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Cannabidiol Finds Dihydrocannabidiol as Its Twin in Anti-Inflammatory Activities and the Mechanism

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“Ethnopharmacological relevance: The hemp (cataloged at the “Medicinal Plant Names Services” as Cannabis sativa L.) extracts, cannabinoids have been used for centuries in Southeast Asia as folk medicines and now authorized by about 50 countries for application in medicine, health care products and cosmetics. As the most consumed cannabinoid, cannabidiol (CBD) has been recognized due to its various bioactivities, including anti-inflammatory and antibacterial properties.

Aims of the study: The utilization of CBD is limited due to its potential conversion to psychoactive Δ9-tetrahydrocannabinol in strong acidic environment, demanding to excavate safer alternatives with clarified bioactivities. Yet the anti-inflammatory and antibacterial properties of CBD still remain unknown, in both of the performances and the corresponding mechanisms. Previously, a synthetic CBD analogue, H2CBD (Dihydrocannabidiol) was found to be effective as CBD does towards some antioxidantive activities and mouse seizure mitigation. Therefore, it is wondering if H2CBD also acted similarly as CBD does in the aspect of anti-inflammatory performance and mechanism, and the safety.

Material and methods: The anti-inflammatory properties of CBD and H2CBD were revealed with enzymatic assays, proteins denaturation and lipopolysaccharide (LPS) stimulated RAW264.7 cells model, with epigallocatechin gallate (EGCG) as the positive control. Their anti-inflammatory mechanism was revealed with ELISA and Western blot assay. The antibacterial properties of CBD and H2CBD were also investigated towards E. faecalis and B. cereus along with their synergistic effect with commercial antibiotics.

Results: CBD and H2CBD exhibited almost same (P> 0.05) performance in all the assayed anti-inflammatory properties, yet their anti-inflammatory efficiencies positively correlated to their antioxidantive activity. Moreover, both of CBD and H2CBD presented anti-inflammation to LPS stimulated RAW264.7 cells through NF-κB and AKT pathway. Furthermore, CBD and H2CBD also supplied strong and very similar (P>0.05) antibacterial activities, comparable to tetracycline in same dose and strength. The erythrocyte hemolytic assay indicates CBD and H2CBD possessing the same safety. All the combinations of H2CBD with other cannabinoids or antibiotics present no antagonism against the bacteria, but nice synergistic or additive effect in some cases.

Conclusion: CBD and H2CBD presented very similarly in all the assayed anti-inflammatory performances, undergoing same inflammatory mechanism with NF-κB and AKT pathway; they also expressed similar antibacterial activity, like twins. These findings will supply CBD a sustainable, safer and economic alternative with same excellent performances.”

https://pubmed.ncbi.nlm.nih.gov/39389390/

“To assess the hypothesis or query that CBD could also find H2CBD performing similar anti-inflammatory properties and mechanism, as well as the safety, this experiment reveals the anti-inflammatory properties of CBD, H2CBD and H2THC using serval enzymatic assays, proteins denaturation assay and LPS-RAW264.7 cells model, with epigallocatechin gallate (EGCG) as the positive control. The results indicate that both of CBD and H2CBD significantly inhibited NO production from the LPS-stimulated RAW.”

https://www.sciencedirect.com/science/article/abs/pii/S0378874124012108?via%3Dihub

Antifungal properties of Abnormal Cannabinoid derivatives: Disruption of Biofilm Formation and Gene Expression in Candida Species

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“Abnormal cannabinoids (including comp 3) are a class of synthetic lipid compounds with non-psychoactive properties and regioisomer configurations, but distinct from traditional cannabinoids since they do not interact with the established CB1 and CB2 receptors. Previous research showed the cardioprotective and anti-inflammatory potentials of comp 3 and more recently its antimicrobial effect on methicillin-resistant Staphylococcus aureus (MRSA).

Given the escalating challenges posed by Candida infections and the rise of antifungal drug resistance, the exploration of novel therapeutic avenues is crucial. This study aimed to assess the anti-Candida properties of newly synthesized AbnCBD derivatives. AbnCBD derivatives were synthesized by acid catalysis-induced coupling and further derivatized. We evaluated the potential of the AbnCBD derivatives to inhibit the growth stages of various Candida species.

