomyelins, ceramides, and phosphatidylethanolamines in VPA rats. Both agonists restored lipid levels to near normal, comparable to controls.

Conclusions: CB1R/CB2R activation ameliorates behavioral abnormalities and rectifies hippocampal lipid dysregulation in VPA-induced ASD models, highlighting cannabinoid receptors as potential therapeutic targets for ASD-associated metabolic disturbances.”

https://pubmed.ncbi.nlm.nih.gov/40852923/

“This study provides new evidence linking ASD-like behaviors, lipid metabolism abnormalities, and endocannabinoid system regulation. Our results demonstrated that CB1R and CB2R activation alleviated VPA-induced ASD-like behaviors and restored disrupted lipid profiles in the hippocampus, suggesting a potential therapeutic approach for ASD. Further research should explore the molecular mechanisms underlying CB1R- and CB2R-mediated lipid regulation and their implications for ASD treatment strategies.”

https://onlinelibrary.wiley.com/doi/10.1111/cns.70591

The Endocannabinoid System: Role in Ocular Physiology and Therapeutic Potential in Eye Diseases: A Narrative Review

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“The endocannabinoid system (ECS) is a multicomponent signaling network that controls several physiological processes, including neurological, immune, cardiovascular, digestive, and ocular functions. The components of ECS (i.e., receptors, ligands, metabolizing enzymes, and carriers) are expressed in eye structures and neurological areas involved in the visual process. Experimental evidence supports ECS involvement in ocular pathophysiology.

Preclinical and clinical studies indicate that cannabinoids (CBs) lower intraocular pressure and exert vasoactive, anti-inflammatory, and protective effects in the retina and ocular surface. However, CBs elicit modest and transient effects while inducing tolerance, dependence, and adverse effects, which prevent their use in ophthalmic clinics.

This review summarizes experimental and clinical data on the role of ECS in ocular pathophysiology. It also reports research on the therapeutic potential of CBs in common eye disorders. Lastly, it highlights promising alternative strategies for modulating ECS and improving ocular drug delivery to improve therapeutic efficiency in ophthalmic clinics.”

https://pubmed.ncbi.nlm.nih.gov/40838892/

The Role of the Endocannabinoid System in Oncology and the Potential Use of Cannabis Derivatives for Cancer Management in Companion Animals

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“The last decades of research have shown that the endocannabinoid system may be a promising therapeutic target for the pharmacological treatment of cancer in human medicine and possibly in veterinary medicine as well.

Compared with the original cells, the expression of gene encoding for receptors and enzymes belonging to the endocannabinoid system has been found to be altered in several tumor types; it has been hypothesized that this aberrant expression may be related to the course of the neoplasm as well as to the patient’s prognosis.

Several studies, conducted both in vitro and in vivo, suggest that both endo- and phytocannabinoids can modulate signaling pathways, controlling cell proliferation and survival. In the complex process of carcinogenesis, cannabinoids seem to intervene at different levels by stimulating cell death, inhibiting the processes of angiogenesis and metastasis, and regulating antitumor immunity.

Although the molecular mechanisms by which cannabinoids act are not always clear and defined, their synergistic activity with the most used antineoplastic drugs in clinical oncology is showing promising results, thus providing veterinary medicine with alternative therapeutic targets in disease control.

This review aims to summarize current knowledge on the potential role of the endocannabinoid system and exogenous cannabinoids in oncology, with specific reference to the molecular mechanisms by which cannabinoids may exert antitumor activity. Additionally, it explores the potential synergy between cannabinoids and conventional anticancer drugs and considers their application in veterinary oncology.”

https://pubmed.ncbi.nlm.nih.gov/40804975/

“Companion animals are more and more becoming considered family members, and their owners wish to offer them the same level of cure and care expected for a human being. The long life expectancy of dogs and cats is associated with new challenges: veterinary medicine must be prepared to diagnose and treat neoplastic pathology with the same high-standard procedures that are currently used in human medicine.

Chemotherapies aim to prolong as long as possible the life of companion animals affected by cancer, but several side effects can be experienced. Thus, an increasing interest in alternative and complementary treatments has arisen in the last years. Among a wide array, cannabinoids seem to be a promising tool to be included in therapeutic protocols since their administration could assist traditional chemotherapeutic agents, promoting a more successful antineoplastic effect, prolonging the prognosis, and contributing to patient well-being thanks to pain relief.

According to all the aforementioned factors, the present review aims to summarize how the endocannabinoid system and phytocannabinoids interact in the complex process of carcinogenesis, exploring current therapeutical applications and future perspectives in veterinary oncology.”

“From the above paragraphs, it can be concluded that cannabinoids show antitumor activity (decrease in tumor growth and invasiveness) in numerous cell lines and in various animal models of cancer, and that, although clinical studies conducted in human and animal patients are limited, the results obtained so far have demonstrated that cannabinoids appear to be safe and effective antineoplastic agents.

Moreover, most of the preclinical evidence currently available demonstrates that the greatest therapeutic potential of cannabinoids lies in their combination with existing chemotherapeutic drugs.

Interestingly, compared to conventional antineoplastic drugs, which have a plethora of side effects, cannabinoids (especially the non-psychoactive ones, such as CBD) have a broad safety margin. “

https://www.mdpi.com/2076-2615/15/15/2185

The Endocannabinoid System in PTSD: Molecular Targets for Modulating Fear and Anxiety

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“Fear and anxiety perform essential protective roles, yet when they become dysregulated, they can trap trauma survivors in persistent hypervigilance and distress. Post-traumatic stress disorder (PTSD) manifests as intrusive memories, avoidance, and heightened arousal long after the precipitating event. Although current pharmacotherapies – including selective serotonin reuptake inhibitors, adrenergic blockers, benzodiazepines, and atypical antipsychotics – provide relief for some, many patients contend with residual symptoms or intolerable adverse effects.

Recent discoveries position the endocannabinoid system as a pivotal regulator of fear acquisition, consolidation, and extinction. Clinical observations of altered anandamide levels and cannabinoid receptor CB₁ upregulation in individuals with severe PTSD underscore the therapeutic potential of restoring endocannabinoid tone.

Preclinical studies demonstrate that direct CB₁ agonists, fatty acid amide hydrolase (FAAH) inhibitors, and phytocannabinoids such as tetrahydrocannabinol (THC) and cannabidiol (CBD) can facilitate extinction learning and attenuate anxiety-like behaviours.

Preliminary human trials report that nabilone alleviates trauma-related nightmares and that acute cannabinoid administration modulates amygdala reactivity to a threat. Yet optimal dosing strategies, sex-specific responses, and ideal THC:CBD ratios remain to be defined. Self-medication with cannabis can offer transient relief but carries a risk of cannabis use disorder and potential worsening of PTSD symptoms. By elucidating molecular targets – including CB₁, CB₂, FAAH, and monoacylglycerol lipase – this review outlines a strategic framework for next-generation cannabinoid-based interventions.

Harnessing the endocannabinoid system promises to expand the therapeutic arsenal for PTSD, offering hope for more effective and better-tolerated treatments.”

https://pubmed.ncbi.nlm.nih.gov/40789309/

https://www.thieme-connect.de/products/ejournals/abstract/10.1055/a-2647-8030