The NLRP3 inflammasome: a vital player in inflammation and mediating the anti-inflammatory effect of CBD

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“Background: The NLRP3 inflammasome is a vital player in the emergence of inflammation. The priming and activation of the NLRP3 inflammasome is a major trigger for inflammation which is a defense response against adverse stimuli. However, the excessive activation of the NLRP3 inflammasome can lead to the development of various inflammatory diseases. Cannabidiol, as the second-most abundant component in cannabis, has a variety of pharmacological properties, particularly anti-inflammation. Unlike tetrahydrocannabinol, cannabidiol has a lower affinity for cannabinoid receptors, which may be the reason why it is not psychoactive. Notably, the mechanism by which cannabidiol exerts its anti-inflammatory effect is still unclear.

Methods: We have performed a literature review based on published original and review articles encompassing the NLRP3 inflammasome and cannabidiol in inflammation from central databases, including PubMed and Web of Science.

Results and conclusions: In this review, we first summarize the composition and activation process of the NLRP3 inflammasome. Then, we list possible molecular mechanisms of action of cannabidiol. Next, we explain the role of the NLRP3 inflammasome and the anti-inflammatory effect of cannabidiol in inflammatory disorders. Finally, we emphasize the capacity of cannabidiol to suppress inflammation by blocking the NLRP3 signaling pathway, which indicates that cannabidiol is a quite promising anti-inflammatory compound.”

https://pubmed.ncbi.nlm.nih.gov/38191853/

https://link.springer.com/article/10.1007/s00011-023-01831-y

How Does CBG Administration Affect Sphingolipid Deposition in the Liver of Insulin-Resistant Rats?

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“Background: Cannabigerol (CBG), a non-psychotropic phytocannabinoid found in Cannabis sativa plants, has been the focus of recent studies due to its potential therapeutic properties. We proposed that by focusing on sphingolipid metabolism, which plays a critical role in insulin signaling and the development of insulin resistance, CBG may provide a novel therapeutic approach for metabolic disorders, particularly insulin resistance.

Methods: In a rat model of insulin resistance induced by a high-fat, high-sucrose diet (HFHS), we aimed to elucidate the effect of intragastrically administered CBG on hepatic sphingolipid deposition and metabolism. Moreover, we also elucidated the expression of sphingolipid transporters and changes in the sphingolipid concentration in the plasma.

Results: The results, surprisingly, showed a lack of changes in de novo ceramide synthesis pathway enzymes and significant enhancement in the expression of enzymes involved in ceramide catabolism, which was confirmed by changes in hepatic sphingomyelin, sphinganine, sphingosine-1-phosphate, and sphinganine-1-phosphate concentrations.

Conclusions: The results suggest that CBG treatment may modulate sphingolipid metabolism in the liver and plasma, potentially protecting the liver against the development of metabolic disorders such as insulin resistance.”

https://pubmed.ncbi.nlm.nih.gov/37892425/

https://www.mdpi.com/2072-6643/15/20/4350

Sila-CBD Derivatives as Inhibitors of Heme-Induced NLRP3 Inflammasome: Application in Hemolytic Diseases

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“Synthesis and biological evaluation of silicon-incorporated phytocannabinoids with improved pharmacological properties toward inflammatory diseases are described. The synthesized sila-analogues 15a, 15b, and 15c displayed potent inhibition of pro-inflammatory cytokines, including IL-1β, TNF-α, and IL-6 at 10 μM. Further, the release of heme during the lysis of red blood cells in hemolytic diseases is one of the major reasons for inflammation associated with the pathophysiology of these diseases. Due to scanty literature related to inhibitors of heme-mediated induction of the NLRP3 inflammasome, we decided to test these compounds against it. Compounds 15a and 15c significantly inhibited the heme-mediated induction of the NLRP3 inflammasome at a concentration of 0.1 μM. Interestingly, the sila-CBD derivatives also showed higher metabolic stability in contrast to their carbon analogues. Anti-NLRP3 inflammasome activity of compounds 15a and 15c were further validated in vivo against heme-mediated peritoneal inflammation. The anti-inflammatory activity of these compounds could be useful in treating diseases such as sickle cell anemia and thalassemia involving the hemolysis-mediated activation of the NLRP3 inflammasome.”