By in vitro colorimetric assays and in vivo mice experiments, we have shown that AbnCBD derivatives induce differential inhibition of Candida growth. The AbnCBD derivatives, especially comp 3, comp 10, and comp 9 significantly reduced the growth of C. albicans, including FLC-resistant strains, and of C. tropicalis and C. parapsilosis but not of C auris compared to their controls (FLC and 0.5% DMSO). Comp 3 also disrupted C. albicans biofilm formation and eradicated mature biofilms. Notably, other derivatives of AbnCBD disrupted the biofilm formation and maturation of C. albicans but did not affect yeast growth. In a murine model of VVC, comp 3 demonstrated significant fungal clearance and reduced C. albicans burden compared to vehicle and FLC controls.

These findings highlight the potential of AbnCBDs as promising antifungal agents against Candida infections.”

https://pubmed.ncbi.nlm.nih.gov/39368567/

https://www.sciencedirect.com/science/article/pii/S1043661824003864?via%3Dihub

Identification of the TRPA1 Cannabinoid-Binding Site

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“Chronic pain accounts for nearly two-thirds of conditions eligible for medical cannabis licenses, yet the mechanisms underlying cannabis-induced analgesia remain poorly understood.

The principal phytocannabinoids, the psychoactive Δ9-tetrahydrocannabinol (THC) and non-psychoactive cannabidiol (CBD), exhibit comparable efficacy in pain management. Notably, THC functions as an agonist of cannabinoid receptor 1 (CB1), whereas CBD shows minimal activity on CB1 and CB2 receptors.

Elucidating the molecular targets through which phytocannabinoids modulate the pain system is required for advancing our understanding of the pain pathway and optimizing medical cannabis therapies.

Transient receptor potential ankyrin 1 (TRPA1), a pivotal chemosensor in the pain pathway, has been identified as a phytocannabinoid target. Unlike most TRPA1 activators, phytocannabinoid activation is not mediated through the electrophilic binding site, suggesting an alternative mechanism. Here, we identified the human TRPA1 channel cannabinoid-binding site (CBS) and demonstrated that mutations at residue Y840 abolished responses to both THC and CBD at saturating concentrations, indicating a shared primary binding site. Molecular modeling revealed distinct interactions of THC and CBD with the Y840 residue within the CBS. Additionally, CBD binds to the adjacent general anesthetic binding site at oversaturating concentrations.

Our findings define the CBS of TRPA1 as overlapping with and adjacent to binding sites for other allosteric activators, suggesting that TRPA1 possesses a highly adaptable domain for binding non-electrophilic activators. This underscores its unique role as a chemosensor in the pain pathway. Furthermore, our results provide new insights into the molecular mechanisms of cannabinoid-induced analgesia and identify novel targets for pain management therapies.”

https://pubmed.ncbi.nlm.nih.gov/39368566/

https://www.sciencedirect.com/science/article/pii/S104366182400389X?via%3Dihub

Nanocarriers for Cannabinoid Delivery: Enhancing Therapeutic Potential

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“Medical cannabis has potential therapeutic benefits in managing pain, anxiety, depression, and neurological and movement disorders. Phytocannabinoids derived from the cannabis plant are responsible for their pharmacological and therapeutic properties. However, the complexity of cannabis components, especially cannabinoids, poses a challenge to effective medicinal administration. Even with the increasing acceptance of cannabis-based medicines, achieving consistent bioavailability and targeted distribution remains difficult. Conventional administration methods are plagued by solubility and absorption problems requiring innovative solutions. After conducting a thorough review of research papers and patents, it has become evident that nanotechnology holds great promise as a solution. The comprehensive review of 36 research papers has yielded valuable insights, with 7 papers reporting enhanced bioavailability, while others have focused on improvements in release, solubility, and stability. Additionally, 19 patents have been analyzed, of which 7 specifically claim enhanced bioavailability, while the remaining patents describe various formulation methods. These patents outline effective techniques for encapsulating cannabis using nanocarriers, effectively addressing solubility and controlled release. Studies on the delivery of cannabis using nanocarriers focus on improving bioavailability, prolonging release, and targeting specific areas. This synthesis highlights the potential of nanotechnology to enhance cannabis therapies and pave the way for innovative interventions and precision medicine.”

https://pubmed.ncbi.nlm.nih.gov/39356097/

https://www.eurekaselect.com/article/141807

Rooted in therapeutics: comprehensive analyses of Cannabis sativa root extracts reveals potent antioxidant, anti-inflammatory, and bactericidal properties

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“Following the legalization of recreational Cannabis in Canada in 2018, the associated waste, including Cannabis roots, has significantly increased. Cannabis roots, comprising 30%-50% of the total plant, are often discarded despite their historical use in Ayurvedic medicine for treating inflammatory and infectious disorders.

