Cannabidiol effectively prevents oxidative stress and stabilizes hypoxia-inducible factor-1 alpha (HIF-1α) in an animal model of global hypoxia

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“Cannabidiol (CBD) is a non-psychotomimetic phytocannabinoid derived from Cannabis sativa. It has therapeutic effects in different paradigms of brain injury, acting as a neuroprotectant.

As oxidative stress is a primary risk factor for brain damage after neonatal hypoxia, we tested the effect of CBD on oxidative status and non-protein-bound iron accumulation in the immature brain after hypoxia. Moreover, we tested whether cannabidiol affects the accumulation of hypoxia-inducible factor-1 alpha (HIF-1α) which plays a key role in the regulation of cellular adaptation to hypoxia and oxidative stress. We used 7-day-old mice randomly assigned to hypoxic or control groups. Immediately after hypoxia or control exposure, pups were randomly assigned to a vehicle or CBD treatment. 24 h later, they were decapitated and the brains were immediately removed and stored for further biochemical analyses.

We found that CBD reduced lipid peroxidation and prevented antioxidant depletion. For the first time, we also demonstrated that CBD upregulated HIF-1α protein level. This study indicates that CBD may effective agent in attenuating the detrimental consequences of perinatal asphyxia.”

https://pubmed.ncbi.nlm.nih.gov/38987284/

“Our results show that CBD applied in a short time after hypoxia attenuates hypoxia-induced oxidative stress, likely due to its antioxidant activity. To the best of our knowledge, this is also the first report showing that the post-hypoxia treatment with CBD increases the concentration of HIF-1α, which is directly involved in the maintenance of oxygen and iron homeostasis. This indicates that CBD is promising agent for new therapies developed for the treatment of hypoxic injury “

https://www.nature.com/articles/s41598-024-66599-5

From bench to bedside: the application of cannabidiol in glioma

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“Glioma is the most common malignant tumor in central nervous system, with significant health burdens to patients. Due to the intrinsic characteristics of glioma and the lack of breakthroughs in treatment modalities, the prognosis for most patients remains poor. This results in a heavy psychological and financial load worldwide.

In recent years, cannabidiol (CBD) has garnered widespread attention and research due to its anti-tumoral, anti-inflammatory, and neuroprotective properties.

This review comprehensively summarizes the preclinical and clinical research on the use of CBD in glioma therapy, as well as the current status of nanomedicine formulations of CBD, and discusses the potential and challenges of CBD in glioma therapy in the future.”

https://pubmed.ncbi.nlm.nih.gov/38987805/

“CBD, a non-psychoactive cannabinoid derived from the cannabis plant, has shown promising potential in the treatment of gliomas. Characterized by its safety, good tolerability, and absence of psychoactive effects, CBD induces apoptosis in glioma cells, mitochondrial dysfunction, and autophagy, thereby inhibiting the proliferation and invasion of glioma cells, suppressing the expression of GSCs properties, and promoting cell death. Additionally, it enhances the sensitivity to radiotherapy and chemotherapy while protecting neural functions, playing a significant role in the management of glioma symptoms. Preclinical and clinical studies have demonstrated encouraging anti-glioma activity. “

https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-024-05477-0

Potential analgesic effect of a novel cannabidiol nanocrystals powder for the treatment of neuropathic pain

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“Background: The current analgesics often prevent patients from getting effective treatment due to their adverse effects. Cannabidiol (CBD) is well tolerated, has few side effects and has been extensively investigated in analgesia. However, its oral bioavailability is extremely low. In order to solve this problem, we developed the cannabidiol nanocrystals (CBD-NC) in the earlier stage.

Methods: In this study, we evaluated the nociceptive behaviours associated with neuropathic pain (NP) induced by the spared nerve injury (SNI) model. Assessment of pain threshold was evaluated by paw withdraw threshold (PWT) and paw withdrawal latency (PWL). The improving effect on the motor dysfunction was determined by rota-rod testing. To assess the neuroprotective effect, nerve demyelination and expression of peripheral myelin protein PMP22 were measured with myelin sheath staining and western blotting. Protein expressions in microglia of spinal cord were tested by western blot to explore the underlying mechanism.

