Cannabidiol Is a Potential Inhibitor of Ferroptosis in Human Articular Chondrocytes

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“The present study investigates the effects of cannabidiol (CBD), the major non-psychoactive compound of Cannabis sativa L. extracts, on ferroptotic cell death in human articular chondrocytes.

Exposure to known ferroptosis inducers RSL3, erastin and its analogue IKE, FINO2 and FIN56 led to a varying extent of reduced cell viability in two chondrocyte cell lines (in C-28/I2, T/C-28/A2) and primary chondrocytes, suggesting different sensitivity and defence mechanisms towards the respective substances. The cytotoxic effects were aggravated by additional exposure to iron and inhibited by the specific ferroptosis inhibitor ferrostatin-1 (Fer-1), proving the occurrence of ferroptosis.

Strikingly, co-treatment of ferroptosis inducers with CBD clearly restored cell viability in a dose-dependent manner (10 nM to 1 μM CBD) in both cell lines and primary chondrocytes. Moreover, CBD restored the activity of GPX4, a major anti-oxidative enzyme, to varying degrees when combined with IKE or RSL3. Increasing evidence has emerged for an important role of iron dyshomeostasis and ferroptosis in the onset and progression of various orthopaedic diseases, including osteoarthritis.

Therefore, the here demonstrated and previously unreported cytoprotective and anti-oxidative effects of CBD in the context of ferroptosis have highly promising therapeutic implications.”

https://pubmed.ncbi.nlm.nih.gov/40576283/

https://onlinelibrary.wiley.com/doi/10.1111/jcmm.70592

Recent Preclinical Evidence on Phytocannabinoids in Neurodegenerative Disorders: A Focus on Parkinson’s and Alzheimer’s Disease

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“The endocannabinoid system (ECS) is a vital biological network essential for maintaining homeostasis and supporting various physiological functions. It comprises cannabinoid receptors, endogenous lipid-based ligands, known as endocannabinoids, as well as metabolic enzymes and associated proteins responsible for regulating their levels within tissues. The ECS plays a central role in modulating processes involving the central nervous system (CNS). Recent studies have highlighted its antioxidant, anti-inflammatory, and neuroprotective properties.

The therapeutic potential of cannabinoids, particularly phytocannabinoids derived from plants, has attracted significant attention in medical and pharmaceutical research. This interest has grown in parallel with the increasing availability of cannabinoid-based food supplements on the pharmaceutical market. Given the complexity of the ECS and its broad range of interactions, the discovery of this system has spurred extensive investigations into the use of cannabinoids for various health conditions.

In this review, we examine recent preclinical evidence supporting the use of phytocannabinoids in the context of neurodegenerative diseases, particularly in Alzheimer’s disease and Parkinson’s disease. Targeting the ECS through phytocannabinoid-based pharmacological modulation offers a promising therapeutic strategy for these neurological disorders. Among these compounds, cannabidiol has emerged as a key focus of research due to its multifaceted effects and favorable safety profile. Nonetheless, continued investigation is necessary to clarify its mechanisms of action, and to develop effective, evidence-based clinical applications.”

https://pubmed.ncbi.nlm.nih.gov/40573285/

“Recent advances in cannabinoid research have shed light on the considerable therapeutic potential of phytocannabinoids, particularly CBD, in the treatment of neurodegenerative diseases.

The preclinical studies presented in this review demonstrate consistent neuroprotective, anti-inflammatory, antioxidant, and neuromodulator effects in models of AD, PD, or HD.

These effects are largely mediated through the complex interplay of phytocannabinoids with the ECS, as well as their interactions with non-cannabinoid targets, such as TRPV1, 5-HT1A receptors, and PPARs.The ECS emerges as a crucial modulator of CNS homeostasis, and its dysregulation appears to be closely linked with the pathophysiology of major neurodegenerative diseases.

Phytocannabinoid-mediated modulation of ECS activity has shown promising outcomes in various animal models, including reductions in neuroinflammation, attenuation of excitotoxicity, and preservation of cognitive and motor function.The evidence suggests that phytocannabinoids may contribute to neuronal preservation, attenuation of neuroinflammatory cascades, and improvement in motor and cognitive performance in disease models. Moreover, their favorable safety profile and ability to act on multiple molecular pathways position them as promising candidates for disease-modifying interventions.

