“Background: Cannabidiol (CBD), a major non-psychoactive phytocannabinoid derived from Cannabis sativa L., has shown therapeutic potential in rheumatoid arthritis (RA). However, the mechanisms by which CBD modulates synovial angiogenesis remain unclear.

Purpose: This study aimed to investigate whether CBD attenuates RA progression by suppressing synovial angiogenesis and to elucidate the underlying molecular mechanisms.

Methods: An adjuvant-induced arthritis (AIA) rat model was established to evaluate the therapeutic effects of CBD in vivo using arthritis scoring, micro-CT, and histopathological, immunohistochemical, and immunofluorescence analyses. In vitro, cytotoxicity was determined using the CCK-8 assay, followed by evaluations of CBD’s direct effects on the proliferation, migration, invasion, and inflammatory responses of RA fibroblast-like synoviocytes (RA-FLS) were evaluated, alongside Cell Counting Kit-8 (CCK-8) for cytotoxicity screening. Furthermore, the paracrine regulation of angiogenesis was assessed using a conditioned medium (CM) transfer system from hypoxia-stimulated RA-FLS applied to human umbilical vein endothelial cells (HUVECs). Molecular mechanisms were analyzed via Western blotting, RT-qPCR, ELISA, co-immunoprecipitation (Co-IP), molecular docking, and targeted proteasome inhibition (MG132).

Results: In vivo, CBD (5 and 10 mg/kg) treatment markedly alleviated joint inflammation, synovial angiogenesis, and structural bone destruction in AIA rats. In vitro, non-cytotoxic concentrations of CBD (2.4-4.8 μM) significantly suppressed aberrant RA-FLS proliferation, migration, invasion, and pro-inflammatory cytokine secretion. Mechanistically, CBD abrogated the hypoxia-induced accumulation of hypoxia-inducible factor-1α (HIF-1α) protein in RA-FLS without significantly altering HIF1A mRNA expression. This reduction was effectively reversed by MG132. Co-IP and molecular docking analyses revealed that CBD directly enhances the polyubiquitination of HIF-1α through stable structural interactions, driving a ubiquitin-proteasome-dependent degradation mechanism. Consequently, CBD dose-dependently decreased the extracellular secretion of vascular endothelial growth factor A (VEGFA) and angiopoietin-2 (ANG-2) from RA-FLS. Functionally, CM from CBD-treated RA-FLS disrupted the pro-angiogenic paracrine crosstalk-independent of direct CBD carryover-significantly impairing HUVEC migration, capillary-like tube formation, and downstream VEGFR2 (Tyr1175) phosphorylation.

Conclusion: CBD attenuates RA pathogenesis not only by directly suppressing RA-FLS hyperactivity but also by severing the pro-angiogenic paracrine crosstalk between RA-FLS and endothelial cells. These effects are driven by the ubiquitin-proteasome-dependent degradation of HIF-1α in RA-FLS via direct structural engagement, which depletes VEGFA/ANG-2 production and subsequent endothelial VEGFR2 activation. These findings highlight CBD as a promising disease-modifying anti-angiogenic therapeutic agent for RA.”

https://pubmed.ncbi.nlm.nih.gov/42542056

“In conclusion, this study demonstrates the potent anti-angiogenic efficacy of CBD in RA through integrated in vivo and in vitro investigations. Mechanistically, CBD alleviates RA pathology by driving the ubiquitin-dependent proteasomal degradation of HIF-1α, thereby curtailing the secretion of VEGFA and ANG-2. This effectively dismantles the pathological paracrine signaling axis between hyperactive RA-FLS and endothelial cells.”

https://www.sciencedirect.com/science/article/abs/pii/S0944711326008925?via%3Dihub

“Background: Rheumatoid arthritis is a chronic autoimmune disease characterized by synovial inflammation, cytokine imbalance, and progressive joint destruction. The endocannabinoid system has emerged as a potential therapeutic target; however, the anti-inflammatory mechanisms of non-psychoactive cannabinoids such as cannabichromene (CBC) remain insufficiently defined. This study aimed to evaluate the anti-inflammatory effects of CBC in vitro and in a collagen-induced arthritis (CIA) rat model, with a focus on key inflammatory signaling pathways.

Methods: CBC effects were assessed in LPS-stimulated HUVEC cells by qPCR analysis of inflammatory markers. In vivo, female Wistar rats were assigned to four groups: CIA + saline (placebo), CIA + CBC, CIA + methylprednisolone, and non-immunized controls receiving saline. Disease progression was evaluated using clinical scoring, paw thickness, and body weight. Synovial tissues and serum were analyzed by qPCR, Western blotting, and ELISA to assess cytokines, inflammasome components, and signaling pathways, including NF-κB and JAK/STAT.

