Author Archives: David Worrell

Potential Anticancer Effect of Cannabis sativa L. Dichloromethane Extract Through Oxidative Stress-Related Pathways and the Inhibition of the Migration and Invasiveness of Human Breast Cancer Cells (MDA-MB-231 and MCF-7)

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“Breast cancer remains a leading cause of cancer-related morbidity and mortality globally, highlighting the urgent need for novel therapeutic strategies.

This study investigates the molecular mechanisms underlying the anti-proliferative potential of Cannabis sativa dichloromethane extract (C. sativa DCM) on oxidative stress, apoptosis, and invasion in human breast cancer cells.

Key biomarkers, such as antioxidant enzymes (Superoxide Dismutase (SOD) and Glutathione (GSH)), the transcription factor Nrf2, apoptotic proteins (p53, caspase-8 and 9), metalloproteinase (MMP-1 and MMP-9), and Transforming Growth Factor Beta (TGF-β) were examined. Cytotoxicity was assessed using an MTT assay in the MDA-MB-231 and MCF-7 breast cancer cell lines, with comparisons to normal skin fibroblasts (HS27). Oxidative stress biomarkers were quantified using enzymatic assays and ELISA kits, while apoptotic and anti-metastatic factors were determined by Western blotting.

Results demonstrated that C. sativa DCM extract induced significant cell death in a concentration-dependent manner, with IC50 values of 75.46 ± 0.132 μg/mL for MDA-MB-231 and 78.68 ± 0.50 μg/mL for MCF-7 cells. The extract decreased SOD and GSH levels while increasing p53 and caspase activity, confirming apoptosis activation. Additionally, C. sativa DCM inhibited migration and invasion by downregulating MMP-1, MMP-9, and TGF-β. The anti-proliferative potential of C. sativa DCM in breast cancer cells is mediated through a continuous biological pathway involving oxidative stress modulation, apoptotic signaling, and anti-invasive effects. Phytochemical analysis revealed terpenoids and steroids, including compounds like cannabidiol and tetrahydrocannabinol acid.

These findings suggest that C. sativa DCM extract holds potential as an anti-breast cancer therapeutic and warrants further preclinical and clinical investigations.”

https://pubmed.ncbi.nlm.nih.gov/41516029

“Cannabis sativa L., known in many slang languages as marijuana, bhang, ganja, for instance, is an herbaceous species originating from Central Asia and widely distributed around the world. It has been used as a source of fiber, food, oil, and for its multiple curative properties, including anti-parasitic, antipyretic, antibacterial, antitumor, vermifuge, dermatic, and pain-killing properties for centuries. Phytocannabinoids, derived from cannabis, have shown anti-cancer activity in cell lines”

“Based on these research findings, we concluded that C. sativa DCM extract possesses the potential to inhibit the proliferation of breast cancer cells (MCF-7 and MDA-MB-231), while exhibiting minimal cytotoxic effect on normal skin cells Hs27.”

“Given these conclusive findings, the presence of bioactive phytochemicals in C. sativa DCM can be considered as a potential source of anti-cancer agents.”

https://www.mdpi.com/1422-0067/27/1/152


Cannabinoid Signaling and Autophagy in Oral Disease: Molecular Mechanisms and Therapeutic Implications

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“Autophagy is a well-preserved biological mechanism that is essential for sustaining homeostasis by degradation and recycling damaged organelles, misfolded proteins, and other cytoplasmic detritus.

Cannabinoid signaling has emerged as a prospective regulator of diverse cellular functions, including immunological modulation, oxidative stress response, apoptosis, and autophagy. Dysregulation of autophagy contributes to pathogenesis and treatment resistance of several oral diseases, including oral squamous cell carcinoma (OSCC), periodontitis, and gingival inflammation.

This review delineates the molecular crosstalk between cannabinoid receptor type I (CB1) and type II (CB2) activation and autophagic pathways across oral tissues. Cannabinoids, including cannabidiol (CBD) and tetrahydrocannabinol (THC), modulate key regulators like mTOR, AMPK, and Beclin-1, thereby influencing autophagic flux, inflammation, and apoptosis.