Results: Compared with the CBD oil solution, CBD-NC significantly reduced mechanical allodynia and thermal hyperalgesia in rats. CBD-NC could improve motor dysfunction induced by SNI in rats, significantly reverse the demyelination and increase the expression of the marker protein of peripheral myelin. Underlying spinal analgesic mechanism of microglia and related factors were preliminarily confirmed.

Conclusions: CBD-NC administration is an effective treatment for NP associated with SNI, and the analgesic effect of CBD-NC was significantly better than that of CBD oil sol. By contrast, CBD-NC has a fast-acting and long-term effect in the treatment of NP. Our study further supports the potential therapeutic effect of CBD-NC on NP.

Significance: The absolute bioavailability of the CBD-NC intramuscular injection formulation can reach 203.31%, which can solve the problem of low oral bioavailability. This research evaluated the therapeutic effect of CBD-NC on NP associated with the SNI model for the first time. All available date showed that whatever the analgesic or neuroprotective effect of CBD-NC, it was significantly better than that of CBD oil sol., which was consistent with the results of the pharmacokinetic. This research supports the initiation of more trials testing the efficacy of CBD-NC for treating NP.”

https://pubmed.ncbi.nlm.nih.gov/38982797/

https://onlinelibrary.wiley.com/doi/10.1002/ejp.2300

Cannabidiol and Neurodegeneration: From Molecular Mechanisms to Clinical Benefits

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“Neurodegenerative disorders (NDs) such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, multiple sclerosis, and amyotrophic lateral sclerosis are severe and life-threatening conditions in which significant damage of functional neurons occurs to produce malfunction of psycho-motor functions. NDs are an important cause of death in the elderly population worldwide. These disorders are commonly associated with the progression of age, oxidative stress, and environmental pollutants, which are the major etiological factors. Abnormal aggregation of specific proteins such as α-synuclein, amyloid-β, huntingtin, and tau, and accumulation of its associated oligomers in neurons are the hallmark pathological features of NDs. Existing therapeutic options for NDs are only symptomatic relief and do not address root-causing factors, such as protein aggregation, oxidative stress, and neuroinflammation.

Cannabidiol is a non-psychotic natural cannabinoid obtained from Cannabis sativa that possesses multiple pharmacological actions, including antioxidant, anti-inflammatory, and neuroprotective effects in various NDs and other neurological disorders both in vitro and in vivo.

Cannabidiol has gained attention as a promising therapeutic drug candidate for the management of neurodegenerative disorders, such as Alzheimer’s disease and Parkinson’s disease, by inhibiting protein aggregation, free radicals, and neuroinflammation. In parallel, CBD has shown positive results in other neurological disorders, such as epilepsy, depression, schizophrenia, and anxiety, as well as adjuvant treatment with existing standard therapeutic agents. Hence, the present review focuses on exploring the possible molecular mechanisms in controlling various neurological disorders as well as its clinical applications in NDs including epilepsy, depression and anxiety. In this way, the current review will serve as a standalone reference for the researchers working in this area.”

https://pubmed.ncbi.nlm.nih.gov/38969143/

https://www.sciencedirect.com/science/article/abs/pii/S1568163724002046?via%3Dihub

Lebanese Cannabis Oil as a Potential Treatment for Acute Myeloid Leukemia: In Vitro and In Vivo Evaluations

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“Ethnopharmacological relevance: The Cannabis sativa L. ssp. indica (Lam.) plant has been historically utilized as a natural herbal remedy for the treatment of several ailments. In Lebanon, cannabis extracts have long been traditionally used to treat arthritis, diabetes, and cancer.

Aim of the study: The current study aims to investigate the anti-cancer properties of Lebanese cannabis oil extract (COE) on acute myeloid leukemia using WEHI-3 cells, and a WEHI-3-induced leukemia mouse model.

Materials and methods: WEHI-3 cells were treated with increasing concentrations of COE to determine the IC50 after 24, 48 and 72-h post treatment. Flow cytometry was utilized to identify the mode of cell death. Western blot assay was performed to assess apoptotic marker proteins. In vivo model was established by inoculating WEHI-3 cells in BALB/c mice, and treatment commencing 10 days post-inoculation and continued for a duration of 3 weeks.

