Author Archives: David

Efficacy and Safety of Transdermal Medical Cannabis (THC:CBD:CBN formula) to Treat Painful Diabetic Peripheral Neuropathy of Lower Extremities

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“Introduction: Diabetic peripheral neuropathy (DPN) represents a prevalent neurological complication affecting millions of patients globally. This clinical investigation evaluated the therapeutic efficacy and safety profile of a novel transdermal medical cannabis formulation (THC:CBD:CBN) in treating painful DPN of the lower extremities.

Methods: This phase III, double-blind, placebo-controlled, randomized clinical trial was conducted at Don Chan Hospital, Thailand, enrolling 100 participants over a 12-week intervention period. Using a computer-generated randomization sequence, participants were allocated to receive either the standardized cannabis formulation or a matched placebo. The primary outcome measure comprised pain intensity assessment using the validated Thai version of the Neuropathic Pain Symptom Inventory (NPSI-T). Secondary outcomes encompassed treatment-emergent adverse events and dermatological manifestations. Statistical analyses were performed using SPSS Version 28.0, incorporating generalized estimating equation (GEE) modeling and Analysis of Covariance (ANCOVA). The study protocol received approval from the Institutional Review Board of Khon Kaen University and the Kalasin Provincial Public Health Office Ethics Committee, with trial registration in the Thai Clinical Trials Registry.

Results: The intervention group demonstrated statistically significant reductions in NPSI-T scores across all measured dimensions (p < 0.001). Mean total NPSI-T scores decreased markedly from 25.60 to 5.57 in the treatment cohort, contrasting with minimal reduction from 25.24 to 22.85 in the placebo group. GEE analysis revealed significant pain amelioration at weeks 4, 8, and 12 (p < 0.001). The cannabis formulation exhibited an excellent safety profile, with only 10% of participants reporting mild adverse events, comparable to placebo group outcomes.

Conclusion: This novel transdermal medical cannabis formulation (THC:CBD:CBN) demonstrated significant therapeutic efficacy in ameliorating painful DPN symptoms while maintaining a favorable safety profile. These findings provide robust clinical evidence supporting its potential as an innovative therapeutic option for managing painful DPN.”

https://pubmed.ncbi.nlm.nih.gov/39720705/

“This randomized controlled trial provides robust evidence supporting the therapeutic efficacy and safety profile of transdermal THC:CBD:CBN formulation in the management of painful DPN. The demonstrated significant reduction in multidimensional pain scores, combined with the pharmacokinetic advantages of transdermal delivery and favorable safety outcomes, suggests substantial clinical potential for this therapeutic approach. As the evidence base continues to expand, cannabinoid-based interventions may emerge as a valuable therapeutic option in addressing the complex challenges of neuropathic pain management.”

https://karger.com/mca/article/8/1/1/916069/Efficacy-and-Safety-of-Transdermal-Medical

Biopeptide-rich fermented hemp seeds: Boosting anti-inflammatory and immune responses through Lactiplantibacillus plantarum probiotic fermentation

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“Cannabis sativa L. (hemp) seeds are increasingly recognized as a promising food source rich in phytochemicals that support inflammatory and immunological reactions.

This study investigates whether fermentation with Lactiplantibacillus plantarum can further enhance these functional properties, paving the way for hemp seeds to be developed into potent functional food ingredients.

Aqueous, 70 % ethanol, and ethyl acetate extracts from both L. plantarum-fermented (FHS) and unfermented hemp seeds (HS) were evaluated for their anti-inflammatory activities using cell-based assays.