Experimental studies indicate that cannabinoids inhibit the PI3K/AKT/mTOR pathway, promote reactive oxygen species (ROS)-induced autophagy, and modulate cytokine secretion, mechanisms that underline their dual anti-inflammatory and anti-cancer capabilities. In addition, cannabinoid-induced autophagy has been shown to enhance stem cell survival and differentiation, offering promise for dental pulp regeneration. Despite these promising prospects, several challenges remain, including receptor selectivity, dose-dependent variability, limited oral bioavailability, and ongoing regulatory constraints.

A deeper understanding of the context-dependent regulation of autophagy by cannabinoid signaling could pave the way for innovative therapeutic interventions in dentistry. Tailored cannabinoid-based formulations, engineered for receptor specificity, tissue selectivity, and optimized delivery, hold significant potential to revolutionize oral healthcare by modulating autophagy-related molecular pathways involved in disease resolution and tissue regeneration.”

https://pubmed.ncbi.nlm.nih.gov/41516397

“Cannabinoids are a diverse class of bioactive lipophilic compounds derived from Cannabis sativa and other plant species, as well as synthesized endogenously and pharmacologically, and have attracted significant attention for their immunomodulatory, anti-inflammatory, antioxidant, and anticancer effects.”

“Cannabinoid-based treatments show promise for managing oral diseases by controlling inflammation and promoting tissue regeneration through specific pathways.”

https://www.mdpi.com/1422-0067/27/1/525

Cannabidiol (CBD) and Other Cannabinoids as a Promising Alternative Antibacterial Agent-Pilot Study on Enterococcus faecalis and Enterococcus faecium Clinical Strains

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“Gram-positive cocci of the Enterococcus genus, despite their prevalence in the environment and the microbiota of healthy people, have become a serious threat in hospitals as opportunistic pathogens. These bacteria have many virulence factors and intrinsic resistance to existing drugs, which significantly narrows the group of effective antimicrobials. Due to the spread of Multi-Drug-Resistant (MDR) strains, there is a need to search for new substances as potential antibiotics.

Our work aimed to evaluate the antimicrobial effect of commercially available products (five oils containing cannabidiol (CBD) and its derivatives and one 99% CBD product in the form of crystals) on 20 clinical strains of E. faecalis and E. faecium. We determined the Minimal Inhibitory Concentration (MIC) of CBD oils using the microdilution method in Mueller-Hinton broth (MHB).

The CBD displayed antibacterial properties against all tested Enterococcus spp. strains (MIC ≤ 1 μg/mL). The higher concentration of CBD resulted in a larger antibacterial effect. The obtained MICs of pure CBD and CBD crystals were statistically lower (W = 97, p < 0.001) for E. feacium than E. faecalis.

This work confirms the antibacterial activity of CBD on Enterococcus spp., providing a solid basis for further research that can help identify new therapeutic options and gain a deeper understanding of the CBD mechanism of action.”

https://pubmed.ncbi.nlm.nih.gov/41515438

“These preliminary investigations provide meaningful insights into the activity of CBD against Enterococcus spp. and highlight their potential as a novel antibacterial agent.”

https://www.mdpi.com/1420-3049/31/1/144


Cannabidiol Protects the Neonatal Mouse Heart from Hyperoxia-Induced Injury

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“Neonatal hyperoxia induces oxidative and inflammatory stress that disrupts cardiac maturation and contributes to long-term cardiovascular morbidity in individuals born preterm. Cannabidiol (CBD), a non-psychoactive phytocannabinoid with antioxidant and anti-inflammatory properties, has demonstrated protective effects in neonatal hyperoxic injury in other organs; however, its impact on the developing heart remains unclear.

