“The management of orofacial pain to alleviate the quality of life of affected patients is becoming increasingly challenging for scientific research and healthcare professionals. From this perspective, in addition to conventional therapies, new alternatives are being sought, increasingly looking at the use of both natural and synthetic products.
Cannabis sativa L. represents an interesting source of bioactive compounds, including non-psychoactive cannabinoids, flavonoids, and terpenes, many of which are effective in improving pain intensity.
Here, we aim to analyze the possible mechanisms of action of the bioactive natural and synthetic hemp-derived compounds responsible for the modulatory effects on pain-related pathways. The ability of these compounds to act on multiple mechanisms through a synergistic effect, reducing both the release of inflammatory mediators and regulating the response of the endocannabinoid system, makes them interesting agents for alternative formulations to be used in orofacial pain.”
“Non-Alcoholic Steatohepatitis (NASH) is the progressive form of Non-Alcoholic Fatty Liver Disease (NAFLD). NASH is distinguished by severe hepatic fibrosis and inflammation. The plant-derived, non-psychotropic compound cannabigerol (CBG) has potential anti-inflammatory effects similar to other cannabinoids. However, the impact of CBG on NASH pathology is still unknown. This study demonstrated the therapeutic potential of CBG in reducing hepatic steatosis, fibrosis, and inflammation.
Methods: 8-week-old C57BL/6 male mice were fed with methionine/choline deficient (MCD) diet or control (CTR) diets for five weeks. At the beginning of week 4, mice were divided into three sub-groups and injected with either a vehicle, a low or high dose of CBG for two weeks. Overall health of the mice, Hepatic steatosis, fibrosis, and inflammation were evaluated.
Results: Increased liver-to-body weight ratio was observed in mice fed with MCD diet, while a low dose of CBG treatment rescued the liver-to-body weight ratio. Hepatic ballooning and leukocyte infiltration were decreased in MCD mice with a low dose of CBG treatment, whereas the CBG treatment did not change the hepatic steatosis. The high dose CBG administration increased inflammation and fibrosis. Similarly, the expression of cannabinoid receptor (CB)1 and CB2 showed decreased expression with the low CBG dose but not with the high CBG dose intervention in the MCD group and were co-localized with mast cells. Additionally, the decreased mast cells were accompanied by decreased expression of transforming growth factor (TGF)-β1.
Conclusions: Collectively, the low dose of CBG alleviated hepatic fibrosis and inflammation in MCD-induced NASH, however, the high dose of CBG treatment showed enhanced liver damage when compared to MCD only group. These results will provide pre-clinical data to guide future intervention studies in humans addressing the potential uses of CBG for inflammatory liver pathologies, as well as open the door for further investigation into systemic inflammatory pathologies.”
“Oxidative stress, neurodegeneration, neuroinflammation, and vascular leakage are believed to play a key role in the early stage of diabetic retinopathy (ESDR). The aim of this study was to investigate the blockade of cannabinoid receptor 1 (CB1R) and activation of cannabinoid receptor 2 (CB2R) as putative therapeutics for the treatment of the early toxic events in DR. Diabetic rats [streptozotocin (STZ)-induced] were treated topically (20 μL, 10 mg/mL), once daily for fourteen days (early stage DR model), with SR141716 (CB1R antagonist), AM1710 (CB2R agonist), and the dual treatment SR141716/AM1710. Immunohistochemical-histological, ELISA, and Evans-Blue analyses were performed to assess the neuroprotective and vasculoprotective properties of the pharmacological treatments on diabetes-induced retinal toxicity. Activation of CB2R or blockade of CB1R, as well as the dual treatment, attenuated the nitrative stress induced by diabetes. Both single treatments protected neural elements (e.g., RGC axons) and reduced vascular leakage. AM1710 alone reversed all toxic insults. These findings provide new knowledge regarding the differential efficacies of the cannabinoids, when administered topically, in the treatment of ESDR. Cannabinoid neuroprotection of the diabetic retina in ESDR may prove therapeutic in delaying the development of the advanced stage of the disease.”
“In closing, our findings suggest that topical administration of the three cannabinoid treatments, such as eye drops, provides protection to the diabetic retina in a differential manner against the four pathologies of ESDR. The actions of both CB2R activation and CB1R blockade in restoring ganglion cell axons (NFL-IR) in ESDR suggest that both agents may be effective in retarding RGC death. AM1710 is efficacious as an antioxidant, anti-inflammatory, neuroprotective and vasculoprotective agent and, thus, a promising new therapeutic for ESDR. Further advancement of retinal imaging to screen and identify the early events in DR, such as neurodegeneration in diabetic patients, is crucial for selecting neuroprotective drugs and implementing personalized treatments. As our findings clearly implicate the endocannabinoid system, the therapeutic benefits of this class of compounds should also extend to patients with diabetic nephropathy and cardiopathy/stroke since DR has been associated with the development of these diseases.”