The 70 % ethanol extract of FHS exhibited marked inhibitory effects on cytokines, including TNF-α, IL-1β, and IL-10, with fermentation significantly enhancing these effects by 25 %, 39.3 %, and 29.6 %, respectively, compared to the unfermented extracts. Additionally, mRNA expression analysis confirmed the strong immunomodulatory potential of the fermented extracts. Intracellular metabolomic analysis revealed that the ‘antifolate resistance’, ‘nicotine addiction’, ‘aminoacyl-tRNA biosynthesis’, and ‘D-amino acid metabolism’ are highlighted in the reasons for this enhancement. Furthermore, FHS significantly prolonged the survival of C. elegans exposed to pathogens, with gene expression analysis indicating modulation of the innate immune system via regulation of genes such as gcs-1, lys-1, dbl-1, pmk-1, elt-2, and dod-22. A comprehensive metabolomic and correlation analysis identified five novel bioactive peptides (AAELIGVP, AAVPYPQ, VFPEVAP, DVIGVPLG, PVPKVL) and bioactive acids (indoleacetic acid and homovanillic acid) that were enriched during fermentation, which are strongly linked to the enhanced anti-inflammatory and immunomodulatory effects observed.

These findings suggest that L. plantarum-fermented hemp seeds hold significant promise as functional ingredients in anti-inflammatory and immunomodulatory food products, with potential applications in health and wellness industries.”

https://pubmed.ncbi.nlm.nih.gov/39706455/

“L. plantarum fermentation amplified the anti-inflammatory properties of hemp seeds.”

https://www.sciencedirect.com/science/article/abs/pii/S014181302409593X?via%3Dihub

Cannabidiol induces autophagy via CB1 receptor and reduces α-synuclein cytosolic levels

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“Numerous studies have explored the role of cannabinoids in neurological conditions, chronic pain and neurodegenerative diseases. Restoring autophagy has been proposed as a potential target for the treatment of neurodegenerative diseases.

In our study, we used a neuroblastoma cell line that overexpresses wild-type α-synuclein to investigate the effects of cannabidiol on autophagy modulation and reduction in the level of cytosolic α-synuclein.

Our results demonstrated that cannabidiol enhances the accumulation of LC3-II- and GFP-LC3-positive vesicles, which indicates an increase in autophagic flux. In addition, cannabidiol-treated cells showed a reduction in cytosolic α-synuclein levels. These effects were inhibited when the cells were treated with a CB1 receptor-selective antagonist, which indicates that the biological effects of cannabidiol are mediated via its interaction with CB1 receptor. Additionally, we also observed that cannabinoid compounds induce autophagy and α-synuclein degradation after they interact with the CB1 receptor.

In summary, our data suggest that cannabidiol induces autophagy and reduces cytosolic α-synuclein levels. These biological effects are mediated preferentially through the interaction of cannabidiol with CB1 receptors, and therefore, cannabinoid compounds that act selectively on this receptor could represent a new approach for autophagy modulation and degradation of protein aggregates.”

https://pubmed.ncbi.nlm.nih.gov/39710053/

https://www.sciencedirect.com/science/article/pii/S0006899324006693?via%3Dihub

Effects of Cannabidiol on Biomineralization and Inflammatory Mediators Expression in Immortalized Murine Dental Pulp Cells and Macrophages under Pro-Inflammatory Conditions

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“Objectives: This study investigated the in vitro effects of cannabidiol (CBD) on dental pulp cells and macrophages under pro-inflammatory conditions.

Materials and methods: Mouse dental pulp undifferentiated cells (OD-21) were pre-stimulated with tumor necrosis factor alpha (10 ng/mL) or left untreated, then exposed to CBD at concentrations of 0.01 µM, 0.1 µM, 1 µM, and 10 µM for 24 hours and 7 days. Cell viability was assessed using the MTT assay, while gene expression related to mineralization-Dentin Sialophosphoprotein (Dspp), Dentin Matrix Protein 1 (Dmp1), Runt-related transcription factor 2 (Runx2), TNF-α (Tnf), and prostaglandin-endoperoxide synthase 2 (Ptgs2) were analyzed via quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Mineralization nodule formation was evaluated using alizarin red staining. Macrophages (RAW 264.7) were stimulated with lipopolysaccharide (LPS) for 2 hours before exposure to the same CBD concentrations. Data analysis included the Shapiro-Wilk normality test and comparisons using ANOVA and Tukey’s post-hoc test (α = 0.05).

