Cannabidiol synergizes with methotrexate to attenuate rheumatoid arthritis via STAT3/NF-κB signalling-mediated M1 macrophage polarization

Posted on by

“Background: Methotrexate (MTX) is the anchor drug for rheumatoid arthritis (RA) treatment, but its clinical application is limited by dose-dependent adverse events, such as hepatotoxicity and gastrointestinal intolerance, and incomplete efficacy in some patients. Cannabidiol (CBD) is a nonpsychotropic cannabinoid that has powerful therapeutic efficacy in alleviating pain and inflammation, as well as favourable safety and tolerability profiles. However, whether CBD can synergize with MTX to enhance therapeutic outcomes and mitigate toxicity remains unclear. This study aimed to investigate the synergistic efficacy, safety profile, and underlying molecular mechanism of the CBD-MTX combination in the treatment of RA.

Methods: Mice were randomly divided into 8 groups (n = 5 per group): a normal control group (NC), a model control group (MC), 3 MTX monotherapy groups (low/medium/high dose), and 3 CBD + MTX combination groups (low/medium/high dose). Arthritis severity was assessed by clinical scoring and micro-CT. Systemic safety was evaluated via histopathological examination of the liver, kidney, and testis. Flow cytometry, ELISA and Western blotting were used to validate the mechanisms involved. Network pharmacology and molecular docking were used to predict potential targets.

Results: Compared with MTX monotherapy, the CBD-MTX combination had dose-dependent synergistic effects, significantly attenuating joint swelling, inflammation, and bone erosion. The medium-dose combination approached the efficacy of high-dose MTX (dose-sparing effect). CBD mitigated MTX-induced testicular toxicity and spermatogenic failure. Mechanistically, the combination suppressed M1 macrophage polarization and proinflammatory cytokine (TNF-α, IL-6, and IL-1β) secretion by inhibiting STAT3 and NF-κB signalling (downregulation of p-STAT3 and p-NF-κB p65).

Conclusion: The CBD-MTX combination exerts superior antiarthritic effects by inhibiting STAT3/NF-κB-mediated M1 macrophage polarization and protecting against MTX-induced reproductive toxicity. This study provides a preclinical rationale for this novel combination strategy in RA management.”

https://pubmed.ncbi.nlm.nih.gov/41955700

“In summary, our findings identify the combination of CBD and MTX as a robust therapeutic strategy for RA management. We demonstrate that this regimen exerts synergistic antiarthritic effects by inhibiting the STAT3/NF-κB axis and suppressing M1 macrophage polarization. Importantly, CBD not only enhances MTX efficacy but also mitigates MTX-induced reproductive toxicity.”

https://www.sciencedirect.com/science/article/abs/pii/S1567576926004728?via%3Dihub

Effect of cannabinol, tetrahydrocannabivarin and cannabidiol on voluntary alcohol consumption

Posted on by

“Aims: Previous studies have demonstrated that the endocannabinoid system plays a significant role in the development of alcohol use disorder (AUD), and CB1 receptor antagonists/inverse agonists show promise as a novel AUD pharmacotherapy. However, these compounds failed in clinical trials due to the severe psychiatric side effects. Non-psychoactive phytocannabinoids may have a better safety profile and could be used as an alternative approach to treat AUD. The aim of this study was to test the potential of three phytocannabinoids in reducing alcohol consumption: CB1 receptor partial agonist cannabinol (CBN), neutral antagonist tetrahydrocannabivarin (THCV) and negative allosteric modulator cannabidiol (CBD).

Methods: Male Wistar rats were subjected to a long-term voluntary alcohol drinking procedure that lasted for several months. Thereafter, rats were given three once daily administrations of CBN, THCV, or CBD. Their side-effect profile was examined by recording changes in water consumption, body weight and locomotor activity. Ultrasonic vocalisations were recorded in alcohol-naïve group-housed rats to monitor if treatment induced discomfort, distress, or other changes in emotional states.

Results: Our data demonstrated that all phytocannabinoids reduced voluntary alcohol consumption; however, the compounds differed in their effectiveness and side-effect profile. Treatment with CBN and THCV reduced alcohol intake and alcohol preference and had a mild sedative effect. CBD had a minor effect on alcohol consumption, did not affect alcohol preference, reduced the locomotor activity and lowered the positive emotional states of rats. None of the compounds caused discomfort or distress.

Conclusions: We conclude that CBN and THCV may have potential in treating AUD.”

https://pubmed.ncbi.nlm.nih.gov/41947574

“Cannabis plants have long been used both medicinally and recreationally, mainly due to the psychoactive compound delta9-tetrahydrocannabinol (THC, a partial agonist of the CB1 receptor). However, the health benefits of these plants may be attributable to over a hundred of other, non-psychoactive compounds or their metabolites, collectively termed phytocannabinoids.”

“In summary, the present study demonstrated that CBN and THCV were more effective in reducing the maintenance of voluntary alcohol consumption and had a better safety profile compared to CBD. The effect of all three phytocannabinoids on alcohol consumption may be related to their action on the CB1 receptor.”

https://academic.oup.com/alcalc/article/61/3/agag019/8607733

A multifunctional conductive physiomimetic scaffold: synergy of rGO coating and cannabis-derived nanotopography for infection-resistant bone repair

Posted on by

“Conventional bone grafts cannot reliably fulfill the dual requirements of rapid osseoinduction and intrinsic infection-resistance to meet clinical needs. We therefore aimed to overcome this dual challenge by fabricating a novel physiomimetic three-dimensional scaffold.

This was achieved by coating the unique nano-grooved cellulosic matrix derived from Cannabis sativa leaf trichomes with reduced graphene oxide (rGO) to mimic the native osteogenic niche.

The plant-derived skeleton serves as a ready-made, topographically complex framework, while the rGO coating provides a microenvironment well suited for bone repair. Comprehensive characterization verified a measurable surface energy, hydrophilicity, roughness, and proper conductivity due to rGO coating. Moreover, in vitro examination confirmed that rGO biofunctionalization synergized with the innate nano-topography, dynamically accelerated the osteogenic differentiation of human adipose-derived stem cells. An upregulated expression of key bone markers, COL1A1, RUNX2, and OPN, sustained alkaline phosphatase activity, and augmented deposition of collagen and mineralized matrix exhibited the potential of the proposed approach for efficient osteal regeneration. An equally important finding was the scaffold’s inherent antibacterial property against Gram-positive and Gram-negative pathogens.

We demonstrated that augmenting a natural cannabis-derived nanostructure with a conductive nanomaterial coating creates a multifaceted therapeutic strategy capable of promoting bone formation and potentially antibacterial effects, addressing two critical obstacles in regenerative orthopedics.”

https://pubmed.ncbi.nlm.nih.gov/41958836

“In conclusion, the rGO-functionalized cannabis-derived scaffold offers a multifaceted therapeutic route toward bone repair, while bioinspired microenvironment is not only structurally supportive but also biologically instructive and inherently protective against microbial threats.”

https://www.frontiersin.org/journals/bioengineering-and-biotechnology/articles/10.3389/fbioe.2026.1766388/full


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

Posted on by

“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

Posted on by

“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

Posted on by

“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

Posted on by

“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

Posted on by

“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

Posted on by

“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

Posted on by

“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