This study evaluates the phytochemical and therapeutic properties of Cannabis root extracts from a high tetrahydrocannabinolic acid, low cannabidiolic acid cultivar (variety Alien Gorilla Glue).

We performed ultra high-performance liquid chromatography coupled with mass spectrometry (UPLC-QTOF-MS) to identify the chemical components of the Cannabis roots. Extracts using water, ethanol and acid-base solvents were tested for antioxidant activity through free radical scavenging, metal chelation, and lipoperoxidation inhibition assays. Mitochondrial membrane protection was assessed using flow cytometry with the MitoPerOx probe in THP-1 monocytic leukemia cells. Anti-inflammatory potential was evaluated by measuring interleukin-6 levels in lipopolysaccharide-stimulated THP-1 cells. Bactericidal/fungicidal efficacy against Escherichia coli, Staphylococcus aureus, and Candida albicans was determined using the p-iodonitrophenyltetrazolium assay. Additionally, we investigated the anticholinesterase activity of Cannabis root extracts, given the potential role of plant alkaloids in inhibiting cholinesterase, an enzyme targeted in Alzheimer’s disease treatments. UPLC-QTOF-MS analysis suggested the presence of several phenolic compounds, cannabinoids, terpenoids, amino acids, and nitrogen-containing compounds.

Our results indicated significant antioxidant, bactericidal, and anticholinesterase properties of Cannabis root extracts from both soil and hydroponic cultivation.

Extracts showed strong antioxidant activity across multiple assays, protected mitochondrial membrane in THP-1 cells, and exhibited anti-inflammatory and bactericidal/fungicidal efficacy. Notably, soil-cultivated roots displayed superior anti-inflammatory effects.

These findings demonstrate the remarkable antioxidant, anti-inflammatory, and anti-microbial activities of Cannabis roots, supporting their traditional uses and challenging their perception as mere waste. This study highlights the therapeutic potential of Cannabis roots extracts and suggests avenues for further research and application.”

https://pubmed.ncbi.nlm.nih.gov/39351095/

“In conclusion, this study sheds light on the chemical profile and significant therapeutic potential of Cannabis root extracts, confirming the validity of their traditional uses and challenging their conventional status as waste products of Cannabis cultivation.

The results presented in this work add evidence to the broad spectrum of biological systems in which Cannabis-sourced derivatives have a potential effect, not only because of cannabinoids, but also because of the possible action of phenolic and nitrogen-containing compounds. Through comprehensive investigation, we have demonstrated their remarkable antioxidant, anticholinesterase, and anti-inflammatory activities, along with their ability to protect mitochondrial membranes.

These findings underscore the importance of reevaluating the utilization of Cannabis roots in various therapeutic contexts, potentially offering new avenues for drug discovery and development. By recognizing the value of these often-overlooked plant components, we may uncover novel treatments for a range of medical conditions, thereby contributing to the advancement of natural product pharmacology and healthcare innovation. Further research in this area is warranted to elucidate the underlying mechanisms and explore the full therapeutic potential of Cannabis root extracts.”

https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2024.1465136/full

Repeated Administration of a Full-Spectrum Cannabidiol Product, Not a Cannabidiol Isolate, Reverses the Lipopolysaccharide-Induced Depressive-Like Behavior and Hypolocomotion in a Rat Model of Low-Grade Subchronic Inflammation

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“Background: Mounting evidence suggests that the phytocannabinoid cannabidiol (CBD) holds promise as an antidepressant agent in conditions underlined by inflammation. Full-spectrum CBD extracts might provide greater behavioral efficacy than CBD-only isolates and might require lower doses to achieve the same outcomes due to the presence of other cannabinoids, terpenes, and flavonoids. However, investigations in this area remain limited. 

Methods: We evaluated the behavioral response to the administration for 7 days of 15 and 30 mg/kg of a CBD isolate and a full-spectrum CBD product in a rat model of subchronic lipopolysaccharide (LPS, 0.5 mg/kg/day/7 days, intraperitoneal)-induced depressive-like and sickness behavior. The forced swim test was used to assess depressive-like behavior, the open field test (OFT) to assess locomotion, and the elevated plus maze to assess anxiety-like behavior. 

Results: The full-spectrum CBD extract at both doses, but not the CBD isolate, reversed the LPS-induced depressive-like behavior in the forced swim test. Moreover, the full-spectrum CBD extract at the higher dose but not the CBD isolate restored the subchronic LPS-induced hypolocomotion in the OFT. Repeated administration of both formulations elicited an anxiogenic-like trend in the elevated plus maze. 