As interest in cannabinoid pharmacotherapy continues to grow, phytocannabinoids represent a promising, multifaceted class of compounds with the potential to address unmet therapeutic needs in the field of neurodegeneration.”

https://www.mdpi.com/1424-8247/18/6/890

Nanoemulsions of Cannabidiol, Δ9-Tetrahydrocannabinol, and Their Combination Similarly Exerted Anticonvulsant and Antioxidant Effects in Mice Treated with Pentyelenetetrazole

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“Background/Objectives: The main biologically active molecules of Cannabis sativa L. are cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC). Both exert anticonvulsant effects when evaluated as single drugs, but their possible interaction as components of C. sativa extracts has been scarcely studied. For this reason, we evaluated CBD and THC, combined or not, in two seizure models in mice, using an improved vehicle formula. 

Methods: Firstly, acute seizures were induced by intraperitoneal (i.p.) pentylenetetrazole (PTZ, 80 mg/kg), and mice received CBD or THC at 1, 3, 6, and 10 mg/kg, or a CBD/THC 1:1 combination at 1.5, 3, and 6 mg/kg, per os (p.o.), one hour before PTZ administration. Secondly, mice received p.o. CBD (10 mg/kg), CBD/THC (1.5, 3, and 6 mg/kg), valproic acid (50 mg/kg), or vehicle (nanoemulsions without CBD or THC), one hour before PTZ (30 mg/kg, i.p.) every other day for 21 days. Behavioral, biochemical, and immunohistochemical analyses were performed to assess the response to PTZ, oxidative stress, and astroglial activation. 

Results: In the acute model, CBD and THC at 3-10 mg/kg, and their combinations, significantly increased latency to generalized seizures and death, and improved survival rates. In the chronic model, similarly to valproic acid, CBD 10 mg/kg and CBD/THC at 1.5 and 3 mg/kg delayed kindling acquisition, while CBD/THC 6 mg/kg had no effect. CBD and CBD/THC treatments reduced oxidative and nitrosative stress and attenuated astrogliosis, as indicated by decreased glial fibrillary acidic protein and GABA transporter 1 expression and increased inwardly rectifying potassium channel 4.1 expression in hippocampal regions. However, no cannabinoid treatment prevented the impairment in novel object recognition and Y maze tests. 

Conclusions: These findings support the potential role of cannabinoids in counteracting seizures, possibly by reducing oxidative stress and astrogliosis. The study also highlights the importance of nanoemulsions as a delivery vehicle to enhance cannabinoid effectiveness while considering the risks associated with direct cannabinoid receptor activation.”

https://pubmed.ncbi.nlm.nih.gov/40573179/

“This study underscores the potential of CBD and THC nanoemulsions in seizure models, highlighting their capacity to reduce convulsions and brain damage. These formulations significantly decreased markers of oxidative and nitrosative stress, enhancing our grasp of their antiseizure mechanisms.”

https://www.mdpi.com/1424-8247/18/6/782

Full-Spectrum Medicinal Cannabis Plant Extract 0.08% THC (NTI164) Improves Symptoms of Rett Syndrome: An Open-Label Study

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“Aim: The aim of this Phase I/II open-label study was to assess the safety and efficacy of NTI164, a novel full-spectrum medicinal cannabis plant extract 0.08% Δ-9-tetrahydrocannabinol (THC), in Rett syndrome (RTT).

Methods: Eleven female participants (5-16 years) with a pathogenic variant in the MECP2 gene were recruited to this study, receiving NTI164 twice daily for 12 weeks. The primary outcome measure was the Clinical Global Impression-Improvement (CGI-I) Scale, with secondary outcomes measured using the CGI-Severity (CGI-S), RTT Behaviour Questionnaire (RSBQ), RTT-Symptom Index Score (RTT-SIS), RTT-Domain-Specific Concerns-Visual-Analog Scale (RTT-DSC-VAS), Impact of Childhood Neurological Disability/Quality of Life (ICND+QoL), and RTT-Caregiver Burden Inventory (RTT-CBI). Paired-samples t-test was used to assess significance between baseline and Week 12.

Results: Improvements were seen in the total CGI-I score (p = 0.028), with improvements in communication skills (p = 0.003), mental alertness (p = 0.033), socialisation/eye contact (p = 0.0004), attentiveness (p = 0.001), and anxiety (p = 0.004). CGI-S also demonstrated better outcomes after NTI164 administration (p = 0.008). RSBQ showed improvements in total score (p = 0.0005), general mood (p = 0.0003), breathing problems (p = 0.041), repetitive face movements (p = 0.004), and fear/anxiety (p = 0.006). RTT-DSC-VAS showed positive developments in abilities to communicate choices (p = 0.041). ICND total score was improved (p = 0.003), as well as cognition (p = 0.027) and Quality of Life (p = 0.0002). Total score on the RTT-CBI was improved (p = 0.006).