Results: The findings indicated that CBD did not significantly affect OD-21 cell viability, except for the 10 µM concentration after 7 days (p < 0.05). CBD treatment promoted mineralization, with significant differences observed among groups (p < 0.05). Notably, Ptgs2 expression varied between time points, while Runx2 expression was significantly reduced at 24 hours (p < 0.05). In macrophages, Ptgs2 expression was low, and TNF-α levels were downregulated across all tested CBD concentrations (p < 0.05).

Conclusion: These results suggest that cannabidiol may positively influence the biomineralization process and modulate inflammatory mediator expression.”

https://pubmed.ncbi.nlm.nih.gov/39706322/

“Cannabidiol is a compelling candidate for innovative dental therapies aimed at both reparative and preventive care.”

https://www.sciencedirect.com/science/article/abs/pii/S0300571224007048?via%3Dihub

Cannabidiol alleviates LPS-inhibited odonto/osteogenic differentiation in human dental pulp stem cells in vitro

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“Aim: Cannabidiol (CBD), derived from the Cannabis sativa plant, exhibits benefits in potentially alleviating a number of oral and dental pathoses, including pulpitis and periodontal diseases. This study aimed to explore the impact of CBD on several traits of human dental pulp stem cells (hDPSC), such as their proliferation, apoptosis, migration and odonto/osteogenic differentiation.

Methodology: hDPSCs were harvested from human dental pulp tissues. The cells were treated with CBD at concentrations of 1.25, 2.5, 5, 10, 25 and 50 μg/mL. Cell responses in terms of cell proliferation, colony-forming unit, cell cycle progression, cell migration, apoptosis and odonto/osteogenic differentiation of hDPSCs were assessed in the normal culture condition and P. gingivalis lipopolysaccharide (LPS)-induced ‘inflammatory’ milieus. RNA sequencing and proteomic analysis were performed to predict target pathways impacted by CBD.

Results: CBD minimally affects hDPSCs’ behaviour under normal culture growth milieu in normal conditions. However, an optimal concentration of 1.25 μg/mL CBD significantly countered the harmful effects of LPS, indicated by the promoting cell proliferation and restoring the odonto/osteogenic differentiation potential of hDPSCs under LPS-treated conditions. The proteomic analysis demonstrated that several proteins involved in cell proliferation and differentiation were upregulated following CBD exposure, including CCL8, CDC42 and KFL5. RNA sequencing data indicated that CBD upregulated the Notch signalling pathway. In an inhibitory experiment, DAPT, a Notch inhibitor, reduced the effect of CBD-rescued LPS-attenuated mineralization in hDPSCs, suggesting that CBD potentially mediates Notch activation to exert its impact on odonto/osteogenic differentiation of hDPSCs.

Conclusions: CBD recovers the proliferation and survival of hDPSCs following exposure to LPS. Additionally, we report that CBD-mediated Notch activation effectively restores the odonto/osteogenic differentiation ability of hDPSCs under inflamed conditions. These results underscore the potential role of CBD as a therapeutic option to enhance dentine regeneration.”

https://pubmed.ncbi.nlm.nih.gov/39697062/

https://onlinelibrary.wiley.com/doi/10.1111/iej.14183

Medical cannabis for severe treatment resistant epilepsy in children: a case-series of 10 patients

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“Objectives To report the findings of a case-series of 10 children suffering with intractable epilepsies in the UK to determine the feasibility for using whole-plant cannabis medicines to treat seizures in children.

Setting This study was conducted retrospectively through collecting clinical data from caretakers and clinicians on study outcome variables. Participants were recruited through the MedCann Support and End our Pain charity groups which are patient representative groups that support children who are using medical cannabis to treat their epilepsies. Medicines were prescribed to patients by clinicians in both National Health Service and private medical practices. Follow-up calls were conducted throughout the period January 2021 to May 2021 to keep data recorded up to date.

Participants Ten children, 18 years old or under, with intractable epilepsies were recruited from two charities. There were no limitations on diagnosis, sex or ethnic origin.

Interventions Participants were treated with a range of whole-plant medical cannabis oils. Individual dosing regimens were determined by clinicians.

Primary outcome measure The primary outcome measure was seizure frequency.