https://pubmed.ncbi.nlm.nih.gov/38116428/

https://pubs.acs.org/doi/10.1021/acsmedchemlett.3c00352

A preliminary study evaluating self-reported effects of cannabis and cannabinoids on neuropathic pain and pain medication use in people with spinal cord injury

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“Approximately 60% of individuals with a spinal cord injury (SCI) experience neuropathic pain, which often persists despite the use of various pharmacological treatments. Increasingly, the potential analgesic effects of cannabis and cannabinoid products have been studied; however, little research has been conducted among those with SCI-related neuropathic pain. Therefore, the primary objective of the study was to investigate the perceived effects of cannabis and cannabinoid use on neuropathic pain among those who were currently or had previously used these approaches. Additionally, the study aimed to determine if common pain medications are being substituted by cannabis and cannabinoids. Participants (N = 342) were recruited from existing opt-in listserv sources within the United States. Of those, 227 met the inclusion criteria and were enrolled in the study. The participants took part in an anonymous online survey regarding past and current use of cannabis and their perceived effects on neuropathic pain, including the use of pain medication. Those in the sample reported average neuropathic pain intensity scores over the past week of 6.8 ± 2.1 (0 to 10 scale), reflecting a high moderate to severe level of pain. Additionally, 87.9% noted that cannabis reduced their neuropathic pain intensity by more than 30%, and 92.3% reported that cannabis helped them to better deal with their neuropathic pain symptoms. Most participants (83.3%) also reported substituting their pain medications with cannabis, with the most substituted medication categories being opioids (47.0%), gabapentinoids (42.8%) and over-the-counter pain medications (42.2%). These preliminary results suggest that cannabis and cannabinoids may be effective in reducing neuropathic pain among those with SCI and may help to limit the need for certain pain medications.”

https://pubmed.ncbi.nlm.nih.gov/38188193/

https://www.frontiersin.org/articles/10.3389/fpain.2023.1297223/full

Caregiver-reported outcomes with real-world use of cannabidiol in Lennox-Gastaut syndrome and Dravet syndrome from the BECOME survey

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“Purpose: Plant-derived highly purified cannabidiol (CBD) reduced the frequency of seizures associated with Lennox-Gastaut syndrome (LGS) and Dravet syndrome (DS) and improved the overall condition of patients in placebo-controlled phase 3 clinical trials. Anecdotal reports also suggest a positive effect on nonseizure outcomes. In this study, we aimed to identify, through a caregiver survey which nonseizure outcomes were most likely to change in these patients.

Methods: The BEhavior, COgnition, and More with Epidiolex® (BECOME) was a 20-minute, cross-sectional, online survey that was developed with extensive input from caregivers, healthcare professionals, and epilepsy researchers, and was based on questions from validated measures and previously published caregiver reports. US-based caregivers (from Jazz Pharmaceuticals patient/caregiver database) of people with LGS or DS who were treated with CBD (Epidiolex®, 100 mg/mL oral solution) for ≥3 months were asked to compare the past month to the period before CBD initiation and rate their impression of changes using symmetrical Likert scales

Results: A total of 498 caregivers (97% parents) of patients with LGS (80%) or DS (20%) completed the survey. Mean (range) age of patients was 16 (1-73) years, and 52% were male. Patients were taking a median CBD dose of 14 mg/kg/d and median 4 concomitant antiseizure medications. A large proportion of respondents reported improvements in ≥1 survey question for all nonseizure-related domains: alertness, cognition, and executive function (85%); emotional functioning (82%); language and communication (79% in nonverbal patients and 74% in verbal); activities of daily living (51%); sleep (51%); and physical functioning (46%). Respondents reported improvements in seizure-related domains, including overall seizure frequency (85%), overall seizure severity (76%), seizure-free days per week for ≥1 seizure type (67%), and seizure freedom during the past month (16%). The majority of respondents who reported reduction in seizure frequency also reported improvements in nonseizure outcomes domains (51-80%). However, improvements in nonseizure outcomes (18-56%) were also reported in patients who either had no change or worsening of seizure frequency.