Conclusion: NTI164 demonstrated safety and improved some clinical and functional outcomes in RTT. These improvements justify ongoing research into NTI164, which may be a potential adjunct therapy in RTT.”

https://pubmed.ncbi.nlm.nih.gov/40568811/

“This paper demonstrates efficacy of this novel medical cannabis compound in reducing complex symptoms of Rett syndrome and improving quality of life in these patients.”

https://onlinelibrary.wiley.com/doi/10.1111/jpc.70122

Cannabidiol Prevents Heart Failure Dysfunction and Remodeling Through Preservation of Mitochondrial Function and Calcium Handling

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“Heart failure (HF) is characterized by energy deprivation, calcium (Ca2+) handling alterations, and inflammation: effects associated with mitochondrial dysfunction.

Cannabidiol previously prevented mitochondrial dysfunction. Thus, it may prevent HF progression.

In mice with HF, subcutaneous cannabidiol attenuated cardiac fibrosis, hypertrophy, loss of ejection fraction, and inflammation; isolated cardiomyocytes preserved cell shortening, Ca2+ handling, mitochondrial function and redox balance. Hypertrophied ventricular cardiomyoblasts suggested cannabidiol-mediated effects through peroxisome proliferator-activated gamma receptors.

Therefore, cannabidiol in HF limited cardiac hypertrophy and preserved contractile function by sustaining cardiomyocyte and mitochondrial function through redox balance maintenance, supporting cannabidiol role as a cardioprotective therapy in HF.”

https://pubmed.ncbi.nlm.nih.gov/40562493/

“This study demonstrated that cannabidiol offers cardioprotection in a HF mouse model induced by L-NAME and ANGII administration. The results showed improved cardiac function and reduced cardiac hypertrophy, remodeling, inflammation, and cell death. In cardiomyocytes from the HF model, cannabidiol restored cell shortening, which was linked to improved calcium Ca2+ handling.

Additionally, it helped preserve cellular oxidative status, mitochondrial bioenergetics, and notably, modulated mCa2+ overload by affecting MCU expression. This suggests that the cardioprotective effects of cannabidiol are caused by the preservation of excitation-contraction-energetic coupling. The identified cellular mechanisms through which cannabidiol exerts its cardioprotective effects include reducing oxidative stress and the activation of PPAR-γ, which helps prevent mitochondrial dysfunction by decreasing MCU hyperactivity.”

“TRANSLATIONAL OUTLOOK: This study contributes to the knowledge of a novel therapy based on cannabidiol on the pathophysiology of HF, which is supported by preclinical data. Here, we described that cardioprotection exerted by cannabidiol on a HF mouse model was caused by the attenuation of cardiac fibrosis and hypertrophy along with improved ejection fraction and cardiac output. This was achieved, in the cardiomyocyte, by preservation of cell shortening, sarcoplasmic reticulum Ca2+ uptake, mitochondrial function, and redox balance, with data supporting the role of a PPAR-γ–dependent mechanism. This study suggests promising therapeutic results of cannabidiol used in the clinical field of HF treatment. In this regard, these results have inspired a translational effort to assess its effects in HF and cardiac dysfunction.”

https://www.jacc.org/doi/10.1016/j.jacbts.2024.12.009

Evaluating the Antitumor Potential of Cannabichromene, Cannabigerol, and Related Compounds from Cannabis sativa and Piper nigrum Against Malignant Glioma: An In Silico to In Vitro Approach

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“Malignant gliomas, including glioblastoma multiforme (GBM), are highly aggressive brain tumors with a poor prognosis and limited treatment options.

This study investigates the antitumor potential of bioactive compounds derived from Cannabis sativa and Piper nigrum using molecular docking, cell viability assays, and transcriptomic and expression analyses from public databases in humans and cell lines.

Cannabichromene (CBC), cannabigerol (CBG), cannabidiol (CBD), and Piper nigrum derivates exhibited strong binding affinities relative to glioblastoma-associated targets GPR55 and PINK1.

In vitro analyses demonstrated their cytotoxic effects on glioblastoma cell lines (U87MG, T98G, and CCF-STTG1), as well as on neuroblastoma (SH-SY5Y) and oligodendroglial (MO3.13) cell lines, revealing interactions among these compounds. The differential expression of GPR55 and PINK1 in tumor versus normal tissues further supports their potential as biomarkers and therapeutic targets.