“The growing interest in the development of drugs that target the endocannabinoid system has extended to conditions that affect the audiovestibular pathway. The expression of cannabinoid (CB) receptors in that pathway has been widely demonstrated, indicating a therapeutic potential for drug development at this level. These medications may be beneficial for conditions such as noise-induced hearing loss, ototoxicity, or various forms of vertigo of central or peripheral origin. The therapeutic targets of interest include natural or synthetic compounds that act as CB1/CB2 receptor agonists/antagonists, and inhibitors of the endocannabinoid-degrading enzymes FAAH and MAGL. Furthermore, genetic variations implicated in the response to treatment and the development of related disorders such as epilepsy or migraine have been identified. Direct methods of administering these medications should be examined beyond the systemic strategy.”
“The following review focuses on the scientific studies related to the role of endocannabinoid system (ECS) in pancreatic islet physiology and dysfunction. Different natural or synthetic agonists and antagonists have been suggested as an alternative treatment for diabetes, obesity and metabolic syndrome. Therapeutic use of Cannabis led to the discovery and characterization of the ECS, a signaling complex involved in regulation of various physiological processes, including food intake and metabolism. After the development of different agonists and antagonists, evidence have demonstrated the presence and activity of cannabinoid receptors in several organs and tissues, including pancreatic islets. Insulin and glucagon expression, stimulated secretion, and the development of diabetes and other metabolic disorders have been associated with the activity and modulation of ECS in pancreatic islets. However, according to the animal model and experimental design, either endogenous or pharmacological ligands of cannabinoid receptors have guided to contradictory and paradoxical results that suggest a complex physiological interaction. In consensus, ECS activity modulates insulin and glucagon secretions according to glucose in media; over-stimulation of cannabinoid receptors affects islets negatively, leading to glucose intolerance, meanwhile the treatment with antagonists in diabetic models and humans suggests an improvement in islets function.”
“Colon cancer is one of the leading causes of death worldwide. In recent years, cannabinoids have been extensively studied for their potential anticancer effects and symptom management. Several in vitro studies reported anandamide’s (AEA) ability to block cancer cell proliferation and migration, but evidence from in vivo studies is still lacking. Thus, in this study, the effects of AEA exposure in zebrafish embryos transplanted with HCT116 cells were evaluated.
Totally, 48 hpf xenografts were exposed to 10 nM AEA, 10 nM AM251, one of the cannabinoid 1 receptor (CB1) antagonist/inverse agonists, and to AEA + AM251, to verify the specific effect of AEA treatment. AEA efficacy was evaluated by confocal microscopy, which demonstrated that these xenografts presented a smaller tumor size, reduced tumor angiogenesis, and lacked micrometastasis formation.
To gain deeper evidence into AEA action, microscopic observations were completed by molecular analyses. RNA seq performed on zebrafish transcriptome reported the downregulation of genes involved in cell proliferation, angiogenesis, and the immune system. Conversely, HCT116 cell transcripts resulted not affected by AEA treatment. In vitro HCT116 culture, in fact, confirmed that AEA exposure did not affect cell proliferation and viability, thus suggesting that the reduced tumor size mainly depends on direct effects on the fish rather than on the transplanted cancer cells.
AEA reduced cell proliferation and tumor angiogenesis, as suggested by socs3 and pcnp mRNAs and Vegfc protein levels, and exerted anti-inflammatory activity, as indicated by the reduction of il-11a, mhc1uba, and csf3b mRNA. Of note, are the results obtained in groups exposed to AM251, which presence nullifies AEA’s beneficial effects.
In conclusion, this study promotes the efficacy of AEA in personalized cancer therapy, as suggested by its ability to drive tumor growth and metastasis, and strongly supports the use of zebrafish xenograft as an emerging model platform for cancer studies.”
“Collectively, our data suggest a pivotal role of AEA in the anti-angiogenic, anti-proliferative, and anti-inflammatory process in intercellular tumor-endothelial cell communication resulting in the containment of tumor and evidenced that zebrafish larvae xenografts constitute a promising fast assay for precision medicine, bridging the gap between genotype and phenotype in an in vivo setting.”
“The endocannabinoid system has been shown to be involved in various skin functions, such as melanogenesis and the maintenance of redox balance in skin cells exposed to UV radiation, as well as barrier functions, sebaceous gland activity, wound healing and the skin’s immune response.
In addition to the potential use of cannabinoids in the treatment and prevention of skin cancer, cannabinoid compounds and derivatives are of interest as potential systemic and topical applications for the treatment of various inflammatory, fibrotic and pruritic skin conditions. In this context, cannabinoid compounds have been successfully tested as a therapeutic option for the treatment of androgenetic alopecia, atopic and seborrhoeic dermatitis, dermatomyositis, asteatotic and atopic eczema, uraemic pruritis, scalp psoriasis, systemic sclerosis and venous leg ulcers. This review provides an insight into the current literature on cannabinoid compounds as potential medicines for the treatment of skin diseases.”
