The iron fist of nature: Cannabinoid derivatives alter iron homeostasis and activate ferroptotic pathways in glioblastoma cells

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“Glioblastoma multiforme is the most commonly diagnosed type of brain tumor, with a poor prognosis and a high rate of recurrence. Because of its highly aggressive nature and the lack of efficient treatment options, novel therapeutic strategies are needed.

Ferroptosis is an iron-dependent, unique type of cell death, which provides an alternative way to eradicate cancer cells that are resistant to apoptosis and other cell death mechanisms.

CP55-940 (CP) and WIN 55212-2 (WIN) are synthetic cannabinoid receptor agonists with various biological activities, including neuroprotective and anticancer effects; however, their mechanism of action has not been fully uncovered.

In the present study, the potential of CP and WIN in glioblastoma cells was investigated.

Cell viability was determined with the MTT assay. Labile iron pool and reactive oxygen species generation were visualized with confocal microscopy. Malondialdehyde assay was performed to detect lipid peroxidation. Gene expressions of ferroptotic hallmarks, glutathione peroxidase-4, and transferrin receptor 1 were determined by RT-qPCR. Protein expression levels of iron-responsive element-binding protein 2, solute carrier family 7 member 11, and glutathione peroxidase-4 were analyzed by western blotting.

Results demonstrated that CP and WIN significantly induce ferroptotic pathways in glioblastoma cells via increased oxidative stress, labile iron pool, and lipid peroxidation. Furthermore, it was determined for the first time that both compounds significantly upregulate the transferrin receptor 1 gene expression.

In conclusion, the present study demonstrated for the first time that cannabinoid derivatives CP and WIN alter iron regulation and initiate ferroptosis in glioblastoma cells, rendering them potential candidates in therapy.

SIGNIFICANCE STATEMENT: We explored the ferroptotic activity of cannabinoid derivatives (CP and WIN) in glioblastoma cells for the first time. Additionally, we report for the first time that cannabinoid derivatives alter cellular iron levels, causing increased labile iron pool via upregulating the transferrin gene significantly.”

https://pubmed.ncbi.nlm.nih.gov/41962357

https://jpet.aspetjournals.org/article/S0022-3565(26)00518-5/abstract

“CP 55,940 is a synthetic cannabinoid which mimics the effects of naturally occurring THC (one of the psychoactive compounds found in cannabis). CP 55,940 was created by Pfizer in 1974 but was never marketed. It is currently used as a research tool to study the endocannabinoid system.”

“WIN 55,212-2 is a chemical described as an aminoalkylindole derivative, which produces effects similar to those of cannabinoids such as tetrahydrocannabinol (THC) but has an entirely different chemical structure.”

Therapeutic potential of phytocannabinoids in depression and cognitive dysfunction: Evidence from preclinical models

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“Depression is a highly prevalent and incident mental illness. Current pharmacological therapies fail in approximately 30-40% of patients, highlighting the urgent need for novel agents with pleiotropic effects.

This preclinical study aimed to identify new antidepressants and cognitive modulators among five phytocannabinoids: cannabichromene, cannabidiol, cannabidivarin, cannabigerol and cannabinol.

Phytocannabinoids were first evaluated in BV-2 microglial cells for cell viability and then, for anti-inflammatory activity, where BV-2 cells were previously stimulated with lipopolysaccharide (50 ng/mL). Based on these profiles, and comparing with ketamine, cannabidiol, cannabidivarin and cannabigerol were selected to be administered (55 µmol/kg, i.p.) once to healthy CD-1 male mice, and subsequently, administered six times to mice submitted to the unpredictable chronic mild stress (UCMS) protocol, which is a validated model of depression.

Among the phytocannabinoids under investigation, cannabigerol exhibited the lowest cytotoxicity, whereas cannabidiol and cannabidivarin demonstrated the strongest anti-inflammatory effects, significantly reducing nitrite, iNOS and pro-IL1β levels. In healthy mice, only cannabigerol produced consistent antidepressant-like effects in the forced swimming test compared to ketamine. Under UCMS protocol, cannabidivarin was anxiogenic and impaired cognitive and hepatic functions. Cannabidiol, despite its favorable safety profile, failed to ameliorate depressive phenotype or cognitive deficits. Notably, cannabigerol significantly improved cognitive performance, associated with increased dendritic spine density in the hippocampus.

Overall, our unprecedented findings demonstrated that a single administration of cannabigerol ameliorates depressive-like behavior in healthy animals, while multiple administrations improved cognitive function in mice exhibiting depressive-like phenotypes.

