Cannabidiol improves maternal obesity-induced behavioral, neuroinflammatory and neurochemical dysfunctions in the juvenile offspring

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“Maternal obesity is associated with an increased risk of psychiatric disorders such as anxiety, depression, schizophrenia and autism spectrum disorder in the offspring. While numerous studies focus on preventive measures targeting the mothers, only a limited number provide practical approaches for addressing the damages once they are already established.

We have recently demonstrated the interplay between maternal obesity and treatment with cannabidiol (CBD) on hypothalamic inflammation and metabolic disturbances, however, little is known about this relationship on behavioral manifestations and neurochemical imbalances in other brain regions. Therefore, here we tested whether CBD treatment could mitigate anxiety-like and social behavioral alterations, as well as neurochemical disruptions in both male and female offspring of obese dams.

Female Wistar rats were fed a cafeteria diet for 12 weeks prior to mating, and during gestation and lactation. Offspring received CBD (50 mg/kg) from weaning for 3 weeks. Behavioral tests assessed anxiety-like manifestations and social behavior, while neuroinflammatory and neurochemical markers were evaluated in the prefrontal cortex (PFC) and hippocampus.

CBD treatment attenuated maternal obesity-induced anxiety-like and social behavioral alterations, followed by rescuing effects on imbalanced neurotransmitter and endocannabinoid concentrations and altered expression of glial markers, CB1, oxytocin and dopamine receptors, with important differences between sexes.

Overall, the findings of this study provide insight into the signaling pathways for the therapeutic benefits of CBD on neuroinflammation and neurochemical imbalances caused by perinatal maternal obesity in the PFC and the hippocampus, which translates into the behavioral manifestations, highlighting the sexual dimorphism encompassing both the transgenerational effect of obesity and the endocannabinoid system.”

https://pubmed.ncbi.nlm.nih.gov/38608740/

https://www.sciencedirect.com/science/article/abs/pii/S0889159124003556?via%3Dihub

Cannabis use disorder and perioperative outcomes following complex cancer surgery

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“Introduction: Cannabis usage is increasing in the United States, especially among patients with cancer. We sought to evaluate whether cannabis use disorder (CUD) was associated with higher morbidity and mortality among patients undergoing complex cancer surgery.

Methods: Patients who underwent complex cancer surgery between January 2016 and December 2019 were identified in the National Inpatient Sample database. CUD was defined according to ICD-10 codes. Propensity score matching was performed to create a 1:1 matched cohort that was well balanced with respect to covariates, which included patient comorbidities, sociodemographic factors, and procedure type. The primary composite outcome was in-hospital mortality and seven major perioperative complications (myocardial ischemia, acute kidney injury, stroke, respiratory failure, venous thromboembolism, hospital-acquired infection, and surgical procedure-related complications).

Results: Among 15 014 patients who underwent a high-risk surgical procedure, a cohort of 7507 patients with CUD (median age; 43 years [IQR: 30-56 years]; n = 3078 [41.0%] female) were matched with 7507 patients who were not cannabis users (median age; 44 years [IQR: 30-58 years); n = 2997 [39.9%] female). CUD was associated with slight increased risk relative to postoperative kidney injury (CUD, 7.8% vs. no CUD, 6.1%); however, in-hospital mortality was slightly lower (CUD, 0.9% vs. no CUD, 1.6%) (both p < 0.001). On multivariable analysis, after controlling for other risk factors, CUD was not associated with higher morbidity and mortality (adjusted odds ratio: 1.06, 95% CI: 0.98-1.15; p = 0.158).

Conclusion: CUD was not associated with a higher risk of postoperative morbidity and mortality following complex cancer surgery.”

https://pubmed.ncbi.nlm.nih.gov/38606521/

https://onlinelibrary.wiley.com/doi/10.1002/jso.27644

[Phytotherapeutic recommendations in medical guidelines for the treatment of gastroenterological diseases – a systematic review]