Results: COE exhibited significant cytotoxicity with IC50 of 7.76, 3.82, and 3.34 μg/mL at 24, 48, and 72 h respectively post-treatment. COE treatment caused an induction of apoptosis through an inhibition of the MAPK/ERK pathway and triggering a caspase-dependent apoptosis via the extrinsic and intrinsic modes independent of ROS production. Animals treated with COE exhibited a significantly higher survival rate, reduction in spleen weight as well as white blood cells count.

Conclusion: COE exhibited a potent anti-cancer activity against AML cells, both in vitro and in vivo. These findings emphasize the potential application of COE as a chemotherapeutic adjuvant in treatment of acute myeloid leukemia.”

https://pubmed.ncbi.nlm.nih.gov/38964627/

“•Lebanese cannabis oil demonstrated potent cytotoxicity against WEHI-3 leukemic cells.

•Cannabis oil induces apoptosis through partial inhibition of the MAPK/ERK pathway.

•Cannabis oil triggers a caspase-dependent apoptosis via the extrinsic and intrinsic pathways.

•Cannabis oil treatment significantly increased survival rate, reduced spleen weight and WBC count in WEHI-3-induced leukemia mouse model.”

“Unlike conventional chemotherapy, which often causes harmful side effects, and can lead to resistance to multiple drugs, cannabis oil offers promise as a safer alternative.”

https://www.sciencedirect.com/science/article/abs/pii/S0378874124008110?via%3Dihub


Understanding the epidemiology and perceived efficacy of cannabis use in patients with chronic musculoskeletal pain

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“Background: The belief that cannabis has analgesic and anti-inflammatory properties continues to attract patients with chronic musculoskeletal (MSK) pain towards its use. However, the role that cannabis will play in the management of chronic MSK pain remains to be determined. This study examined 1) the rate, patterns of use, and self-reported efficacy of cannabis use among patients with chronic MSK pain and 2) the interest and potential barriers to cannabis use among patients with chronic MSK pain not currently using cannabis.

Methods: Self-reported cannabis use and perceived efficacy were prospectively collected from chronic MSK pain patients presenting to the Orthopaedic Clinic at the University Health Network, Toronto, Canada. The primary dependent variable was current or past use of cannabis to manage chronic MSK pain; bivariate and multivariable logistic regression were used to identify patient characteristics independently associated with this outcome. Secondary outcomes were summarized descriptively, including self-perceived efficacy among cannabis users, and interest as well as barriers to cannabis use among cannabis non-users.

Results: The sample included 629 patients presenting with chronic MSK pain (mean age: 56±15.7 years; 56% female). Overall, 144 (23%) reported past or present cannabis use to manage their MSK pain, with 63.7% perceiving cannabis as very or somewhat effective and 26.6% considering it as slightly effective. The strongest predictor of cannabis use in this study population was a history of recreational cannabis use (OR 12.7, p<0.001). Among cannabis non-users (N=489), 65% expressed interest in using cannabis to manage their chronic MSK pain, but common barriers to use included lack of knowledge regarding access, use and evidence, and stigma.

Conclusions: One in five patients presenting to an orthopaedic surgeon with chronic MSK pain are using or have used cannabis with the specific intent to manage their pain, and most report it to be effective. Among non-users, two-thirds reported an interest in using cannabis to manage their MSK pain, but common barriers to use existed. Future double-blind placebo-controlled trials are required to understand if this reported efficacy is accurate, and what role, if any, cannabis may play in the management of chronic MSK pain.”

https://pubmed.ncbi.nlm.nih.gov/38961506/

“One in five patients presenting to an orthopaedic surgeon with chronic MSK pain are using or have used cannabis with the specific intent to manage their pain, and most report it to be effective. Among non-users, two-thirds reported an interest in using cannabis to manage their MSK pain, but common barriers to use existed. Future double-blind placebo-controlled trials are required to understand if this reported efficacy is accurate, and what role, if any, cannabis may play in the management of chronic MSK pain.”