Conclusion: Full-spectrum CBD products might have greater therapeutic efficacy in resolving inflammation-induced depressive and sickness behavior compared to a CBD-only isolate.”

https://pubmed.ncbi.nlm.nih.gov/39347620/

https://www.liebertpub.com/doi/10.1089/can.2024.0086

Hemp Seed (Cannabis sativa L.) Varieties: Lipids Profile and Antioxidant Capacity for Monogastric Nutrition

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“The present research aimed to study the proximate composition, fatty acid profile, antiox-idant activity, total phenolic and N-trans-Caffeoyltyramine content of three distinct varieties of hemp seeds (Carmaenecta, Enectaliana and Enectarol, grown in a Mediterranean area (Central Italy), as feed in the diet of farm animals. Proximate composition was determined using the official methods of analyses; the fatty acid profile was determined by gas chromatography, total phenolic content (TPC) and the scavenging activity (DPPH• and ABTS•+) by the colorimetric method, and N-trans-Caffeoyltyramine content by HPLC analysis. The hemp seed Enectarol showed the highest total lipid content and the best antioxidant activity with the highest TPC, N-trans-Caffeoyltyramine content, and ABTS•+, and the lowest peroxidation index and DPPH•; Carmaenecta showed the best fatty acid profile and nutritional indices (atherogenic and thrombogenic indices and hypocholesterolemic/hypercholesterolemic ratio), and Enectaliana showed the highest crude protein and dietary fiber content. The differences observed in the chemical composition, fatty acid profile and antioxidant activity are because of the varieties, considering that all other growing conditions were the same. The results obtained suggest that hemp seed can be used as a source of lipid and protein in animal diets due to their valuable antioxidant activity and as a rich source of essential fatty acids.”

https://pubmed.ncbi.nlm.nih.gov/39335288/

“(Cannabis sativa L.), due to its distinctive nutritional profile, can be considered an interesting and promising alternative resource for agriculture in human and animal nutrition.

In conclusion, the results highlight that hemp seeds can be used in the food industry as a source of oil and protein and as a supplement in feed mixtures for the valuable antioxidant activity and fatty acid profile, promoting better health in farm animals.”

https://www.mdpi.com/2076-2615/14/18/2699

Cannabis-Containing Cream for CKD-Associated Pruritus: A Double-Blind, Placebo Controlled Trial

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“Rationale & objective: This study aims to compare the efficacy of a cannabis cream and a placebo in the treatment of chronic kidney disease (CKD)-associated pruritus.

Study design: A double-blind randomized controlled study.

Setting & participants: Sixty hemodialysis patients with the worst itching intensity numerical rating scale (WI-NRS) ≥3.

Exposure: Patients received cannabis cream or placebo.

Outcomes: The primary endpoint was the WI-NRS score at week 4. The secondary endpoints included the WI-NRS at week 2, the Skindex-10 score at weeks 2 and 4, and the mean difference score between baseline and week 4 for the WI-NRS and the Skindex-10 score.

Analytical approach: We used unpaired t tests or Mann Whitney U tests, along with χ2 or Fisher exact tests as appropriate. The adjusted mean differences were determined using ANCOVA, adjusting for baseline scores.

Results: Among 60 participants, the mean age was 61.6 ± 14.4 years and the mean baseline WI-NRS was 6.7 ± 1.7. The placebo and cannabis cream groups were similar at baseline, although more individuals in the placebo group had diabetes. At 4 weeks, the WI-NRS dropped to 2.6 in the cannabis group and 3.6 in the placebo group (the mean difference after adjustment for baseline scores:-1.1, 95% CI, -2.1 to -0.2; P = 0.02). Skindex-10 scores at week 4 were also lower in the cannabis group, but after adjustment for baseline scores, statistical significance was not maintained. No side effects were observed in either group.

Limitations: A single study with a small sample size restricts its generalizability. Variances in participants’ diabetes statuses might have affected the itch outcomes. The absence of cannabinoid level assessment in blood prevents conclusive determination of the potential systemic impacts. A 4-week follow-up period inadequately captures long-term effect.

Conclusions: In CKD-associated pruritus, the topical cream containing cannabis significantly reduced the severity of itching symptoms compared to the placebo.”

https://pubmed.ncbi.nlm.nih.gov/39328960/

https://www.kidneymedicinejournal.org/article/S2590-0595(24)00105-5/fulltext

Effect of Cannabistilbene I in Attenuating Angiotensin II-Induced Cardiac Hypertrophy: Insights into Cytochrome P450s and Arachidonic Acid Metabolites Modulation

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“Introduction: This research investigated the impact of Cannabistilbene I on Angiotensin II (Ang II)-induced cardiac hypertrophy and its potential role in cytochrome P450 (CYP) enzymes and arachidonic acid (AA) metabolic pathways. Cardiac hypertrophy, a response to increased stress on the heart, can lead to severe cardiovascular diseases if not managed effectively. CYP enzymes and AA metabolites play critical roles in cardiac function and hypertrophy, making them important targets for therapeutic intervention. 