This study investigated whether CBD mitigates hyperoxia-induced cardiac injury in a neonatal mouse model. Newborn mice were exposed to 80% O2 for 48 h from postnatal day (P)5 to P7 and received vehicle, 10 mg/kg CBD, or 30 mg/kg CBD intraperitoneally, while controls remained in room air. Hearts were collected at P7 or after recovery until P14. Hyperoxia triggered oxidative stress (Nrf2), inflammation (IL1β, TNFα, IL6, CXCL1; p < 0.05), and dysregulated apoptosis/autophagy, leading to reduced cardiomyocyte proliferation (Ki67+ -50% at P14; p < 0.01) and adverse remodeling (hypertrophy, fibrosis; p < 0.01).

CBD attenuated these responses and normalized autophagy (Atg5, Atg12; p < 0.05). Notably, 10 mg/kg CBD, but not 30 mg/kg, preserved proliferative capacity and reduced wall thickness, suggesting a narrow therapeutic window, while both doses limited collagen deposition and apoptosis (Casp3, AIF; p < 0.05). Several effects were sex-dependent, with males exhibiting more pronounced long-term structural and proliferative impairments and greater responsiveness to low-dose CBD.

These findings identify CBD as a potential cardioprotective modulator of neonatal hyperoxia-induced injury and highlight the importance of dose- and sex-specific mechanisms in early cardiac maturation.”

https://pubmed.ncbi.nlm.nih.gov/41516025

“In summary, this study demonstrates that neonatal hyperoxia induces persistent oxidative, inflammatory, and structural cardiac damage and that CBD administration attenuates these effects in a dose-dependent manner, preserves cardiomyocyte proliferation, and reduces maladaptive remodeling at optimal dosages. These findings underscore the potential of CBD as a cardioprotective intervention in the neonatal period, provided that dosage, timing, and developmental safety are carefully considered. Translation into clinical practice will require rigorous functional, mechanistic, and safety studies. Nonetheless, the present data support further investigation of CBD in the context of neonatal oxygen therapy and cardiac protection.”

https://www.mdpi.com/1422-0067/27/1/146

Medicinal cannabis plant extract (NTI164) modifies epigenetic, ribosomal, and immune pathways in paediatric acute-onset neuropsychiatric syndrome

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“Paediatric acute-onset neuropsychiatric syndrome (PANS) is a syndrome of infection-provoked abrupt-onset obsessive-compulsive disorder (OCD) or eating restriction.

Based on the hypothesis that PANS is an epigenetic disorder of immune and brain function, a full-spectrum medicinal cannabinoid-rich low-THC cannabis (NTI164) was selected for its known epigenetic and immunomodulatory properties.

This open-label trial of 14 children with chronic-relapsing PANS (mean age 12·1 years; range 4-17; 71 % male) investigated the safety and efficacy of 20 mg/kg/day NTI164 over 12 weeks. Clinical outcomes were assessed using gold standard tools. To define the biological effects of NTI164, blood samples were collected pre- and post-treatment for bulk and single-cell transcriptomics, proteomics, phosphoproteomics, and DNA methylation.

NTI164 was well-tolerated, and 12 weeks of treatment decreased the mean Clinical Global Impression-Severity (CGI-S) score from 4·8 to 3·3 (p = 0·002). Significant improvements were observed in emotional regulation (RCADS-P, p < 0·0001), obsessive-compulsive disorder (CYBOCS-II, p = 0·0001), tics (YGTSS, p < 0·0001), attention-deficit hyperactivity disorder (Conner’s, p = 0·028), and overall quality of life (EQ-5D-Y, p = 0·011).

At baseline, the multi-omic approach revealed that leucocytes from patients with PANS had dysregulated epigenetic (chromatin structure, DNA methylation, histone modifications, transcription factors), ribosomal, mRNA processing, immune, and signalling pathways. These pathways were significantly modulated by NTI164 treatment.

NTI164 shows promise as a disease-modifying therapeutic for PANS.

