“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.”
“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.”
“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. “
“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.”
“Spinal cord injury (SCI) is a debilitating condition that leads to severe motor and sensory dysfunction, largely due to inflammation, neuronal damage, and disrupted neural circuits.
In this study, we developed an injectable hydrogel (C/F/Gel) co-loaded with fibroblast growth factor 21 (FGF21) and cannabidiol micelles (CBDm) to enhance SCI repair. The hydrogel, composed of PF127 and α-cyclodextrin (α-CD), provides sustained drug release and improves drug stability at the injury site.
Our findings demonstrate that C/F/Gel effectively modulates the inflammatory microenvironment by promoting microglial polarization toward the anti-inflammatory M2 phenotype via cannabinoid receptor 2 (CB2R) activation.
Additionally, it regulates the balance between excitatory and inhibitory neurons, and significantly improves motor function in SCI mice. Behavioral assessments, histological analysis, and molecular studies confirmed the superior therapeutic efficacy of C/F/Gel compared to single-agent treatments.
These results highlight C/F/Gel as a promising biomaterial-based strategy for SCI repair, offering a synergistic approach that integrates inflammation modulation, neuroprotection, and functional recovery.”
“Our study shows that the developed C/F/Gel is a promising therapeutic strategy for SCI repair, offering a multi-faceted approach through controlled drug release, inflammation modulation, neural regeneration, and motor function recovery. The synergy between FGF21 and CBDm, particularly via CB2R activation, highlights a novel mechanistic pathway for SCI treatment.”
“Background: Aging is a multifaceted process marked by the progressive accumulation of cellular damage in various tissues, resulting in a decline in physiological functions. The primary aim of aging research is to identify compounds that can delay or mitigate these detrimental changes. As cannabis legalization becomes more widespread and with limited empirical studies on its effects in the aging human population, there is a pressing need for research into the impact of Cannabis and cannabinoids on healthy aging and age-related diseases.
Methods: Our study aims to evaluate the effects of chronic, intermittent exposure, defined as 6 weeks of use of EU-GMP certified Cannabis sativa L. (Cannabixir® Medium Flos) administration, dosed at 6.25 and 25 mg/kg on neurobiological changes in naturally aged rats and its potential efficacy in mitigating age-related alterations. The impact of the Cannabixir® Medium Flos was assessed through clinical, histopathological, immunohistochemical, and behavioral evaluations.
Results: Cannabixir® Medium Flos was found to be generally safe, with no significant effects on motor performance and a neutral effect on anxiety-like behavior. Histological analysis revealed that the hippocampus of aged rats treated with this compound-an area known for its abundance of endocannabinoids and cannabinoid receptor type 1-exhibited characteristics similar to those observed in young adult rats. Additionally, the study suggests that chronic, intermittent treatment with Cannabixir® Medium Flos may modulate astrocyte function, reduce neuroinflammation, and potentially influence cell proliferation and neuronal apoptosis in a dose-dependent manner. However, these preliminary findings should be interpreted with caution, as the study’s exploratory nature.
Conclusions: These preliminary findings suggest that cannabinoid therapy targeting the endocannabinoid system may offer potential neuroprotective benefits in aging.
While the study offers valuable preclinical insights into the effects of an EU-GMP-certified cannabinoid receptor ligand in reducing age-related cognitive decline, these effects are likely mediated by a combination of mechanisms. Given the complex phytochemical composition, the observed outcomes cannot be attributed exclusively to cannabinoid receptor activation. Accordingly, these findings should be interpreted with caution, and further studies employing more targeted methodologies are needed to elucidate the underlying mechanisms.”
“Cellular plasticity enables cancer cells to escape therapy by adopting stem-like or alternate lineage states. Here, we identify a mechanism by which cannabinoid receptor 2 (CB2R) activation promotes irreversible lineage commitment in breast cancer. Using patient-derived and murine organoids, we show that brief, low-dose exposure to CB2R agonists—either phytogenic or synthetic—induces a basal-to-luminal transition, accompanied by reduced self-renewal, invasiveness, and tumor-initiating potential. These changes are retained under conditions that normally promote dedifferentiation, including fibroblast co-culture, immune pressure, and mechanical shear stress.
Mechanistically, CB2R engagement initiates a transient chromatin remodeling program, marked by early expression of pluripotency-associated genes followed by silencing and differentiation commitment. This epigenetically stabilized state renders tumor cells more responsive to tamoxifen and limits the emergence of resistant clones.
Our findings uncover a previously unrecognized role for CB2R in modulating cancer cell identity and suggest new opportunities to constrain tumor plasticity by directing differentiation through a drug-responsive pathway.”
“Tumor adaptability relies on the ability of cancer cells to dedifferentiate and acquire stem-like features, fueling therapeutic resistance and metastasis. Differentiation therapy aims to reprogram tumor cells into more mature, less aggressive states to counteract this plasticity.
Here, we identify cannabinoid receptor 2 (CB2R) as a novel therapeutic target that promotes sustained differentiation in breast cancer. Using tumor-derived organoids from both mouse models and patient biopsies, we show that brief, low-dose exposure to phytogenic or synthetic CB2R ligands induces a basal-to-luminal switch, suppresses stemness, and reduces invasiveness and self-renewal. These phenotypic changes are associated with decreased tumor initiation and aggressiveness in vivo .