“Based on the current publications, it can be summarised that cannabinoid compounds have great potential in the treatment of skin diseases, both as topical applications and as systemic medications.”
“Cannabis sativa has chemically active compounds called cannabinoids, where Δ9- tetrahydrocannabinol (THC) and Cannabidiol (CBD) are the major ones responsible for the various pharmacological effects.
The endocannabinoid system is an endogenous system considered a unique and widespread homeostatic physiological regulator. It is made up of type 1 (CB1) and type 2 (CB2) cannabinoid receptors. CBD, in turn, has a low affinity for CB1 and CB2 receptors, and regulates the effects arising from THC as a CB1 partial agonist, which are tachycardia, anxiety, and sedation. It also acts as a CB2 inverse agonist, resulting in anti-inflammatory effects.
Furthermore, its anticonvulsant, neuroprotective, antipsychotic, antiemetic, anxiolytic, anticancer, and antioxidant effects seem to be linked to other discovered receptors such as GRP55, 5TH1a, TRPV I, TRPV II and the regulation of the intracellular concentration of Ca2+. Regarding oxidative stress, O2- can act as an oxidizing agent, being reduced to hydrogen peroxide (H2O2), or as a reducing agent, donating its extra electron to NO to form peroxynitrite (ONOO-). The ONOO- formed is capable of oxidizing proteins, lipids, and nucleic acids, causing several cell damages.
In this sense, CBD can prevent cardiac oxidative damage in many conditions, such as hypertension, diabetes, or even through the cardiotoxic effects induced by chemotherapy, which makes it a potential target for future clinical use to minimize the deleterious effects of many pathophysiologies.”
“Introduction: Cannabidiol (CBD) is the second most abundant Phytocannabinoid in Cannabis extracts. CBD has a binding affinity for several cannabinoid and cannabinoid-associated receptors. Epidiolex (oral CBD solution) has been lately licensed by the Food and Drug Administration (FDA) for the treatment of pediatric epileptic seizures.
Methods: In this review, we discussed the most promising applications of CBD for chronic inflammatory conditions, namely CBD’s anti-inflammatory effects during inflammatory bowel disease, coronavirus disease (antiviral effect), brain pathologies (neuroprotective and anti-inflammatory properties), as well as CBD immunomodulatory and antitumoral activities in the tumor microenvironment. Special focus was shed on the main therapeutic mechanisms of action of CBD, particularly in the control of the immune system and the endocannabinoid system.
Results: Findings suggest that CBD is a potent immunomodulatory drug as it has manifested immunosuppressive properties in the context of sterile inflammation (e.g., inflammatory bowel disease, rheumatoid arthritis, and neurodegenerative diseases), and immunoprotective effects during viral infections (e.g. COVID-19) Similarly, CBD has exhibited a selective response toward cancer types by engaging different targets and signaling pathways. These results are in favor of the primary function of the endocannabinoid system which is homeostatic maintenance.
Conclusion: The presented evidence suggests that the endocannabinoid system is a prominent target for the treatment of inflammatory and autoimmune diseases, rheumatoid diseases, viral infections, neurological and psychological pathologies, and cancer. Moreover, the antitumoral activities of CBD have been suggested to be potentially used in combination with chemo- or immunotherapy during cancer. However, clinical results are still lacking, which raises a challenge to apply translational cannabis research to the human immune system.”
“Background: The endocannabinoid (eCB) system plays an important role in homeostatic regulation of anxiety and stress responses; however, the eCB system can be disrupted following traumatic stressors. Additionally, traumatic or chronic stressors that occur during adulthood or early life can cause long-lasting disturbances in the eCB system. These alterations interfere with hypothalamic-pituitary-adrenal axis function and may be involved in lifelong increased fear and anxiety behaviors as well as increased risk for development of post-traumatic stress disorder (PTSD).
Methods: This review focuses on the implications of trauma and significant stressors on eCB functionality and neural pathways, both in adolescence and into adulthood, as well as the current state of testing for CBD efficacy in treating pediatric and adult patients suffering from stress-induced eCB dysregulation. Articles were searched via Pubmed and included studies examining eCB modulation of stress-related disorders in both clinical settings and preclinical models.
Conclusion: Given the potential for lifelong alterations in eCB signaling that can mediate stress responsiveness, consideration of pharmaceutical or nutraceutical agents that impact eCB targets may improve clinical outcomes in stress-related disorders. However, caution may be warranted in utilization of medicinal cannabinoid products that contain delta-9-tetrahydrocannabinol due to pronounced euphorigenic effects and potential to exacerbate stress-related behaviors. Other cannabinoid products, such as cannabidiol (CBD), have shown promise in reducing stress-related behaviors in pre-clinical models. Overall, pre-clinical evidence supports CBD as a potential treatment for stress or anxiety disorders resulting from previously stressful events, particularly by reducing fearful behavior and promoting extinction of contextual fear memories, which are hallmarks of PTSD. However, very limited clinical research has been conducted examining the potential effectiveness of CBD in this regard and should be examined further.”