Results Seizure frequency across all 10 participants reduced by 86% with no significant adverse events. Participants reduced use of antiepileptic drugs from an average of seven to one following treatment with medical cannabis. We also noted significant financial costs of £874 per month to obtain these medicines through private prescriptions.

Conclusions This study establishes the feasibility of whole-plant medical cannabis as an effective and well-tolerated medicine for reducing seizure frequency in children suffering with intractable epilepsies. These findings justify the potential value of further research into the reported therapeutic benefit of whole-plant medicinal cannabis products.”

https://bmjpaedsopen.bmj.com/content/5/1/e001234

“Epileptic seizure frequency fell by 86% in kids treated with whole plant medicinal cannabis”

https://medicalxpress-com.cdn.ampproject.org/c/s/medicalxpress.com/news/2021-12-epileptic-seizure-frequency-fell-kids.amp

Tobacco and marijuana use and their association with serum prostate-specific antigen levels among African American men in Chicago

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“African American (AA) men experience more than twice the prostate cancer mortality as White men yet are under-represented in academic research involving prostate-specific antigen (PSA), a biomarker of prostate cancer aggressiveness.

We examined the impact of self-reported tobacco (cigarette pack-years and current tobacco use including e-cigarettes) and current regular marijuana use on serum PSA level based on clinical laboratory testing among 928 AA men interviewed 2013-2018 in Chicago. We defined outcome of elevated PSA ≥ 4.0 ng/mL for logistic regression models and continuous PSA increases for general linear models. All models were adjusted for age, sociodemographic characteristics, healthcare utilization, body mass index, and self-reported health.

Among 431 AA men age ≥ 55 years, we observed ∼ 5 times the odds of elevated PSA among those with > 1 pack-years of cigarette smoking vs. never-smokers (odds ratio [OR] = 5.09; 95% confidence interval [CI] = 1.57-16.6) and a quarter the odds of elevated PSA among current marijuana users vs. non-users (OR = 0.27; 95% CI = 0.08-0.96). PSA increased on average 1.20 ng/mL among other current tobacco users vs. non-users.

Among older AA men, cigarette smoking history and current tobacco use were positively associated with an increase in PSA levels and current marijuana use were inversely associated with PSA levels.

Future work with studies of diverse patient populations with cancer outcomes are needed to assess whether these behavioral characteristics contribute to racial/ ethnic disparities in prostate cancer outcomes.

Our study provides novel evidence regarding potential differences in PSA levels among older AA men according to behavioral characteristics.”

https://pubmed.ncbi.nlm.nih.gov/33088675/

“Tobacco use was associated with an increase in PSA among older AA men.”

“Marijuana use was associated with a decrease in PSA among older AA men.”

https://www.sciencedirect.com/science/article/pii/S2211335520301339


Cannabis sativa extracts inhibit LDL oxidation and the formation of foam cells in vitro, acting as potential multi-step inhibitors of atherosclerosis development

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“Atherosclerotic disease is the leading cause of death world-wide. Our goal was to explore the effect of phytocannabinoids on the molecular mechanisms triggering the development of the atheromatous lesion.

Three cannabis sativa extracts of different chemotypes were chemically characterized by UPLC-DAD. The capacity of the extracts to prevent the oxidation of LDL, the formation of foam cells and the activation of an inflammatory response by J774 cells, were monitored by UV-Vis spectrometry, confocal-microscopy and western blot. Three varieties of cannabis sativa, with high (E1), intermediate (E2) and low (E3) THC/CBD ratios were selected.

The three cannabis extracts inhibited the oxidation of LDL by copper ions and the formation of foam cells by J774.1 cells challenged with oxLDL (ED50 5-12 μg mL-1). The effect of the cannabinoid extracts on the endocytic process was independent of the canonical cannabinoid receptors, CB1 and CB2, but related to the action of non-canonical receptors (TRPV1, TRPV4 and GPR55), involved in calcium signaling. Decreased levels of CD36 and OLR1 scavenger receptors were, at least partially, responsible for the diminished uptake of oxLDL induced by phytocannabinoids. The downregulation of CD36 and OLR1 could be explained by the observed inhibitory effect of the cannabis extracts on the activation of the NFκB pathway by oxLDL.