https://jcannabisresearch.biomedcentral.com/articles/10.1186/s42238-024-00231-1

Full-spectrum cannabidiol reduces UVB damage through the inhibition of TGF-β1 and the NLRP3 inflammasome

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“The thermodynamic characteristics, antioxidant potential, and photoprotective benefits of full-spectrum cannabidiol (FS-CBD) against UVB-induced cellular death were examined in this study. In silico analysis of CBD showed antioxidant capacity via proton donation and UV absorption at 209.09, 254.73, and 276.95 nm, according to the HAT and SPLET methodologies. FS-CBD protected against UVB-induced bacterial death for 30 min. FS-CBD protected against UVB-induced cell death by 42% (1.5 μg/mL) and 35% (3.5 μg/mL) in an in vitro keratinocyte cell model. An in vivo acute irradiated CD-1et/et mouse model (UVB-irradiated for 5 min) presented very low photoprotection when FS-CBD was applied cutaneously, as determined by histological analyses. In vivo skin samples showed that FS-CBD regulated inflammatory responses by inhibiting the inflammatory markers TGF-β1 and NLRP3. The docking analysis showed that the CBD molecule had a high affinity for TGF-β1 and NLRP3, indicating that protection against inflammation might be mediated by blocking these proinflammatory molecules. This result was corroborated by the docking interactions between CBD and TGF-β1 and NLRP3, which resulted in a high affinity and inhibition of both proteins The present work suggested a FS-CBD moderate photoprotective agent against UVB light-induced skin damage and that this effect is partially mediated by its anti-inflammatory activity.”

https://pubmed.ncbi.nlm.nih.gov/38958000/

https://onlinelibrary.wiley.com/doi/10.1111/php.13993

Cannabidiol Alleviates Oral Mucositis by Inhibiting PI3K/Akt/NF-κB-Mediated Pyroptosis

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“Background: Cannabidiol (CBD), extracted from Cannabis sativa, has anticancer, anti-inflammation, and analgesic effects. Nevertheless, its therapeutic effect and the mechanism by which it alleviates oral mucositis (OM) remain unclear.

Aims: To explore the impact of CBD on OM in mice and on human oral keratinocyte (HOK) cells.

Study design: Expiremental study.

Methods: The Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform, GeneCard, DisGeNET, and Gene Expression Omnibus databases were used to conduct therapeutic target gene screening for drugs against OM. Cytoscape software was used to build networks linking components, targets, and diseases. The STRING database facilitated analysis of intertarget action relationships, and the target genes were analyzed for Kyoto Encyclopedia of Genes and Genomes pathway enrichment. Occurrence of serum inflammation-related factors, hematoxylin and eosin staining, and immunohistochemistry were used to assess OM injury. Cell proliferation, migration, pyroptosis, and apoptosis of HOK cells under different treatments were assessed. Molecular mechanisms were elucidated through western blot and quantitative real-time polymerase chain reaction analyses.

Results: A total of 49 overlapping genes were pinpointed as potential targets, with NF-κB1, PIK3R1, NF-κBIA, and AKT1 being recognized as hub genes among them. Additionally, the PI3K/Akt/NF-κB and interleukin-17 signaling pathways were identified as relevant. Our in vivo experiments showed that CBD significantly reduced the proportion of lesion area, mitigated oral mucosal tissue lesions, and downregulated the expression levels of genes and levels of proteins, including NLRP3, P65, AKT, and PI3K. In vitro experiments indicated that CBD enhanced HOK cell proliferation and migration and reduced apoptosis through inhibition of the PI3K/Akt/NF-κB signaling pathway and pyroptosis.

Conclusion: Our findings suggest a novel mechanism for controlling OM, in which CBD suppresses the PI3K/Akt/NF-κB signaling pathway and pyroptosis, thereby mitigating OM symptoms.”

https://pubmed.ncbi.nlm.nih.gov/38966918/

“Our study used bioinformatics data analysis alongside experimental validation, providing novel insights into the therapeutic role of CBD in OM. We discovered that CBD can alleviate pyroptosis in OM through the PI3K/AKT/NF-κB pathway. “

http://balkanmedicaljournal.org/text.php?lang=en&id=2614

Examining the association between prenatal cannabis exposure and child autism traits: A multi-cohort investigation in the environmental influences on child health outcome program

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“This study examined the association between prenatal cannabis exposure and autism spectrum disorder (ASD) diagnoses and traits.