Transcriptomic profiling reveals that CB2R activation initiates transient chromatin remodeling and epigenetic reprogramming, resulting in a stably differentiated state. Importantly, CB2R-driven differentiation sensitizes tumor cells to tamoxifen, enabling lower therapeutic doses with improved efficacy-supporting the principles of adaptive therapy aimed at long-term disease control.
Our findings position CB2R modulation as a promising non-cytotoxic strategy to restrict cancer plasticity and enhance the effectiveness of existing breast cancer treatments.”
“Many neurodegenerative diseases are associated with immune system disorders, while neurodegenerative processes often occur in inflammatory conditions of the Central Nervous System (CNS).
Cannabinoids exhibit significant therapeutic potential due to their dual ability to modulate both neural and immune functions. These compounds have a broad spectrum of action, allowing them to target multiple pathological mechanisms underlying neurodegenerative and inflammatory CNS diseases.
The present review outlines the therapeutic potential of cannabinoids, with a focus on their anti-inflammatory properties, in the treatment of neurodegenerative conditions, including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and Huntington’s disease, as well as inflammatory CNS disorders like multiple sclerosis and HIV-associated dementia.”
“Cannabinoids, the active compounds derived from Cannabis sativa, are attracting increasing interest for their therapeutic potential in neurodegenerative disorders (Parkinson’s disease, Alzheimer’s disease, and Huntington’s disease) and inflammatory CNS conditions (multiple sclerosis and HIV-associated dementia).
Their multimodal mechanisms of action include the following: (1) modulating pathological protein aggregation and mitochondrial dysfunction, and (2) exerting neuroprotective and anti-inflammatory effects which are mediated through microglial regulation.
The neurodegenerative diseases and inflammatory CNS disorders discussed in this work represent a serious challenge for healthcare systems due to their complex etiology or pathophysiology, severe symptoms, and the limited effectiveness of existing treatments. Consequently, improving therapeutic strategies for these disorders remains a priority.
Many studies suggest that pharmacological modulation of the endocannabinoid system could influence neurodegenerative processes, providing a basis for further research into cannabinoid-based therapies. In particular, the inhibition of FAAH in the endocannabinoid system has emerged as a potential therapeutic approach to control neuroinflammatory processes.”
“Introduction: Stroke is a leading cause of morbidity and mortality worldwide, with ischemic stroke accounting for the majority of cases. The endocannabinoid system (ECS), comprising cannabinoid receptors CB1 and CB2, has been implicated in regulating physiological processes and has shown potential neuroprotective effects in preclinical studies. However, the precise impact of cannabinoid receptor modulation on stroke outcomes remains unclear. This systematic review and meta-analysis aimed to evaluate the impact of cannabinoid receptor modulation on infarct volume and behavioral deficits in animal models of focal ischemic stroke, with a primary focus on infarct outcomes.
Method: A comprehensive literature search was conducted following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, yielding 29 eligible studies for inclusion.
Results: The analysis revealed significant reductions in infarct volume with cannabinoid agonists, particularly CB1 and CB2 agonists, indicating their potential as neuroprotective agents. Subgroup analyses further highlighted specific agonists, such as ACEA and KN38-72717, as particularly effective in reducing infarct volume. Additionally, CB antagonists, particularly CB1 antagonists, such as SR141716, showed promising results in reducing infarct volume. Although improvements in neurological scores were observed with both agonists and antagonists, statistical significance was not reached, indicating the need for further investigation.
Conclusion: These results highlight the potential of cannabinoid receptor modulation as a neuroprotective strategy in ischemic strokes and underscore the need for further research to elucidate the underlying mechanisms and optimize therapeutic approaches.”
“Numerous studies carried out in the last 30-40 years have strongly demonstrated that the endocannabinoid system exerts important modulatory functions in the central nervous system (CNS). These neuromodulatory functions encompass the whole life of animals, with specific activities during neurodevelopment (prenatal, postnatal and adolescent periods), adulthood and possibly senescence too. However, this is the life stage less investigated in relation with the endocannabinoid system to date.
In the aged brain, the activity of this system appears to be altered, which contributes to subtle impairments that typically occur during ageing in learning and memory, motor behaviour, social behaviour and other neurobiological functions. Some of the changes in endocannabinoid activity may represent a process to attenuate ageing-related impairment in the brain function, which is consistent with its role as a pro-homeostatic system.
An important observation is that these alterations become extreme when normal brain ageing acquires pathological characteristics, as happens in chronic neurodegenerative disorders. This includes the cannabinoid type-1 (CB1) receptor downregulation or impairment in its signalling and the increase in endocannabinoid-inactivating enzymes, both hypothesised to contribute to pathogenic events. By contrast, elevated levels of endocannabinoids due to a reduced Fatty acid amide hydrolase (FAAH) and monoacyl glycerol lipase (MAGL) expression and the upregulation of cannabinoid type-2 (CB2) receptors may in turn serve as endogenous pro-homeostatic adaptations against brain impairment.
This review synthesises information on: (i) subtle alterations in the endocannabinoid system in the senescent brain in the absence of pathology, with the purpose of demonstrating that these alterations are representative of the extreme changes experienced by this system in the brain pathological ageing; and (ii) the development of neuroprotective therapies based on the pharmacological management of specific endocannabinoid targets to combat neurodegenerative pathologies.
Together, research in this area comes at a critical time as global lifespan is increasing, incidence of age-related neurodegenerative disorders is expanding, and the unmet need for efficacious neuroprotective treatments is a public health necessity.”