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“Phytotherapeutics are gaining influence in the treatment of gastroenterological diseases. Their popularity and growing evidence of efficacy contribute to their integration into medical guidelines. A systematic screening identified recommended phytotherapeutic approaches. Based on current scientific data, some recommendations for the use of phytotherapeutic agents are given. For irritable bowel syndrome the use of peppermint oil is “strongly recommended”, especially for pain and flatulence. Other phytotherapeutics such as STW-5, Tibetan Padma Lax or warm caraway oil pads have proven effective in alleviating symptoms. It is “recommended” to integrate them into the treatment concept. For chronic constipation, 30g of fiber per day is recommended. Best data exists for plantago psyllium with moderate evidence and chicory inulin. In case of ulcerative colitis, plantago psyllium as well as the combination of myrrh, chamomile flower extract, and coffee charcoal can be used as a complementary treatment in maintaining remission. There is also an “open recommendation” for curcumin for both, remission induction and maintenance. Some phytotherapeutic treatments (e.g., Artemisia absintium, Boswellia serata) show evidence of effectiveness for the treatment of Crohn’s disease, but data are not yet sufficient for recommendations. Cannabis-based medicines can be considered for abdominal pain and clinically relevant appetite loss if standard therapy is ineffective or contraindicated, but they should not be used for acute inflammation in active Crohn’s disease. Further recommendations for other gastroenterological diseases are discussed. The safety and tolerability of the phytotherapeutics were rated as predominantly “very good” to “acceptable”. Some clear recommendations for the use of phytotherapeutics to treat gastroenterological diseases show their great potential. Due to their wide range of effects, phytotherapeutics can be used very well as a complement to conventional medicines in case of complex regulatory disorders. However, further methodologically well-conducted impact studies would be helpful in order to be able to make further recommendations.”

https://pubmed.ncbi.nlm.nih.gov/38604221/

https://www.thieme-connect.de/products/ejournals/abstract/10.1055/a-2279-5045


Cannabidiol Inhibits Epithelial Ovarian Cancer: Role of Gut Microbiome

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“Epithelial ovarian cancer is among the deadliest gynecological tumors worldwide. Clinical treatment usually consists of surgery and adjuvant chemo- and radiotherapies. Due to the high rate of recurrence and rapid development of drug resistance, the current focus of research is on finding effective natural products with minimal toxic side effects for treating epithelial ovarian tumors.

Cannabidiol is among the most abundant cannabinoids and has a non-psychoactive effect compared to tetrahydrocannabinol, which is a key advantage for clinical application. Studies have shown that cannabidiol has antiproliferative, pro-apoptotic, cytotoxic, antiangiogenic, anti-inflammatory, and immunomodulatory properties. However, its therapeutic value for epithelial ovarian tumors remains unclear.

This study aims to investigate the effects of cannabidiol on epithelial ovarian tumors and to elucidate the underlying mechanisms.

The results showed that cannabidiol has a significant inhibitory effect on epithelial ovarian tumors. In vivo experiments demonstrated that cannabidiol could inhibit tumor growth by modulating the intestinal microbiome and increasing the abundance of beneficial bacteria. Western blot assays showed that cannabidiol bound to EGFR/AKT/MMPs proteins and suppressed EGFR/AKT/MMPs expression in a dose-dependent manner. Network pharmacology and molecular docking results suggested that cannabidiol could affect the EGFR/AKT/MMPs signaling pathway.”

https://pubmed.ncbi.nlm.nih.gov/38603577/

https://pubs.acs.org/doi/10.1021/acs.jnatprod.3c00782

Cannabidiol exerts multitarget immunomodulatory effects on PBMCs from individuals with psoriasis vulgaris

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“Introduction: The involvement of endocannabinoid system (ECS) in the inflammatory cascade, and the ability of phytocannabinoids, endocannabinoids and their synthetic analogues to modulate it has become an interesting research area for new therapeutic approaches in inflammatory skin diseases. Cannabidiol (CBD) appears to be the most promising among phytocannabinoids, due to the lack of psychotropic effects and low toxicity profile. Its anti-inflammatory action has been highlighted in different preclinical models, ranging from experimental colitis to arthritis and neuroinflammation. Our aim was to evaluate CBD immune-modulatory effects in peripheral blood mononuclear cells (PBMC) of psoriasis individuals with particular attention to both innate and adaptative immune arms.

Methods: We performed in vitro immune functional experiments to analyze CBD action on various immune cells active in psoriatic lesions.

Results: The results showed that CBD produced a shift from Th1 to Th2 response, while boosting cytotoxic activity of Natural Killer (NK) cells. Furthermore, it also exerted a potent action on monocyte differentiation as, after CBD treatment, monocytes from psoriatic individuals were unable to migrate in response to inflammatory stimuli and to fully differentiate into mature dendritic cells. Finally, a M2 skewing of monocyte-derived macrophages by CBD also contributed to the fine tuning of the magnitude of immune responses.

Conclusions: These data uncover new potential immunomodulatory properties of this cannabinoid suggesting a possible therapeutic action in the treatment of multiple inflammatory skin diseases.”

https://pubmed.ncbi.nlm.nih.gov/38601151/

https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1373435/full

A novel insight into the neuroprotective effects of cannabidiol: maintained apelin/dopamine synthesis, NRF2 signaling, and AKT/CREB/BDNF gene expressions

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“Neuroinflammation is a process associated with degeneration and loss of neurons in different parts of the brain. The most important damage mechanisms in its formation are oxidative stress and inflammation.