Multi-omics reveal broad epigenetic and immune dysregulation in patients, which was modified by NTI164, presenting epigenetic machinery as a therapeutic target in PANS.”

https://pubmed.ncbi.nlm.nih.gov/41513541

“Cannabis sativa L. has long been used in medicine, and increasingly proposed as a treatment of psychiatric disorders and neurodevelopmental disorders (NDDs).”

https://www.neurotherapeuticsjournal.org/article/S1878-7479(25)00306-X/fulltext

Cannabidiol improves cognitive impairment after traumatic brain injury by attenuating neuronal oxidative stress and apoptosis via the SET/PP2A/Akt signaling axis

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“Background: Cognitive impairment is a major complication of traumatic brain injury (TBI), yet effective therapies remain lacking. As a natural compound extracted from Cannabis sativa, cannabidiol (CBD) possesses antioxidant properties and has shown neuroprotective potential in several neurological disorders. However, its effects in cognitive impairment after TBI remain unclear.

Purpose: This study aimed to investigate the therapeutic effects of CBD on cognitive impairment after TBI and elucidate its underlying molecular mechanisms.

Study design: In vitro H2O2 model and in vivo TBI model were used to evaluate the neuroprotective effects of CBD.

Methods: Neuronal oxidative stress models induced by H2O2 and controlled cortical impact model were used to detect the neuroprotective effects of CBD. Western blotting, histological staining, and biochemical assays were employed to investigate the effects of CBD on oxidative stress and apoptosis in neurons. RNA-Seq analysis, co-immunoprecipitation, molecular dynamics simulations, CETSA, SPR and immunofluorescence were performed to elucidate the molecular mechanisms.

Results: CBD can inhibit neuronal oxidative stress and apoptosis both in vivo and in vitro. Mechanistically, we identify a novel SET/PP2A/Akt signaling axis, in which CBD directly bound to SET, induced conformational changes in its nuclear localization signal and promoted its retention in the cytoplasm. Elevated cytoplasmic SET suppresses PP2A activity, activates Akt signaling pathway, and inhibits oxidative stress and pro-apoptotic cascades, promoting neuronal survival.

Conclusion: CBD exerts its neuroprotective effects by inhibiting neuronal oxidative stress and apoptosis through SET/PP2A/Akt signaling axis. These findings provide a novel potential drug target for the treatment of cognitive impairment after TBI.”

https://pubmed.ncbi.nlm.nih.gov/41512358

“Cannabidiol alleviates cognitive impairment after traumatic brain injury in mice.”

“This work not only enhances understanding of post-TBI pathophysiology but also provides mechanistic insights supporting the potential clinical application of CBD in post-TBI cognitive impairment.”

https://www.sciencedirect.com/science/article/abs/pii/S0944711326000061?via%3Dihub

Evaluation of the antimicrobial effect of cannabidiol (CBD) in a multispecies subgingival biofilm model

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“Background: This study evaluated the antimicrobial effect of cannabidiol (CBD) on a multi-species subgingival biofilm model.

Materials and methods: Biofilms were formed using 33 bacterial species on a Calgary device. Two protocols were tested: (A) biofilm in contact with CBD (125, 250 and 500 µg/mL) and chlorhexidine 0.12% (CHX) for the entire period; (B) treatments with CBD (500 and 1000 µg/mL) and CHX started on day 3, twice a day, for 1 minute. The total biofilm counts, the proportion of complexes, and the counts of each species were evaluated by DNA-DNA hybridization (Checkerboard).

Results: In Experiment A, CBD at concentrations of 250 and 500 µg/mL, as well as CHX, significantly reduced the total biofilm count. At 500 µg/mL, CBD also decreased the proportion of the red complex and reduced the counts of 10 bacterial species, whereas CHX affected 20 species. In Protocol B, both CBD at 1000 µg/mL and CHX reduced the total biofilm count and the proportion of the red complex, while increasing the proportion of the green complex. Both protocols led to a reduction in Porphyromonas gingivalis and Tannerella forsythia.