These findings provide a basis for the development of novel therapies and suggest unexplored molecular pathways for the treatment of malignant glioma.”

https://pubmed.ncbi.nlm.nih.gov/40565152/

“While docking studies suggest strong interactions between Piper nigrum derivatives, cannabinoids, and targets such as PINK1 and GPR55, in vitro experiments confirmed the cytotoxic potential of these compounds in glioblastoma cell lines, with cannabinoids like CBG and CBD showing significant dose-dependent reductions in cell viability, comparable to established chemotherapeutic agents.”

https://www.mdpi.com/1422-0067/26/12/5688

Cannabinol’s Modulation of Genes Involved in Oxidative Stress Response and Neuronal Plasticity: A Transcriptomic Analysis

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“Cannabis sativa is a remarkable source of bioactive compounds, with over 150 distinct phytocannabinoids identified to date. Among these, cannabinoids are gaining attention as potential therapeutic agents for neurodegenerative diseases.

Previous research showed that cannabinol (CBN), a minor cannabinoid derived from Δ9-tetrahydrocannabinol, exhibits antioxidant, anti-inflammatory, analgesic, and anti-bacterial effects.

The objective of this study was to assess the protective potential of 24 h CBN pre-treatment, applied at different concentrations (5 µM, 10 µM, 20 µM, 50 µM, and 100 µM), in differentiated neuroblastoma × spinal cord (NSC-34) cells. Transcriptomic analysis was performed using next-generation sequencing techniques.

Our results reveal that CBN had no negative impact on cell viability at the tested concentrations. Instead, it showed a significant effect on stress response and neuroplasticity-related processes. Specifically, based on the Reactome database, the biological pathways mainly perturbed by CBN pre-treatment were investigated.

This analysis highlighted a significant enrichment in the Reactome pathway’s cellular response to stress, cellular response to stimuli, and axon guidance.

Overall, our results suggest that CBN holds promise as an adjuvant agent for neurodegenerative diseases by modulating genes involved in neuronal cell survival and axon guidance.”

https://pubmed.ncbi.nlm.nih.gov/40563376/

“Aging and neurodegenerative diseases are characterized by a progressive decline in cellular functions, including genomic instability, epigenetic alterations, mitochondrial dysfunction, and chronic inflammation. Our study supports that CBN exerts pleiotropic effects by modulating key molecular pathways involved in oxidative stress response, DNA repair, and neuronal survival. These results suggest that CBN positively modulates the response to cellular damage, stimulating the antioxidant response through the Nrf2 pathway and reducing the sensitivity to programmed cell death, as demonstrated by the regulation of caspases and other genes related to neuronal survival. These effects indicate that CBN may be able to support neuronal health under conditions of chronic stress, a hallmark of neurodegenerative diseases. These findings pave the way for further research into CBN’s therapeutic potential, emphasizing the need for in vivo studies to validate its efficacy and safety profile in neurodegenerative disease models.”

https://www.mdpi.com/2076-3921/14/6/744

How to ESCAPE from Pain? An Observational Study on Improving Pain and Quality of Life with the Cannamedical® Hybrid Cannabis Extract

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“Introduction: Chronic pain remains a challenge, with standard therapies often providing inadequate pain relief and causing undesirable side effects. Medicinal cannabis has emerged as promising alternative. This study assessed the impact of a cannabis hybrid extract on pain intensity and quality of life in daily clinical use.

Methods: ESCAPE was an observational study and included patients aged ≥ 18 years with chronic pain in Germany. The primary objective was to evaluate the effectiveness of the Cannamedical® Hybrid Cannabis Extract THC25:CBD25 on pain during four visits (V1-V4) in clinical practice, and key secondary objectives were pain interference and quality of life. Pain intensity was measured using the Numeric Rating Scale (NRS) of the Brief Pain Inventory (BPI) questionnaire. Pain interference was evaluated with the BPI pain interference subscore, and quality of life-particularly physical and mental health-was assessed with the Short Form-12 (SF-12) questionnaire. Additionally, patient and physician satisfaction with the extract was assessed.

Results: The study included 64 patients (50% female) with chronic pain (intention-to treat population; ITT). Cannabis-naïve patients of the ITT were defined as a subgroup and analyzed separately (N = 35). Mean (± SD) NRS-assessed pain intensity decreased during the study, in both the ITT (5.46 ± 1.73 at V1 vs. 3.37 ± 2.43 at V4) and in the cannabis-naïve subgroup (5.92 ± 1.34 at V1 vs. 2.37 ± 1.69 at V4). Mean pain interference subscore decreased between V1 and V4 for the ITT (5.39 ± 1.92 vs. 3.38 ± 2.46) and the cannabis-naïve group (5.68 ± 1.46 vs. 2.54 ± 1.99). Physical and mental health improved in both groups and high satisfaction with the hybrid cannabis extract was reported by patients and physicians.