This study aimed to investigate the protective effects of cannabidiol (CBD) against neuroinflammation through various mechanisms.

Thirty‑two female rats were randomly divided into 4 groups as control, lipopolysaccharide (LPS), LPS + CBD and CBD groups. After six hours following LPS administration, rats were sacrificed, brain and cerebellum tissues were obtained. Tissues were stained with hematoxylin‑eosin for histopathological analysis. Apelin and tyrosine hydroxylase synthesis were determined immunohistochemically. Total oxidant status and total antioxidant status levels were measured, and an oxidative stress index was calculated. Protein kinase B (AKT), brain-derived neurotrophic factor (BDNF), cyclic‑AMP response element‑binding protein (CREB) and nuclear factor erythroid 2‑related factor 2 (NRF2) mRNA expression levels were also determined. In the LPS group, hyperemia, degeneration, loss of neurons and gliosis were seen in all three tissues. Additionally, Purkinje cell loss in the cerebellum, as well as neuronal loss in the cerebral cortex and hippocampus, were found throughout the LPS group. The expressions of AKT, BDNF, CREB and NRF2, apelin and tyrosine hydroxylase synthesis all decreased significantly.

CBD treatment reversed these changes and ameliorated oxidative stress parameters. CBD showed protective effects against neuroinflammation via regulating AKT, CREB, BDNF expressions, NRF2 signaling, apelin and tyrosine hydroxylase synthesis.”

https://pubmed.ncbi.nlm.nih.gov/38587319/

https://ane.pl/index.php/ane/article/view/2546

Cannabidiol improves the cognitive function of SAMP8 AD model mice involving the microbiota-gut-brain axis

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“Cannabidiol (CBD), a natural component extracted from Cannabis sativa L. exerts neuroprotective, antioxidant, and anti-inflammatory effects in Alzheimer’s disease (AD), a disease characterized by impaired cognition and accumulation of amyloid-B peptides (Aβ). Interactions between the gut and central nervous system (microbiota-gut-brain axis) play a critical role in the pathogenesis of neurodegenerative disorder AD. At present investigations into the mechanisms underlying the neuroprotective action of CBD in AD are not conclusive.

The aim of this study was thus to examine the influence of CBD on cognition and involvement of the microbiota-gut-brain axis using a senescence-accelerated mouse prone 8 (SAMP8) model.

Data demonstrated that administration of CBD to SAMP8 mice improved cognitive function as evidenced from the Morris water maze test and increased hippocampal activated microglia shift from M1 to M2. In addition, CBD elevated levels of Bacteriodetes associated with a fall in Firmicutes providing morphologically a protective intestinal barrier which subsequently reduced leakage of intestinal toxic metabolites. Further, CBD was found to reduce the levels of hippocampal and colon epithelial cells lipopolysaccharide (LPS), known to be increased in AD leading to impaired gastrointestinal motility, thereby promoting neuroinflammation and subsequent neuronal death.

Our findings demonstrated that CBD may be considered a beneficial therapeutic drug to counteract AD-mediated cognitive impairment and restore gut microbial functions associated with the observed neuroprotective mechanisms.”

https://pubmed.ncbi.nlm.nih.gov/38590254/

https://www.tandfonline.com/doi/full/10.1080/15287394.2024.2338914

Cannabidiol induces ERK activation and ROS production to promote autophagy and ferroptosis in glioblastoma cells

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“Small molecule-driven ERK activation is known to induce autophagy and ferroptosis in cancer cells. Herein the effect of cannabidiol (CBD), a phytochemical derived from Cannabis sativa, on ERK-driven autophagy and ferroptosis has been demonstrated in glioblastoma (GBM) cells (U87 and U373 cells).

CBD imparted significant cytotoxicity in GBM cells, induced activation of ERK (not JNK and p38), and increased intracellular reactive oxygen species (ROS) levels. It increased the autophagy-related proteins such as LC3 II, Atg7, and Beclin-1 and modulated the expression of ferroptosis-related proteins such as glutathione peroxidase 4 (GPX4), SLC7A11, and TFRC. CBD significantly elevated the endoplasmic reticulum stress, ROS, and iron load, and decreased GSH levels. Inhibitors of autophagy (3-MA) and ferroptosis (Fer-1) had a marginal effect on CBD-induced autophagy/ferroptosis. Treatment with N-acetyl-cysteine (antioxidant) or PD98059 (ERK inhibitor) partly reverted the CBD-induced autophagy/ferroptosis by decreasing the activation of ERK and the production of ROS.