Methods: Adult human ventricular cardiomyocyte cell line (AC16) was cultured and treated with Cannabistilbene I in the presence and absence of Ang II. The effects on mRNA expression related to cardiac hypertrophic markers and CYP were analyzed using real-time polymerase chain reaction, while CYP protein levels were measured by Western blot analysis. AA metabolites were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS). 

Results: Results showed that Ang II triggered hypertrophy, as evidenced by the increase in hypertrophic marker expression, and enlarged the cell surface area, effects that were alleviated by Cannabistilbene I. Gene expression analysis indicated that Cannabistilbene I upregulated CYP1A1, leading to increased enzymatic activity, as evidenced by 7-ethoxyresorufin-O-deethylase assay. Furthermore, LC-MS/MS analysis of AA metabolites revealed that Ang II elevated midchain (R/S)-hydroxyeicosatetraenoic acid (HETE) concentrations, which were reduced by Cannabistilbene I. Notably, Cannabistilbene I selectively increased 19(S)-HETE concentration and reversed the Ang II-induced decline in 19(S)-HETE, suggesting a unique protective role. 

Conclusion: This study provides new insights into the potential of Cannabistilbene I in modulating AA metabolites and reducing Ang II-induced cardiac hypertrophy, revealing a new candidate as a therapeutic agent for cardiac hypertrophy.”

https://pubmed.ncbi.nlm.nih.gov/39324890/

https://www.liebertpub.com/doi/10.1089/can.2024.0148

“Cannabistilbene I (CBG-I) is a naturally occurring derivative of the plant cannabis. It is a polyphenol compound found in the resinous glandular trichomes of the cannabis plant. CBG-I is known for its potent antioxidant, anti-inflammatory, and neuroprotective properties, making it a promising area of research in various fields.

Cannabistilbene I was first isolated and identified in 1975 by scientists from the University of Mississippi. It is a distinct compound from other cannabinoids and is found in different cannabis varieties. CBG-I is the precursor to THC, CBD, and other cannabinoids, which makes it essential in the biosynthesis of these compounds.”

https://www.smolecule.com/products/s579399


Cannabidiol Modulation of Nicotine-Induced Toxicity: Assessing Effects on Behavior, Brain-Derived Neurotrophic Factor, and Oxidative Stress in C57BL/6 Male Mice

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“High doses of nicotine administered to rodents serve as a model for studying anxiety and test compounds’ potential anxiolytic effects. At these doses, anxiety in rodents is accompanied by disruption of brain-derived neurotrophic factor (BDNF). The endocannabinoids and nicotine modulate several central nervous system processes via their specific receptors, impacting locomotion, anxiety, memory, nociception, and reward.

Cannabidiol (CBD), an active ingredient of Cannabis sativa L., is devoid of psychoactive actions and has gained attention for its anxiolytic, antioxidant, and anti-inflammatory properties, among others. This work aims to examine the potential anxiety-reducing properties of CBD in a well-established experimental mouse model of anxiety-like behavior induced by high doses of nicotine on male C57BL/6 mice.

In this context, the open-field behavioral test was specially conducted to assess CBD’s effects on anxiety-like behavior and locomotion. Brain neuronal plasticity, modulated by BDNF, along with a diverse array of blood’s metabolic markers, was examined as a means of evaluating systemic toxicity under various treatments. Finally, oxidative stress was evaluated through the measurement of glutathione (GSH), superoxide dismutase (SOD), and malondialdehyde (MDA), while pro-inflammatory cytokine assessments were conducted to evaluate redox status and immune system function.

Our research suggests that CBD shows potential in reducing anxiety-like behaviors induced by high doses of nicotine, by mitigating changes in BDNF protein levels in cerebral hemispheres and cerebellum. At the same time, CBD targets specific liver enzymes, maintains tissue’s systemic toxicity (i.e., renal, kidney, and pancreatic), balances redox status (SOD, GSH, and MDA), and regulates the secretion of pro-inflammatory cytokines (TNF-alpha and IL-6).”

https://pubmed.ncbi.nlm.nih.gov/39297526/

https://onlinelibrary.wiley.com/doi/10.1002/jnr.25384