Together, these results highlight the therapeutic potential of cannabigerol in mood and cognitive disorders.”

https://pubmed.ncbi.nlm.nih.gov/41934896

“CBG has anxiolytic and antidepressant effects in healthy male CD-1 mice.”

https://www.sciencedirect.com/science/article/pii/S0753332226003318?via%3Dihub


The role of cannabinoid ligands in neurodegenerative diseases: emerging anti-inflammatory, immunomodulation and disease-modifying perspectives

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“Neurodegenerative diseases (NDs) constitute a growing global health burden driven by population aging and remain without disease-modifying therapies. Although chronic neuroinflammation and aberrant protein aggregation are widely recognized as shared pathological hallmarks of major NDs – including Alzheimer’s, Parkinson’s, Huntington’s diseases and multiple sclerosis – the causal relationships linking immunoinflammatory signaling to neurodegenerative progression remain contentious. Therapeutic strategies targeting neuroinflammation have thus far yielded limited clinical success, underscoring the need for mechanistically grounded and context-specific interventions.

The endocannabinoid system (ECS) is a key regulator of synaptic function, glial activity, and immune homeostasis in the central nervous system (CNS), and its dysregulation has been consistently reported in neurodegenerative settings. However, ECS alterations across NDs are heterogeneous and often disease- and stage-dependent, with conflicting findings regarding cannabinoid receptor expression, endocannabinoid tone, and functional outcomes.

Moreover, while preclinical studies demonstrate robust anti-inflammatory and neuroprotective effects of cannabinoid ligands, clinical translation has been constrained by issues of receptor specificity, psychoactive side effects, limited brain penetration, and an incomplete understanding of long-term ECS modulation.

In this Review, we critically evaluate current evidence linking ECS signaling to neuroinflammatory mechanisms in neurodegeneration, highlighting both convergent pathways and unresolved controversies. We discuss the translational implications of ECS-targeted strategies, including the development of selective receptor modulators, allosteric and/or bitopic/dualsteric ligands, and enzyme inhibitors, as well as emerging approaches to mitigate adverse effects and improve therapeutic precision.

By integrating mechanistic insights with clinical challenges, this Review delineates key obstacles and opportunities for advancing ECS-based interventions toward disease-modifying therapies for neurodegenerative disorders.”

https://pubmed.ncbi.nlm.nih.gov/41937092

“These findings are particularly relevant for the development of next-generation cannabinoid therapeutics designed to selectively engage beneficial signaling pathways while minimizing adverse effects.”

https://www.sciencedirect.com/science/article/pii/S1043661826001003?via%3Dihub


Cannabidiol hinders lipopolysaccharide-induced neutrophils migration to the lungs through suppressing nuclear factor kappa-B signal and expression of interleukin-1 beta in macrophages

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“Background: Acute lung injury and its more severe form, acute respiratory distress syndrome, are life-threatening diseases characterized by uncontrolled pulmonary inflammation, impaired gas exchange, and high mortality rates. Effective therapeutic agents remain limited. As a non-addictive component derived from hemp seed, the anti-inflammatory activity of cannabidiol (CBD) has been suggested by multiple pathological models.

Purpose: The purpose of this study is to investigate the potent anti-inflammatory effects of CBD in lipopolysaccharide-induced pulmonary inflammation and the mechanisms involved herein.

Methods: Mice were treated with lipopolysaccharide (LPS) intranasally to construct pulmonary inflammation model while CBD was administrated intraperitoneally at 25 mg/kg, 50 mg/kg, and 100 mg/kg. The percentage of immune cell subsets and the concentration of cytokines and chemokines were assayed to evaluate the inflammatory status of the lungs. The molecular expression of whole lungs and macrophages was obtained through RNA sequencing.

Results: The number of interstitial macrophages and neutrophils in lungs responded to the progression of inflammation and the anti-inflammatory function of CBD. In line with this, the transcriptome of lung tissue upregulated innate immune cell-related features and nuclear factor kappa-B signaling which was downregulated by CBD treatment at 50 mg/kg. CBD at this dose reduced the expression of interleukin-1 beta in both interstitial and alveolar macrophages and suppressed the expression of vascular cell adhesion molecule 1 in endothelial cells. During these processes, the mediation of inflammation was potentially conducted by interstitial macrophages.