Conclusions: This survey characterized and quantified caregiver impression of changes in the seizure and nonseizure outcomes in patients taking add-on CBD treatment. Overall, 93% of caregivers reported planning to continue CBD treatment, primarily because of reduced seizure burden but also because of improvements in nonseizure-related outcomes. Despite the limitations that are associated with a retrospective survey-based study design, these results support further evaluation of the effect of CBD treatment on nonseizure outcomes among patients with LGS or DS.”

https://pubmed.ncbi.nlm.nih.gov/38183688/

https://www.sciencedirect.com/science/article/pii/S092012112300205X?via%3Dihub

Cannabinoids improve mitochondrial function in skeletal muscle of exhaustive exercise training rats by inhibiting mitophagy through the Pink1/Parkin and Bnip3 pathways

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“Cannabidiol (CBD) is a pure natural phytocannabinoid derived from cannabis that has anti-inflammatory, antiapoptotic and antioxidative stress abilities. In recent years, an increasing number of studies have reported the regulatory effect of CBD on skeletal muscle injury induced by exercise, but its mechanism is still unclear. Mitochondria are the main organelles responsible for the energy supply within eukaryotic cells, and their function has been closely linked to cellular health. Moderate exercise improves mitochondrial function, but the excessive exercise has a negative impact on mitochondria. Therefore, we speculate that CBD may promote exercise induced skeletal muscle cell damage by improving mitochondrial function. In this study, by establishing an animal model of exhaustive exercise training in rats, the effects of CBD on the protective effect of CBD on skeletal muscle mitochondrial structure and function was elaborated, and the possible molecular mechanism was discussed based on transcriptomics. Our results indicate that skeletal muscle mitochondrial structure and function were improved after CBD intervention. GO and KEGG pathway enrichment analysis showed that exhaustive exercise training induced mitochondrial dysfunction in skeletal muscle is associated with excessive autophagy/mitophagy, the signaling pathways involved in FOXO3 and GABARAPL1 may play important roles. After CBD intervention, the protein expression of Pink1, Parkin and Bnip3 was down-regulated, indicating that CBD may improve the mitochondrial function by inhibiting mitophagy through the Pink1/Parkin and Bnip3 pathway.”

https://pubmed.ncbi.nlm.nih.gov/38182033/

https://www.sciencedirect.com/science/article/abs/pii/S0009279724000012?via%3Dihub

Awareness and interest in cannabis use for cancer management among cancer survivors

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“Background: We examined the awareness, interest, and information sources relating to cannabis use for cancer management (including management of cancer symptoms and treatment-related side effects) and determined factors associated with cancer survivors’ awareness and interest in learning about cannabis use for cancer management.

Methods: This was a cross-sectional study of adult cancer survivors (N = 1886) receiving treatment at a comprehensive cancer center. Weighted prevalence and multivariable logistic regression analyses were conducted.

Results: Among cancer survivors, 88% were aware and 60% were interested in learning about cannabis use for cancer management. Common sources of information to learn about cannabis use for cancer management were cancer doctors/nurses (82%), other patients with cancer (27%), websites/blogs (26%), marijuana stores (20%), and family/friends (18%). The odds of being aware of cannabis use for cancer management was lower among male compared to female survivors (adjusted odds ratio [AOR]: 0.61; 95% confidence interval [CI]: 0.41-0.90), non-Hispanic Blacks compared to non-Hispanic Whites (AOR: 0.36; 95% CI: 0.21-0.62), and survivors who do not support the legalization of cannabis for medical use compared to those who do (AOR: 0.10; 95% CI: 0.04-0.23). On the other hand, the odds of being interested in cannabis use for cancer management was higher among non-Hispanic Blacks compared to non-Hispanic Whites (AOR: 1.65; 95% CI: 1.04-2.62), and among cancer survivors actively undergoing cancer treatment compared to patients on non-active treatment (AOR: 2.25; 95% CI: 1.74-2.91).