Conclusion: CBD reduced the total bacterial count and the red complex, inhibiting known periodontal pathogens. Within the limitations, the results provide exploratory evidence that CBD may reduce the total bacterial count in the proposed polymicrobial biofilm model, including the red complex bacteria, and may thus be postulated as an inhibitor of known periodontal pathogens. However, future in vivo studies with robust sample sizes and standardized CFU-based quantification are required to confirm these findings.”

https://pubmed.ncbi.nlm.nih.gov/41509036

“These exploratory observations demonstrated a notable antimicrobial activity of CBD by reducing red complex bacteria and key periodontopathogens, including Porphyromonas gingivalis and Tannerella forsythia, in a multispecies subgingival biofilm model, comparable to CHX.”

https://www.tandfonline.com/doi/full/10.1080/20002297.2025.2603706

Intravesical Cannabidiol for Inflammation and Pain in Interstitial Cystitis/Bladder Pain Syndrome via TLR4/NF-κB and TRPV1 Modulation

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“Purpose: This study explored the anti-inflammatory and analgesic mechanisms of intravesical cannabidiol (CBD) in cyclophosphamide (CYP)-induced interstitial cystitis/bladder pain syndrome (IC/BPS) rats.

Materials and methods: Female Sprague-Dawley rats were divided into four groups of control, IC/BPS, IC/BPS+10 mg/kg CBD, and IC/BPS+100 mg/kg CBD (n=5/group). IC/BPS was induced by CYP injections, followed by intravesical CBD administration. Pain sensitivity and bladder function were assessed via Von Frey tests and cystometrograms. Histological, Western blot, and immunofluorescence analyses were performed on bladder tissues. SV-HUC1 cells were analyzed using western blot and scratch assays.

Results: CBD improved bladder function, reducing instability, prolonging intercontractile intervals, and enhancing detrusor contraction pressure. The CBD 100 mg/kg group showed greater pain relief in Von Frey tests compared with other groups. Histology revealed reduced inflammation, mast cell infiltration, and fibrosis in bladder tissues. CBD decreased TNF-α, COX2, IL-6, and TRPV1 levels and inhibited the TLR4/MyD88/pNF-κB pathway. In SV-HUC1 cells, CBD suppressed epithelial injury and downregulated TRPV1, TLR4, MyD88, p-NF-κB, and Bax/Bcl-xL, demonstrating anti-inflammatory and anti-apoptotic effects.

Conclusions: Intravesical CBD alleviates inflammation by inhibiting the TLR4/MyD88/pNF-κB pathway, reduces neuropathic pain via TRPV1 channels, and improves cell apoptosis and migration in CYP-induced IC/BPS model animals.”

https://pubmed.ncbi.nlm.nih.gov/41508393

“Cannabidiol (CBD) is a non-psychoactive cannabinoid with a variety of biological activities and a wide range of benefits such as antioxidant, anti-inflammatory, and immunomodulatory effects. Research has demonstrated the therapeutic significance of CBD in neurological disorders, cardiomyopathy, diabetes, and other diseases.”

“In the present study, we investigated the potential therapeutic effects of CBD in IC/BPS. We conducted intravesical instillation of CBD in a rat model of IC/BPS and evaluated the effects on inflammation and bladder function and pain. We further analyzed its mechanism of action. Our study provides evidence of the potential effectiveness of CBD in the treatment of IC/BPS.”

https://wjmh.org/DOIx.php?id=10.5534/wjmh.250152

CBD-Rich Cannabis Therapy in Children with Autism Spectrum Disorder May Improve Symptoms of Hyperactivity and Attention Deficit: An Open-Label Study

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“Introduction: Medical cannabis has gained growing attention as a potential treatment for children with Autism Spectrum Disorder (ASD), particularly in cases where conventional pharmacological approaches have proven ineffective. Emerging evidence suggests that cannabinoid-based therapies may alleviate Attention Deficit Hyperactivity Disorder (ADHD) related symptoms in children with ASD. The objective of this study is to evaluate changes in ADHD symptoms over six months of treatment with a CBD-rich cannabis oil, using the Conners’ Teacher Rating Scale as the assessment tool.