Conclusion: CBD at 50 mg/kg significantly attenuates LPS-induced pulmonary inflammation and markedly suppresses the LPS-induced elevation in the number of neutrophils and interstitial macrophages in the lung. CBD could directly inhibit the expression of vascular cell adhesion molecule 1 in pulmonary endothelial cells and indirectly inhibit it by suppressing interleukin-1 beta secretion from macrophages, thereby reducing neutrophil infiltration into the lung and alleviating lung injury. These findings uncover the molecular mechanism whereby CBD alleviates inflammation via inhibiting granulocyte trafficking to the lungs, providing novel insights into the therapeutic potential of this compound.”

https://pubmed.ncbi.nlm.nih.gov/41935460

“Cannabidiol (CBD) is the non-addictive component in hemp seeds, known for its effects in treating constipation, reducing inflammation and pain, and providing antioxidant benefits. The anti-inflammatory properties of CBD have been well documented across diverse inflammatory disease models, with growing research interest in its therapeutic potential for pulmonary conditions”

https://www.sciencedirect.com/science/article/abs/pii/S0944711326003570?via%3Dihub

Cannabis use among cancer survivors: a systematic review and meta-analysis

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“The use of medical cannabis has been receiving growing attention as a potential therapeutic option for a diverse range of medical conditions, including cancer-related symptoms. The aim of this study was to estimate the prevalence of cannabis use among cancer survivors (post-treatment survivorship populations) and, secondarily, to compare these estimates with non-cancer control groups.

Methods

Following PRISMA guidelines (PROSPERO CRD42024510013), we searched PubMed, Scopus, PsycINFO, Web of Science, CINAHL Complete, and grey literature through November 1, 2025. We included observational studies reporting the prevalence of cannabis use among cancer survivors (i.e., individuals with a history of cancer in survivorship/follow-up settings), regardless of whether a comparison group was available. In studies with comparator groups, controls were individuals without a history of cancer drawn from general population or other non-cancer reference samples. Random-effects (REML) models were used to pool prevalence estimates, while comparative odds ratios (ORs) were analyzed as a secondary outcome.

Results

Twenty-seven studies (176,072 participants; 21,025 cancer survivors and 155,047 controls) were included. Among survivors, pooled prevalences of cannabis use were 36.39% (95% CI 24.53–48.25) for lifetime use and 15.2% (95% CI 10.64–19.76) for past 30-day use, with lower estimates for current use (11.72%; 95% CI 5.02–18.43) and past-year use (7.96%; 95% CI 2.22–13.70). In studies with non-cancer controls, cancer survivors had lower odds of past 30-day use (OR 0.54; 95% CI 0.35–0.85; p = 0.01), however, no statistically significant differences were observed for current use (OR 0.93; 95% CI 0.79–1.10; p = 0.42), past-year (OR 0.40; 95% CI 0.12–1.30; p = 0.13), and lifetime cannabis use (OR 0.98; 95% CI 0.70–1.37; p = 0.92).

Conclusion

Cannabis use is common among cancer survivors. Compared with non-cancer populations, survivors showed lower odds of recent (past 30-day) use, while no statistically significant differences were observed for current, past-year, or lifetime cannabis use. These findings underscore the need for open, evidence-based counseling about potential benefits, risks, and safe use in survivorship care.”

https://pubmed.ncbi.nlm.nih.gov/41923168

https://link.springer.com/article/10.1186/s13690-026-01911-5

Elucidating the putative role of cannabigerol: a hypothesis-generating review of neuroinflammatory and neuroprotective mechanisms with implications for drug-resistant epilepsy

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“Drug-resistant epilepsy (DRE) affects approximately 30% of individuals with epilepsy and remains a major clinical challenge despite the availability of multiple antiseizure medications (ASMs). Beyond recurrent seizures, accumulating evidence implicates chronic neuroinflammation, blood-brain barrier (BBB) dysfunction, excitotoxic injury, and progressive neurodegeneration as processes associated with epileptogenesis and disease progression.

While cannabidiol (CBD) has demonstrated clinical efficacy in specific DRE syndromes, increasing recognition of these mechanisms has motivated interest in exploratory, mechanism-oriented approaches that extend beyond direct seizure suppression.

Cannabigerol (CBG) is a non-psychoactive phytocannabinoid with a pleiotropic pharmacological profile, interacting with cannabinoid receptors, transient receptor potential (TRP) channels, nuclear receptors such as peroxisome proliferator-activated receptor gamma (PPARγ), and additional neuromodulatory targets.