Conclusion: Awareness of cannabis use for cancer management is high within the cancer survivor population. Results indicated health care providers are leading information source and should receive continued medical education on cannabis-specific guidelines. Similarly, tailored educational interventions are needed to guide survivors on the benefits and risks of cannabis use for cancer management.”

https://pubmed.ncbi.nlm.nih.gov/38180296/

“In conclusion, most cancer survivors are aware of and interested in cannabis use for medical management. “

https://onlinelibrary.wiley.com/doi/10.1002/cam4.6902

Cannabidiol Mediates In Vitro Attenuation of Proinflammatory Cytokine Responses in Psoriatic Disease

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“Background: Cannabidiol (CBD), a substance that belongs to the phytocannabinoids, appears to exert antioxidant, neuroprotective, antipsychotic, anticonvulsant, and anticancer properties. Recent evidence supports the immunoregulatory effect of CBD on autoimmune and/or inflammatory disease. Psoriasis is a chronic skin disease. The main immune cell population involved in the pathogenesis of the disease is the interleukin- (IL-) 17-producing T helper (Th) 17 subset. Other subpopulations, such as interferon-γ (IFNγ) -producing Th1 and T cytotoxic (Tc) 1, IL-17-producing Tc17, as well as natural killer (NK) and natural killer T cells (NKT) have been implicated in psoriasis development. 

Purpose: The aim of the present study was to evaluate the in vitro effect of CBD on the aforementioned subpopulations isolated from patients with psoriasis using flow cytometry. 

Methods: Cells were stimulated in the presence or absence of CBD, stained and examined using surface and intracellular markers. 

Results: CBD decreased IL-17 production within the CD3, Th, and NKT cell compartments and IFNγ production within the CD3 compartment in cells isolated from patients with psoriasis. Interestingly, CBD supplementation did not inhibit production of proinflammatory cytokines in cells isolated from healthy individuals. On the contrary, IFNγ-producing Th, Tc, and NK cells increased after CBD supplementation. 

Conclusion: CBD provides anti-inflammatory effects in T cells isolated from patients with psoriasis. Our results could be the impetus for future investigations regarding the immunomodulatory properties of CBD and its utilization for development of CBD-containing antipsoriatic agents.”

https://pubmed.ncbi.nlm.nih.gov/38181167/

Cannabis Sativa targets mediobasal hypothalamic neurons to stimulate appetite

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“The neurobiological mechanisms that regulate the appetite-stimulatory properties of cannabis sativa are unresolved. This work examined the hypothesis that cannabinoid-1 receptor (CB1R) expressing neurons in the mediobasal hypothalamus (MBH) regulate increased appetite following cannabis vapor inhalation. Here we utilized a paradigm where vaporized cannabis plant matter was administered passively to rodents. Initial studies in rats characterized meal patterns and operant responding for palatable food following exposure to air or vapor cannabis. Studies conducted in mice used a combination of in vivo optical imaging, electrophysiology and chemogenetic manipulations to determine the importance of MBH neurons for cannabis-induced feeding behavior. Our data indicate that cannabis vapor increased meal frequency and food seeking behavior without altering locomotor activity. Importantly, we observed augmented MBH activity within distinct neuronal populations when mice anticipated or consumed food. Mechanistic experiments demonstrated that pharmacological activation of CB1R attenuated inhibitory synaptic tone onto hunger promoting Agouti Related Peptide (AgRP) neurons within the MBH. Lastly, chemogenetic inhibition of AgRP neurons attenuated the appetite promoting effects of cannabis vapor. Based on these results, we conclude that MBH neurons contribute to the appetite stimulatory properties of inhaled cannabis.”

https://pubmed.ncbi.nlm.nih.gov/38151493/

https://www.nature.com/articles/s41598-023-50112-5

Hemp-Derived CBD Used in Food and Food Supplements

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“Cannabis sativa L., a plant historically utilized for textile fibers, oil, and animal feed, is progressively being recognized as a potential food source. This review elucidates the nutritional and functional attributes of hemp and cannabidiol (CBD) within the context of food science. Hemp is characterized by the presence of approximately 545 secondary metabolites, among which around 144 are bioactive cannabinoids of primary importance. The study looks in detail at the nutritional components of cannabis and the potential health benefits of CBD, encompassing anti-inflammatory, anxiolytic, and antipsychotic effects. The review deals with the legislation and potential applications of hemp in the food industry and with the future directions of cannabis applications as well. The paper emphasizes the need for more scientific investigation to validate the safety and efficacy of hemp components in food products, as current research suggests that CBD may have great benefits for a wide range of consumers.”

https://pubmed.ncbi.nlm.nih.gov/38138537/

https://www.mdpi.com/1420-3049/28/24/8047