Monthly Archives: September 2024

Molecular Targets of Minor Cannabinoids in Breast Cancer: In Silico and In Vitro Studies

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“Background: Breast cancer therapy has been facing remarkable changes. Classic treatments are now combined with other therapies to improve efficacy and surpass resistance. Indeed, the emergence of resistance demands the development of novel therapeutic approaches. Due to key estrogen signaling, estrogen receptor-positive (ER+) breast cancer treatment has always been focused on aromatase inhibition and ER modulation. Lately, the effects of phytocannabinoids, mainly Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), have been evaluated in different cancers, including breast. However, Cannabis sativa contains more than 120 phytocannabinoids less researched and understood.

Methods: Here, we evaluated, both in silico and in vitro, the ability of 129 phytocannabinoids to modulate important molecular targets in ER+ breast cancer: aromatase, ER, and androgen receptor (AR).

Results: In silico results suggested that some cannabinoids may inhibit aromatase and act as ERα antagonists. Nine selected cannabinoids showed, in vitro, potential to act either as ER antagonists with inverse agonist properties, or as ER agonists. Moreover, these cannabinoids were considered as weak aromatase inhibitors and AR antagonists with inverse agonist action.

Conclusions: Overall, we present, for the first time, a comprehensive analysis of the actions of the phytocannabinoids in targets of ER+ breast tumors, pointing out their therapeutic potential in cancer and in other diseases.”

https://pubmed.ncbi.nlm.nih.gov/39338407/

“From the best of our knowledge, this is the first study exploring the molecular targets of minor cannabinoids and, together with previous studies, it reinforces the importance and therapeutic potential of cannabinoids in breast cancer, paving the way for novel and alternative therapeutic approaches and highlighting the medicinal potential of Cannabis.”

https://www.mdpi.com/1424-8247/17/9/1245

Cannabis sativa L. Extract Alleviates Neuropathic Pain and Modulates CB1 and CB2 Receptor Expression in Rat

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“Introduction: Cannabis sativa L. (CSL) extract has pain-relieving potential due to its cannabinoid content, so the effects of two CSL extracts on alleviating neuropathic pain were investigated in vivo. Methods and groups: Male Wistar rats (n = 130) were divided into groups and received vincristine (0.1 mg/kg) and gabapentin (60 mg/kg) to induce and relieve neuropathic pain or CSL extracts (D and B). The mRNA and protein expression of the cannabinoid receptors type 1 and 2 (CB1R, CB2R) were evaluated in the cerebral cortex, hippocampus, and lymphocytes. Behavioural tests (Tail-Flick and von Frey) were performed on all animals.

Results: VK-induced neuropathic pain was accompanied by decreased CB1R protein level and CB2R mRNA expression in the cortex. Gabapentin relieved pain and increased CB1R protein levels in the hippocampus compared to the vincristine group. Hippocampus CB1R protein expression increased with the administration of extract D (10 mg/kg, 40 mg/kg) and extract B (7.5 mg/kg, 10 mg/kg) compared to VK group. In the cerebral cortex CSL decreased CB1R protein expression (10 mg/kg, 20 mg/kg, 40 mg/kg of extract B) and mRNA level (5 mg/kg, 7.5 mg/kg of extract B; 20 mg/kg of extract D) compared to the VK-group.CB2R protein expression increased in the hippocampus after treatment with extract B (7.5 mg/kg) compared to the VK-group. In the cerebral cortex extract B (10 mg/kg, 20 mg/kg) increased CB2R protein expression compared to VK-group.

Conclusion: Alterations in cannabinoid receptor expression do not fully account for the observed behavioural changes in rats. Therefore, additional signalling pathways may contribute to the initiation and transmission of neuropathic pain. The Cannabis extracts tested demonstrated antinociceptive effects comparable to gabapentin, highlighting the antinociceptive properties of Cannabis extracts for human use.”

https://pubmed.ncbi.nlm.nih.gov/39334832/

“Furthermore, both tested Cannabis sativa L. extracts demonstrated antinociceptive effects comparable to gabapentin, highlighting the potential medical value of Cannabis extracts for human use.”

https://www.mdpi.com/2218-273X/14/9/1065

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

Cannabidiol Alleviates Imiquimod-Induced Psoriasis by Inhibiting JAK2-STAT3 in a Mouse Model

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“Cannabidiol (CBD), a non-psychoactive compound from Cannabis sativa, has shown efficacy in treating psoriasis, a chronic inflammatory skin disease affecting 1-3% of the global population; however, the mechanisms remain unclear.

This study investigated CBD’s effects on imiquimod (IMQ)-induced psoriasis in mice, which were divided into five groups: Control, IMQ, Clobetasol, 0.01% CBD, and 0.1% CBD. After inducing psoriasis with IMQ, clobetasol or CBD was applied. Psoriasis severity was assessed using the Psoriasis Area and Severity Index (PASI), with histopathological changes examined via hematoxylin and eosin staining. Gene expression of inflammatory markers (Il1b, Il6, Il12b, Il17a, Il22, and Tnf) was analyzed by RT-PCR, while protein levels of signal transducer and activator of transcription (STAT)3, P-STAT3, Janus kinase (JAK)2, and JAK3 were evaluated through western blot and immunohistochemistry.