Preclinical studies indicate that CBG can modulate inflammatory, oxidative, and cell-survival pathways across diverse experimental models of neuroinflammatory and neurodegenerative injury. Importantly, most available evidence derives from non-epilepsy paradigms or in vitro systems, and direct support for antiseizure efficacy or disease modification in epilepsy remains limited.

This review synthesizes current preclinical evidence on the molecular targets and mechanistic actions of CBG, with particular emphasis on neuroimmune modulation and neuronal vulnerability, while critically addressing the limitations and translational gaps of the existing literature. Rather than providing confirmatory evidence, this work is intended as a hypothesis-generating framework to inform future epilepsy-focused studies evaluating whether modulation of neuroinflammatory and neurodegenerative pathways by CBG may hold relevance within disease-modifying research strategies for DRE.”

https://pubmed.ncbi.nlm.nih.gov/41919226

“Recent preclinical research has highlighted CBG as a multi-target phytocannabinoid capable of modulating neuroinflammatory, oxidative, and cell-survival pathways across diverse experimental systems.”

https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2026.1755956/full

Cannabidiol and pBDNF Cotreatment Attenuates Pathological Symptoms and Improves Cognition in 3 month-Old 5XFAD Mice

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“The marginal efficiency observed with the existing therapies in Alzheimer’s Disease (AD) can be attributed to the timing of the treatment. The beneficiaries of symptomatic or disease-modifying therapy for AD are mild-cognitive-impairment (MCI) or late-stage dementia patients. At this stage, the pathological features are already advanced and irreversible, as the shift in biomarker levels starts in a continuum 15-20 years prior. Early intervention, therefore, is a plausible solution to this issue. Consequently, we selected 3 month-old 5XFAD AD mice as an early intervention model.

We administered cannabidiol (CBD) and plasmid brain-derived neurotrophic factor (BDNF) encapsulated in liposome nanoparticles, functionalized with penetratin and mannose for brain-targeting, as a therapy.

Neuroinflammation is emerging as a key driver of AD progression by its interaction with amyloid plaques and phosphorylated tau. Therefore, CBD, which is anti-inflammatory and neuroprotective, was used.

BDNF, a synaptic modulation and cognitive maintenance agent, is declined and, thus, aggravates pathology and cognition in AD. BDNF expressed from the liposome nanoparticles supplements the reduced BDNF and aids in ameliorating AD pathology.

We found four weekly doses of our formulation reduced the amyloid burden by 3.04-fold (p-value < 0.0001), declined pro-inflammatory cytokines TNF-α by 2.51-fold (p-value < 0.0001), IL-1β by 2.34-fold (p-value < 0.0001) and microglial activation by 2.15-fold (p-value < 0.0001) than saline controls. In addition, it increased the synaptic markers level and promoted adult hippocampal neurogenesis, eventually improving cognitive functions.

These findings suggest the use of CBD and pBDNF has a potential therapeutic combination for AD management if intervened early.”

https://pubmed.ncbi.nlm.nih.gov/41924980

https://pubs.acs.org/doi/10.1021/acschemneuro.5c01009

Cannabidiol as a Modulator of the Gut-Liver Axis: Clinical and Pharmacological Insights into Hepatic and Metabolic Disorder Therapies

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“A non-intoxicating substance produced from Cannabis sativa, cannabidiol (CBD) has shown promise as a treatment for metabolic and hepatic diseases, primarily due to its capacity to alter the gut-liver axis.

A vital bidirectional communication pathway, the gut-liver axis is where substances produced from the liver affect gut homeostasis and gut-derived microbial products and metabolites influence liver health. Conditions including alcoholic liver disease (ALD), metabolic syndrome, and non-alcoholic fatty liver disease (NAFLD) are mostly caused by dysregulation of this axis.

According to preclinical research, CBD has hepatopro-tective benefits via improving the integrity of the gut barrier, decreasing intestinal permea-bility, altering the gut microbiota, and suppressing inflammatory signaling pathways such NF-κB and NLRP3 inflammasome activation. Furthermore, CBD improves insulin sensitivi-ty and lowers hepatic steatosis via modifying lipid and glucose metabolism via the PPARγ and CB1/CB2 receptor pathways. Its antioxidant qualities also help to lessen cellular dam-age and oxidative stress in hepatic tissues.

Despite these encouraging results, there is still inconsistency in the clinical data because of variations in dosage, formulation, administra-tion method, and patient-specific variables including liver function and microbiota makeup. Furthermore, broad therapeutic usage is restricted by issues with hepatic metabolism, pos-sible drug-drug interactions, and regulatory obstacles.