Conclusion: Treatment with the Cannamedical® Hybrid Cannabis Extract THC25:CBD25 in daily clinical practice showed positive effects on patients’ pain and quality of life.”

https://pubmed.ncbi.nlm.nih.gov/40560527/

https://link.springer.com/article/10.1007/s12325-025-03262-z

In vitro antimicrobial activity of Thai stick cannabis Hang Kra Rog Phu Phan (Cannabis sativa L.), sugar leaves extract against pathogenic bacteria

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“Objective: Cannabis sativa L. is aware of a rich source of bioactive substances with various structures that exhibit pharmacological activity in the central nervous system, cardiovascular, cerebrovascular, respiratory, reproductive, and gastrointestinal systems.

Materials and methods: In this study, cannabis sugar leaves were soaked in 99% ethanol, followed by evaporation. The antibacterial effect of the cannabis sugar leaf extract was then evaluated using the disc diffusion method. The minimum inhibitory concentration (MIC) and the minimum bactericidal concentration (MBC) were determined using broth dilution.

Results: The results of this study indicated that the cannabis sugar leaf extract inhibited Bacillus cereusVibrio choleraeEscherichia coliStaphylococcus aureus, and Staphylococcus epidermidis when compared to tetracycline, but it did not inhibit Pseudomonas aeruginosa. The MIC and MBC of the cannabis sugar leaves extract against BcereusVcholeraeEcoliSaureus, and Sepidermidis were 0.977, 1.953, 31.25, 62.5, 125, 250, 250, 500, 250, and 500 mg/ml, respectively. The bioactive compounds in cannabis sugar leaf extract were identified using high-performance liquid chromatography.

Conclusion: The results indicated that the major bioactive compounds were Δ-9- tetrahydrocannabinol (THC) and cannabidiol (CBD). While minor bioactive compounds included gallic acid and tannic acid. These results support the benefits of cannabis sugar leaf extract, which has been used for its pharmacological properties and may be useful as an alternative antimicrobial agent in medicine.”

https://pubmed.ncbi.nlm.nih.gov/40568500/

https://www.ejmanager.com/mnstemps/39/39-1729498509.pdf?t=1750936743

The effect of medical cannabis on gastrointestinal symptoms in fibromyalgia and disorders of gut-brain interaction: a patient‑centred real‑world observational study

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“Objectives: Fibromyalgia (FM) is frequently associated with gastrointestinal (GI) disorders such as disorders of gut-brain interaction (DGBIs). Current treatments for FM offer limited relief, leading to the exploration of alternative therapies such as medical cannabis. This study evaluates in the impact of Bedrocan® medical cannabis in FM patients and GI symptoms over six months.

Methods: Sixty FM patients were enrolled, receiving a Bedrocan® cannabis treatment for 6 months. A standardised questionnaire evaluating upper and lower GI symptoms and the Revised Fibromyalgia Impact Questionnaire (FIQR) evaluating FM severity were administered at enrolment and 3 and 6-month follow-up evaluations. DGBIs, in particular, irritable bowel syndrome (IBS), and functional dyspepsia (FD) were diagnosed according to Rome IV criteria.

Results: Forty-six/60 (76.6%) FM patients fulfilled the diagnostic criteria for at least one DGBI; 10/60 (16.7%) FM patients fulfilled the diagnostic criteria for IBS, 17/60 (28.3%) for FD, and 19/60 (31.7%) for both IBS/FD. The FIQR severity score log-transformed significantly decreased during the months-by-month comparison period (repeated-measures ANOVA, p<0.001). Among GI symptoms, the log-transformed intensity-frequency score of epigastric pain, epigastric burning, abdominal pain, abdominal distension, and bloating significantly decreased during the month-by-month comparison period (repeated-measures ANOVA, p<0.01).

Conclusions: This study supports Bedrocan® medical cannabis as an alternative treatment for FM with a potential effect on FD and IBS symptoms. Despite positive outcomes, the study acknowledges limitations, such as the small sample size and absence of a control group. Further research is required to confirm the efficacy of medical cannabis in FM patients, particularly regarding its effects on GI symptoms.”

https://pubmed.ncbi.nlm.nih.gov/40556630/

https://www.clinexprheumatol.org/abstract.asp?a=22389