Overall, CBD induced autophagy and ferroptosis through the activation of ERK and generation of ROS in GBM cells.”

https://pubmed.ncbi.nlm.nih.gov/38583854/

“In this study, we investigated the anti-cancer effect of CBD. CBD activated ROS production and ERK pathway and modulated the expression of proteins related to autophagy and ferroptosis. Additionally, CBD suppressed the activity of SLC7A11, a component of the System Xc-cystine/glutamate receptor, and enhanced the expression of TFRC, an iron ion channel. Through these mechanisms, our study provides evidence that CBD stimulates both autophagy and ferroptosis in GBM cells”

https://www.sciencedirect.com/science/article/abs/pii/S0009279724001418?via%3Dihub

Cannabidiol and positive effects on object recognition memory in an in vivo model of Fragile X Syndrome: obligatory role of hippocampal GPR55 receptors

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“Cannabidiol (CBD), a non-psychotomimetic constituent of Cannabis sativa, has been recently approved for epileptic syndromes often associated with Autism spectrum disorder (ASD). However, the putative efficacy and mechanism of action of CBD in patients suffering from ASD and related comorbidities remain debated, especially because of the complex pharmacology of CBD. We used pharmacological, immunohistochemical and biochemical approaches to investigate the effects and mechanisms of action of CBD in the recently validated Fmr1-Δexon 8 rat model of ASD, that is also a model of Fragile X Syndrome (FXS), the leading monogenic cause of autism.

CBD rescued the cognitive deficits displayed by juvenile Fmr1-Δexon 8 animals, without inducing tolerance after repeated administration. Blockade of CA1 hippocampal GPR55 receptors prevented the beneficial effect of both CBD and the fatty acid amide hydrolase (FAAH) inhibitor URB597 in the short-term recognition memory deficits displayed by Fmr1-Δexon 8 rats. Thus, CBD may exert its beneficial effects through CA1 hippocampal GPR55 receptors. Docking analysis further confirmed that the mechanism of action of CBD might involve competition for brain fatty acid binding proteins (FABPs) that deliver anandamide and related bioactive lipids to their catabolic enzyme FAAH.

These findings demonstrate that CBD reduced cognitive deficits in a rat model of FXS and provide initial mechanistic insights into its therapeutic potential in neurodevelopmental disorders.”

https://pubmed.ncbi.nlm.nih.gov/38583687/

“CBD improved cognition in a rat model of Fragile X Syndrome, the leading monogenic cause of autism.”

https://www.sciencedirect.com/science/article/pii/S1043661824001208?via%3Dihub

Investigating the Impact of Cannabis Consumption on Hospital Outcomes in Patients With Primary Spontaneous Pneumothorax: A Nationwide Analysis

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“Introduction Existing data suggest an association between primary spontaneous pneumothorax (PSP) and cannabis consumption, although evidence remains controversial.

Methods This study used the 2016-2019 National Inpatient Sample Database to examine inpatients with PSP, categorizing them as cannabis users and non-users. Multivariate regression analyzed continuous variables, chi-square assessed categorical variables, and logistic regression models were built. Propensity score matching (PSM) mitigated the confounding bias.

Results A total of 399,495 patients with PSP were admitted during the study period (13,415 cannabis users and 386,080 non-cannabis users). Cannabis users were more likely to be younger (p<0.001) and male (p<0.001) with a lower risk of baseline comorbidities than non-users. Cannabis users had a lower risk of sudden cardiac arrest, vasopressor use, the development of acute kidney injury, venous thromboembolism, the requirement for invasive and non-invasive mechanical ventilation, hemodialysis, ventilator-associated pneumonia, and the need for a tracheostomy. Cannabis use was associated with a 3.4 days shorter hospital stay (p<0.001), as confirmed by PSM analysis (2.3 days shorter, p<0.001). Additionally, cannabis users showed a lower risk of in-hospital mortality (p<0.001), a trend maintained in the PSM analysis (p<0.001).

Conclusions Our study revealed correlations suggesting that cannabis users with PSP might experience lower in-hospital mortality and fewer complications than non-cannabis users.”

https://pubmed.ncbi.nlm.nih.gov/38586642/

“Our study makes a significant contribution to understanding the association between cannabis use and PSP outcomes. It reveals correlations suggesting that cannabis users with PSP might experience lower in-hospital mortality and fewer complications compared to non-cannabis users.”

https://www.cureus.com/articles/226735-investigating-the-impact-of-cannabis-consumption-on-hospital-outcomes-in-patients-with-primary-spontaneous-pneumothorax-a-nationwide-analysis#!/