This review highlights information gaps, critically assesses the available preclinical and clinical evidence, and investigates the mechanisms underlying CBD’s impact on the gut-liver axis. Additionally, it identifies po-tential avenues for future optimization of CBD-based therapies targeting liver and metabol-ic illnesses through personalized medicine, sophisticated delivery methods, and standard-ized clinical trial procedures.”

https://pubmed.ncbi.nlm.nih.gov/41935387

https://www.eurekaselect.com/article/154488


Safety and Tolerability of Low-Dose Full-Spectrum Cannabidiol in Long-Term Virally Suppressed Adults with HIV: A Randomized Double-Blind Placebo-Controlled Trial

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“Introduction: People with long-term virologically suppressed HIV (PWH) experience chronic inflammation. Beneficial effects such as lower levels of inflammation were reported for cannabis-based medicine, but data on the safety of standardized low-dose full-spectrum cannabidiol (CBD) are limited.

Methods: This double-blind randomized placebo-controlled trial (NCT05306249) included 80 ART-treated PWH with undetectable viremia (median time on efficient ART 14 years, median age 54 years), encompassing 30% women. Participants received 1 mg/kg CBD oil twice daily (full-spectrum, tetrahydrocannabinol < 0.3%) or placebo for 12 weeks plus a 4-week follow-up. Primary trial end-point (autophagy gene expression) will be described elsewhere; here we evaluate the treatment impact on prespecified safety outcomes such as hemodynamic with electrocardiograms, HIV immunovirological parameters, and comprehensive assessments of liver and kidney functions, performed using standard blood tests. Mixed-effects models adjusted for baseline age, sex, body mass index, CD4 count and duration of viral suppression assessed longitudinal changes.

Results: Of 80 randomized participants, 35 PWH in CBD and 37 in placebo groups completed week 12. No clinically meaningful differences emerged in creatinine, aminotransferases (alanine aminotransferase, aspartate aminotransferase), or conjugated bilirubin. Total bilirubin decreased in the CBD arm vs placebo (mixed effect model considering time, group and time*group, adjusted for covariates, p = 0.046). In exploratory sex-stratified analysis, a significant difference starting at week 12 (-8.0 bpm [95% CI: -15.6; -0.4], p = 0.0425) and persisting at week 16 (-7.9 bpm [95% CI: -14.6; -1.3], p = 0.0191) evidences a lower heart rate in men belonging to the CBD group compared with the placebo group; no change in females. There was no change in plasma viral load, cell-associated HIV-DNA levels, and CD4/CD8 ratio.

Discussion: Low-dose full-spectrum GMP-certified CBD was well tolerated over 12 weeks in virally suppressed people with HIV. Observed reductions in total bilirubin and male heart rate are exploratory and warrant confirmation in adequately powered trials incorporating inflammatory biomarkers and pharmacokinetics.”

https://pubmed.ncbi.nlm.nih.gov/41934259

https://journals.sagepub.com/doi/10.1177/25785125261439014

Radical Revelations: The Interplay of Nitrosative Stress, the Endocannabinoid System, and Treatment of Age-Related Disorders

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“The crosstalk between the endocannabinoid system (ECS) and reactive nitrogen species (RNS) has emerged as an important area of investigation in recent years.

Although many aspects of this interaction remain elusive, accumulating evidence demonstrates that the ECS plays a critical role in regulating RNS-mediated signaling under physiological conditions. This modulation can be either inhibitory or stimulatory, depending on the specific receptor subtype, cell type, and tissue location involved.

While ECS-RNS interactions support normal cellular homeostasis, their dysregulation contributes to various disease states, particularly neurodegenerative disorders. Studies in both rodent models and human subjects show that ECS modulation can reduce anxiety, attenuate neuroinflammatory responses, and slow disease progression in neurodegenerative conditions.

This review examines how cannabinoid-based interventions modulate nitrosative stress and neuroinflammation in Alzheimer’s disease (AD) and Parkinson’s disease (PD), highlighting their potential as targeted therapeutics that address multiple pathological mechanisms simultaneously and may offer advantages over conventional treatment approaches.”

https://pubmed.ncbi.nlm.nih.gov/41898672

“cannabinoid treatment offers a promising alternative to conventional treatments by addressing symptomology and the underlying molecular mechanisms of these diseases. Cannabinoid treatment uniquely addresses AD and PD pathology via crosstalk between the RNS and ECS, which provides hope for disease modification as an alternative to/supplement to conventional treatments.”

https://www.mdpi.com/1422-0067/27/6/2813