Methods: This was a prospective, single-arm, open-label study conducted at a single center. A total of 109 children and young adults diagnosed with ASD and ADHD symptoms were recruited between November 2019 and April 2021. Of these, 53 participants were assessed by their schoolteachers using the Conners’ Teacher Rating Scale (CTRS) questionnaire, both before and after a three- to sixmonth treatment period with a CBD-rich, cannabis oil-based product. Blood samples were collected before and after treatment to measure cannabinoid levels, including CBD, 6-OH-CBD, 7-COOHCBD, and 7-OH-CBD.

Results: Significant improvements were observed in the following categories: anxious-shyness, perfectionism, ADHD index, emotional lability, and hyperactivity-impulsivity (p < 0.001). Additional trends toward improvement were identified in oppositional behavior (p = 0.009), cognitive inattention (p = 0.009), hyperactivity (p = 0.006), the Conners’ Global Index (p = 0.007), and DSM-IV inattention scores (p = 0.003). No significant correlations were found between cannabinoid dosage or blood levels and changes in CTRS scores, except for emotional lability, where higher CBD concentrations were predictive of greater symptom improvement.

Discussion: This is the first prospective study to evaluate the effects of CBD-rich cannabis on ADHD symptoms in children with ASD using standardized teacher-based Assessments (CTRS). The findings indicate improvements in core behavioral domains. While previous studies have focused primarily on parent-reported outcomes or small-scale trials, our results support emerging evidence on the role of cannabinoids in modulating attention and emotional regulation. The main limitations of the study were its open-label design.

Conclusion: CBD-rich cannabis oil may reduce ADHD symptoms in children with ASD. These findings support the need for future clinical trials to validate efficacy and determine optimal dosing.”

https://pubmed.ncbi.nlm.nih.gov/41503912

https://www.eurekaselect.com/article/152283

UK medical Cannabis registry: A two-year case series of clinical outcomes in depression

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“Background: Whilst preclinical evidence details the effects of cannabinoids on mood regulation, there is a paucity of clinical evidence on the use of cannabis-based medicinal products (CBMPs) in individuals with depression. This study aims to evaluate longitudinal changes in patient-reported outcome measures (PROMs) and the incidence of adverse events over 24 months in patients treated with CBMPs for depression.

Methods: Patient data from the UK Medical Cannabis Registry were used for analysis. PROMs, including the Patient Health Questionnaire-9 (PHQ-9), Generalised Anxiety Disorder-7 (GAD-7), Single-Item Sleep Quality Scale (SQS), EuroQol 5-Dimension 5-Level (EQ-5D-5L), and Patient Global Impression of Change (PGIC), were measured at baseline, 1, 3, 6, 12, 18, and 24 months. Adverse events (AEs) were also recorded. P < 0.050 was considered statistically significant.

Results: Of the 34,563 patients in the UK Medical Cannabis Registry on January 6th 2025, 698 (2.02 %) patients were included in the analysis. Improvements were observed across the PHQ-9. GAD-7, SQS, and EQ-5D-5L index value at all time points compared to baseline (p < 0.001). At baseline, half of the patients reported severe anxiety (GAD-7 ≥ 15: 50.86 %, n = 355), which was correlated with depression severity (PHQ-9; r = 0.67, p < 0.001). Sixty-three patients (9.03 %) reported at least one AE during treatment, of which 85 % (n = 411) were mild or moderate.

Discussion: Initiation of CBMPs was associated with statistically and clinically significant improvements in depression, anxiety, sleep quality, and health-related quality of life among patients. Improvements were most prominent in the first 3 months. Limitations of the study mean that no causal relationship can be ascertained.

Conclusion: The positive findings from this and other observational data support future evaluation of CBMPs for the treatment of depression to establish their efficacy.”

https://pubmed.ncbi.nlm.nih.gov/41506388

“This UK Medical Cannabis Registry study of patients with treatment-resistant depression prescribed CBMPs demonstrated sustained and clinically meaningful improvements in depression, anxiety, health-related quality of life, and sleep quality over 24 months. Improvements were most pronounced within the first three months and were sustained thereafter. Adverse events were infrequent and predominantly mild to moderate.”

https://www.sciencedirect.com/science/article/pii/S0165032725025728?via%3Dihub