Phytocannabinoids interfere with the main events leading to the development of the atheromatous plaque, opening new venues on atherosclerosis therapy.”

https://pubmed.ncbi.nlm.nih.gov/39705234/

“Our results highlight the capacity of phytocannabinoids to ameliorate the processes leading to the development and progression of atherosclerotic lesions through inhibiting LDL oxidation, decreasing the formation of foam cells after oxLDL challenge and reducing scavenger receptor synthesis by interfering with NFκB activation, supporting the therapeutic potential of medicinal cannabis in atherosclerosis and the need to unravel the molecular mechanisms of phytocannabinoids on the cardiovascular system.”

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0310777

Cannabidiol Suppresses Metastatic Castration-Resistant Prostate Cancer Progression and Recurrence through Modulating Tryptophan Catabolism

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“Metastatic castration-resistant prostate cancer (mCRPC) is an aggressive phenotype of prostate cancer (PC). Tryptophan oxidative catabolism by indoleamine 2,3-dioxygenase-1 (IDO1) cleaves the indole ring to kynurenine (Kyn), an endogenous ligand for the aryl hydrocarbon receptor (AhR), which activates multiple tumorigenesis pathways. The IDO1-Kyn-AhR axis is aberrantly dysregulated in mCRPC. (-)-

Cannabidiol (CBD) is a nonpsychoactive phytocannabinoid. CBD showed antitumor activities against human malignancies, including PC.

CBD showed potent in vitro dose-dependent reduction of viability and clonogenicity of diverse human PC cell lines. CBD reduced the expression of IDO1 and AhR in PC cells. A daily 15 mg/kg oral dose of CBD for 30 days effectively suppressed the progression of the mCRPC CWR-R1ca-Luc cells xenografted in male nude mice. Continued CBD oral dosing for an additional 45 days suppressed the CWR-R1ca-Luc tumor locoregional and distant recurrences after the primary tumors’ surgical excision.

Collected CBD-treated tumors showed a reduced level of IDO1 expression. CBD-treated mice displayed a significant systemic reduction of Kyn.

CBD is a novel, nonpsychoactive phytocannabinoid lead useful for the control of mCRPC via targeting the tryptophan catabolism.”

https://pubmed.ncbi.nlm.nih.gov/39698265/

https://pubs.acs.org/doi/10.1021/acsptsci.4c00448

Cannabidiol promotes apoptosis and downregulation of oncogenic factors

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“Patients with high-grade serous carcinoma of tubo-ovarian origin (HGSC) often experience significant side effects related to their disease and treatments, such as pain, discomfort, nausea, and vomiting.

Over the last two decades, the use of cannabinoids (CBD) to manage pain and anxiety has become more mainstream. However, there is limited data on how CBD interacts with HGSC tumor cells or whether CBD impacts the effect of chemotherapy.

Prior preclinical data has suggested the antitumor benefits of cannabinoids; however, the mechanism and data in ovarian cancer are limited.

The objectives of this proposed research are to define the endocannabinoid system milieu in ovarian cancer, determine if CBD influences the growth of ovarian cancer cells, measure the cell viability when cannabinoids such as CBD are combined with standard-of-care therapies, and identify potential molecular pathways in which cannabinoids have a therapeutic effect.

We conducted publicly available database searches, in vitro proliferation and apoptotic assays, functional protein signaling via reverse phase protein array analysis of CBD-treated cells using 2D cultured cells, and immunohistological analysis of ex vivo cultured patient-derived tumor slices treated with CBD.

Our data suggests that CBD is unlikely to affect the growth of cancer cells at physiologic doses but promotes apoptosis and can have growth inhibitory effects at higher concentrations.

The inhibitory effects seen at high dose concentrations are likely from the upregulation of apoptotic pathways and inhibition of oncogenic pathways. Overall, physiologic CBD levels have minimal impact on cancer cell growth or chemotherapy efficacy.”

https://pubmed.ncbi.nlm.nih.gov/39677720/

https://www.biorxiv.org/content/10.1101/2024.11.30.626177v1