A total sample of 11,570 children (ages 1-18; 53% male; 25% Hispanic; 60% White) from 34 cohorts of the National Institutes of Health-funded environmental influences on child health outcomes consortium were included in analyses.

Results from generalized linear mixed models replicated previous studies showing that associations between prenatal cannabis exposure and ASD traits in children are not significant when controlling for relevant covariates, particularly tobacco exposure. Child biological sex did not moderate the association between prenatal cannabis exposure and ASD.

In a large sample and measuring ASD traits continuously, there was no evidence that prenatal cannabis exposure increases the risk for ASD. This work helps to clarify previous mixed findings by addressing concerns about statistical power and ASD measurement.”

https://pubmed.ncbi.nlm.nih.gov/38953698/

https://onlinelibrary.wiley.com/doi/10.1002/aur.3185

“The evidence is not currently sufficient to conclude that perinatal cannabis use is a cause or a risk factor for the development of ASD.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8525188/

Selected phytocannabinoids inhibit SN-38- and cytokine-evoked increases in epithelial permeability and improve intestinal barrier function in vitro

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“Irinotecan use is linked to the development of gastrointestinal toxicity and inflammation, or gastrointestinal mucositis. Selected phytocannabinoids have been ascribed anti-inflammatory effects in models of gastrointestinal inflammation, associated with maintaining epithelial barrier function.

We characterised the mucoprotective capacity of the phytocannabinoids: cannabidiol, cannabigerol, cannabichromene and cannabidivarin in a cell-based model of intestinal epithelial stress occurring in mucositis.

Transepithelial electrical resistance (TEER) was measured to determine changes in epithelial permeability in the presence of SN-38 (5 μM) or the pro-inflammatory cytokines TNFα and IL-1β (each at 100 ng/mL), alone or with concomitant treatment with each of the phytocannabinoids (1 μM). The DCFDA assay was used to determine the ROS-scavenging ability of each phytocannabinoid following treatment with the lipid peroxidant tbhp (200 μM).

Each phytocannabinoid provided significant protection against cytokine-evoked increases in epithelial permeability. Cannabidiol, cannabidivarin and cannabigerol were also able to significantly inhibit SN-38-evoked increases in permeability. None of the tested phytocannabinoids inhibited tbhp-induced ROS generation.

These results highlight a novel role for cannabidiol, cannabidivarin and cannabigerol as inhibitors of SN-38-evoked increases in epithelial permeability and support the rationale for the further development of novel phytocannabinoids as supportive therapeutics in the management of irinotecan-associated mucositis.”

https://pubmed.ncbi.nlm.nih.gov/38950639/

  • “•Phytocannabinoids may have efficacy in alleviating intestinal mucositis
  • •Cannabidiol, cannabidivarin, cannabichromene and cannabigerol (CBG) were tested for effects on intestinal epithelial permeability
  • •Intestinal epithelial Caco-2 cells were exposed to irinotecan metabolite SN-38 or cytokines with or without selected phytocannabinoids
  • •Phytocannabinoids variably protected against cytokine and SN-38-evoked increases in epithelial permeability without antioxidant effects
  • •Minor phytocannabinoids may contribute to mucoprotection and improve epithelial barrier function”

https://www.sciencedirect.com/science/article/pii/S0887233324001188?via%3Dihub

“Irinotecan, sold under the brand name Camptosar among others, is an anti-cancer medication used to treat colon cancer and small cell lung cancer. For colon cancer it is used either alone or with fluorouracil. For small cell lung cancer it is used with cisplatin. It is given intravenously.”

https://en.wikipedia.org/wiki/Irinotecan#:~:text=Irinotecan%2C%20sold%20under%20the%20brand,It%20is%20given%20intravenously.