The results demonstrated that CBD significantly reduced PASI scores, epidermal thickness, keratosis, hyperproliferation, and inflammation. Moreover, CBD inhibited the IL-23 receptor-mediated JAK2-STAT3 signaling pathway, leading to the downregulation of Il1b, Il6, Il12b, Il17a, Il22, and Tnf expression.

These findings suggest that CBD effectively alleviates psoriasis-like symptoms in mice and may serve as a promising therapeutic agent for psoriasis by targeting the JAK2-STAT3 pathway.”

https://pubmed.ncbi.nlm.nih.gov/39335596/

“Our results showed that CBD treatment markedly alleviated psoriasis symptoms in an IMQ-induced mouse model by targeting the JAK2–STAT3 signaling pathway. Therefore, CBD may have beneficial effects in treating psoriasis.”

https://www.mdpi.com/2227-9059/12/9/2084

Exploring the therapeutic potential of cannabinoids in cancer by modulating signaling pathways and addressing clinical challenges

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“For centuries, cannabinoids have been utilized for their medicinal properties, particularly in Asian and South-Asian countries. Cannabis plants, known for their psychoactive and non-psychoactive potential, were historically used for spiritual and remedial healing. However, as cannabis became predominantly a recreational drug, it faced prohibition.

Recently, the therapeutic potential of cannabinoids has sparked renewed research interest, extending their use to various medical conditions, including cancer. This review aims to highlight current data on the involvement of cannabinoids in cancer signaling pathways, emphasizing their potential in cancer therapy and the need for further investigation into the underlying mechanisms.

A comprehensive literature review was conducted using databases such as PubMed/MedLine, Google Scholar, Web of Science, Scopus, and Embase. The search focused on peer-reviewed articles, review articles, and clinical trials discussing the anticancer properties of cannabinoids. Inclusion criteria included studies in English on the mechanisms of action and clinical efficacy of cannabinoids in cancer.

Cannabinoids, including Δ9-THC, CBD, and CBG, exhibit significant anticancer activities such as apoptosis induction, autophagy stimulation, cell cycle arrest, anti-proliferation, anti-angiogenesis, and metastasis inhibition. Clinical trials have demonstrated cannabinoids’ efficacy in tumor regression and health improvement in palliative care. However, challenges such as variability in cannabinoid composition, psychoactive effects, regulatory barriers, and lack of standardized dosing remain.

Cannabinoids show promising potential as anticancer agents through various mechanisms. Further large-scale, randomized controlled trials are essential to validate these findings and establish standardized therapeutic protocols. Future research should focus on elucidating detailed mechanisms, optimizing dosing, and exploring cannabinoids as primary chemotherapeutic agents.”

https://pubmed.ncbi.nlm.nih.gov/39331301/

https://link.springer.com/article/10.1007/s12672-024-01356-8

“Cannabis Compounds Show ‘Promising Potential As Anticancer Agents’”

https://www.forbes.com/sites/ajherrington/2024/10/08/cannabis-compounds-show-promising-potential-as-anti-cancer-agents/

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


Cannabinoids as a Natural Alternative for the Management of Neuropathic Pain: A Systematic Review of Randomized Placebo-Controlled Trials

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“Dysfunction or damage to the nervous system may develop into and result in a chronic pain condition known as neuropathic pain. Neuropathic pain is defined as the structural and functional alteration of the somatosensory component of the nervous system. The treatment of neuropathic pain is a complex endeavor, which often requires specialist care and intensive drug therapy. Recently, cannabinoids have emerged as an alternative and natural option for the treatment of chronic pain, with tetrahydrocannabinol (THC) and cannabidiol (CBD) being the most extensively studied neuroactive components. The therapeutic potential of cannabis remains largely underexplored, primarily due to its social stigma and the restrictions that are in place on its cultivation. The primary aim of this systematic review was to explore the therapeutic value of cannabinoids in the management of chronic pain and thus achieve an improved quality of life for those patients.

A systematic review of the literature published over the last two decades was performed using the following databases: PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), Turning research into practice (Trip), and Google Scholar. Studies that were completed and published between January 01, 2000 and August 31, 2024, in English language, were extracted and appraised. A combination of keywords and Boolean operators Cannabis OR Chronic Pain OR End of life OR Pain Management AND Drug therapy was employed for data extraction. The Cochrane risk-of-bias tool for randomized trials (RoB 2) was used for risk-of-bias assessment. The initial search resulted in 125282 articles; 86,781 of the articles were identified as duplicates and were removed from the primary analysis, and 38,501 abstracts were thus screened. Abstracts, case studies, reports, editorials, viewpoints, cross-sectional studies, cohort studies, case-control studies, case series, and letters to the editor/correspondence manuscripts (n =38,492) were furthermore excluded. Nine full-text articles were critically assessed and tested against the inclusion and exclusion criteria, and a further four articles were excluded with a total of five placebo-controlled randomized control studies being ultimately included in the final systematic review.

Compared to placebo, cannabinoids provided significant relief from chronic pain (33% vs 15%) as measured by the visual analog scale. The transdermal application of CBD led to a more pronounced reduction in sharp pain, according to the neuropathic pain scale. Minimal to no side effects were recorded, further highlighting the potential benefits of cannabinoids. 

The potential benefit of cannabinoids is that they are naturally derived drugs that have already been shown to have the potential to effectively decrease chronic pain with minimal side effects as compared to the standard drugs being used. The ability of cannabinoids to provide pain relief with minimal side effects and concurrently be a naturally derived product may potentially be a life-changing alternative that the pharmaceutical market is in dire need of.”

https://www.cureus.com/articles/297124-cannabinoids-as-a-natural-alternative-for-the-management-of-neuropathic-pain-a-systematic-review-of-randomized-placebo-controlled-trials#!/

The endocannabinoid system as a therapeutic target in neuropathic pain: a review

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“Introduction: This review highlights the critical role of the endocannabinoid system (ECS) in regulating neuropathic pain and explores the therapeutic potential of cannabinoids. Understanding the mechanisms of the ECS, including its receptors, endogenous ligands, and enzymatic routes, can lead to innovative treatments for chronic pain, offering more effective therapies for neuropathic conditions. This review bridges the gap between preclinical studies and clinical applications by emphasizing ECS modulation for better pain management outcomes.

Areas covered: A review mapped the existing literature on neuropathic pain and the effects of modulating the ECS using natural and synthetic cannabinoids. This analysis examined ECS components and their alterations in neuropathic pain, highlighting the peripheral, spinal, and supraspinal mechanisms. This review aimed to provide a thorough understanding of the therapeutic potential of cannabinoids in the management of neuropathic pain.

Expert opinion: Advances in cannabinoid research have shown significant potential for the management of chronic neuropathic pain. The study emphasizes the need for high-quality clinical trials and collaborative efforts among researchers, clinicians, and regulatory bodies to ensure safe and effective integration of cannabinoids into pain management protocols. Understanding the mechanisms and optimizing cannabinoid formulations and delivery methods are crucial for enhancing therapeutic outcomes.”

https://pubmed.ncbi.nlm.nih.gov/39317147/

“Research on the modulation of the endocannabinoid system in nervous tissue related to neuropathic pain reveals complex mechanisms of pain modulation. Dysregulation of the endocannabinoid system, microglial activation, and interactions between various signaling pathways contribute to the onset and persistence of neuropathic pain. Understanding these molecular and cellular processes is crucial for developing targeted therapies that leverage the endocannabinoid system to alleviate neuropathic pain.”

https://www.tandfonline.com/doi/full/10.1080/14728222.2024.2407824

“Smoked Cannabis Proven Effective In Treating Neuropathic Pain”

https://www.sciencedaily.com/releases/2007/10/071024141745.htm

Cannabidiol, a plant-derived compound, is an emerging strategy for treating cognitive impairments: comprehensive review of randomized trials

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“Background: Finding new strategies to treat cognitive disorders is a challenging task. Medication must defeat the blood-brain barrier. Cannabidiol (CBD), a non-intoxicating compound of the cannabis plant, has gained recognition as a nutraceutical for its potential effectiveness in treating anxiety, oxidative stress, convulsions, and inflammation. However, the dose, tolerable upper intake, formulation, administration routes, comorbidities, diet, and demographic factors to reverse cognitive impairments have not been completely explored. Trials using CBD as a primary intervention have been conducted to alleviate cognitive issues. This review evaluates the benefits of CBD supplementation, research design, formulations, and outcomes reported in randomized clinical trials.

Methods: An evidence-based systematic literature review was conducted using PUBMED and the Florida International University Research Library resources. Fourteen randomized trials were selected for review, and their designs and outcomes were compared conceptually and in the form of resume tables.

Results: CBD showed improvement in anxiety and cognitive impairments in 9 out of 16 analyzed trials. However, the variability could be justified due to the diversity of the trial designs, underpowered studies, assayed population, uncontrolled results for comorbidities, medications, severity of drug dependence, compliances, and adherences. Overall, oral single doses of 200 mg-1,500 mg or vaporized 13.75 mg of CBD were shown to be effective at treating anxiety and cognition with a good safety profile and no drug addiction behaviors. Conversely, results that did not have a significant effect on treating cognitive impairments can be explained by various factors such as THC or other abuse drugs masking effect, low dose, and unknown purity of CBD. Furthermore, CBD shows potential properties that can be tested in the future for Alzheimer’s disease.

Conclusion: As medical cannabis becomes more accessible, it is essential to understand whether medication rich in CBD exerts a beneficial effect on cognitive disorders. Our study concludes that CBD is a promising candidate for treating neurocognitive disorders; however, more studies are required to define CBD as a therapeutic candidate for managing cognitive disorders.”

https://pubmed.ncbi.nlm.nih.gov/39323633/

“Cannabidiol (CBD), a phytocannabinoid, is derived from the cannabis plant.”

https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2024.1403147/full