Results: CBC reduced TNF-α expression in vitro at low micromolar concentrations. In vivo, CBC significantly decreased arthritis scores compared to placebo and attenuated weight loss, although it did not significantly reduce paw swelling. Molecular analyses revealed downregulation of IL-6, STAT3, and IL-17 A, indicating suppression of the TNF-NF-κB-IL-6-STAT3-Th17 axis. CBC also significantly inhibited inflammasome components (NLRP3, NLRP1A, caspase-11). However, MMP-3 and MMP-9 levels were not significantly affected.

Conclusions: CBC exhibits significant anti-inflammatory activity in vitro and in vivo by modulating key cytokine and inflammasome pathways. While its effects on structural joint damage markers were limited, CBC represents a promising candidate for inflammatory arthritis therapy, warranting further investigation.”

https://pubmed.ncbi.nlm.nih.gov/42343451

https://link.springer.com/article/10.1186/s42238-026-00464-2

“Background/Objectives: Rheumatoid arthritis (RA) is a chronic, inflammatory, autoimmune disease that primarily affects the joints. Current treatments aim to relieve pain and limit joint damage; however, many are associated with significant side effects or high costs. Neutrophils play a critical role in RA development and progression by driving synovial inflammation and tissue damage, yet no approved therapies directly target neutrophil-mediated pathogenic mechanisms. Cannabinoids have demonstrated anti-inflammatory potential. Although cannabinoids have been studied in RA, the direct modulation of neutrophil-driven mechanisms by purified CBG has not been systematically addressed. To harness the cannabinoid potential, we investigated the effects of the purified cannabinoid Cannabigerol (CBG) on neutrophil-mediated immune responses in RA. 

Methods: We assessed the effects of CBG on human blood isolated neutrophil cytokine secretion, signal transduction and migration as ex vivo models. In addition, collagen antibody-induced arthritis (CAIA) was applied in C57BL/6 wt mice, and immune-cell recruitment and cytokine secretion were examined after CBG treatment. 

Results: Ex vivo experiments demonstrated that CBG hampered the secretion of pro-inflammatory cytokines from human neutrophils in a dose-dependent manner (TNF-α and IL-6 by 68% and 72%, respectively). Furthermore, CBG downregulated inflammatory signal transduction, such as P38-MAPK, ERK1/2 and Akt phosphorylationpost neutrophil activation by 41%, 54% and 78%, respectively. Importantly, 60% of the CBG downregulation of IL-6 was consistent with the CB2 receptor axis in a selective way. In addition, CBG attenuated neutrophil migration toward IL-8 by 67%. To further evaluate CBG therapeutic capacity, we used CAIA as an in vivo model. CBG treatment resulted in improving mice arthritis clinical scores and body weight in comparison to RA-diseased mice. Moreover, CBG reduced leukocyte recruitment to the inflamed joints by 48%, primarily through the inhibition of neutrophil and monocyte cells to 27% and 49%, respectively. Additionally, CBG showed its anti-inflammatory effect by decreasing inflammatory cytokines like IL-6 and IL-1β by 98% and 60% in the blood. Also, CBG reduced MCP-1 and IL-1β cytokines in the joints by 22% and 38%, respectively. 

Conclusions: These results show that CBG has anti-inflammatory capacity and therapeutic potential in regulating neutrophil-mediated immunity in RA. These findings are preclinical and require further validation before therapeutic positioning.”

https://pubmed.ncbi.nlm.nih.gov/42075816

“So far, these findings highlight CBG as an effective preclinical modulator candidate for affecting neutrophil-mediated immune responses and attenuating inflammation in rheumatoid arthritis.”

https://www.mdpi.com/1424-8247/19/4/560

“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

“Introduction: Rheumatoid arthritis (RA) is a debilitating autoimmune disease affecting approximately 1% of the global population and is associated with significant morbidity and mortality. Given the known anti-inflammatory effects of cannabinoids, we investigated the therapeutic potential of a high-CBD extract, termed CBD-X, by assessing its effects on immune cells and disease progression. This study investigates the therapeutic potential of a high-CBD extract (CBD-X) in RA.

Methods: We evaluated the effects of CBD-X on cells involved in RA pathogenesis using macrophages and primary human neutrophils as ex vivo models. In addition, two murine models of RA were applied: collagen-induced arthritis (CIA) and collagen antibody-induced arthritis (CAIA).

Results: Ex vivo experiments demonstrated that CBD-X inhibited the secretion of pro-inflammatory cytokines, including IL-1β from macrophages and IL-8, IL-6, and TNF-α from human neutrophils, suggesting its potential to modulate inflammatory responses. Moreover, CBD-X attenuated NF-κB p65 and Akt phosphorylation downstream LPS-activation signal in neutrophils. To further evaluate its therapeutic effects, we employed two murine models of RA: collagen-induced arthritis (CIA) and collagen antibody-induced arthritis (CAIA). In both models, CBD-X treatment resulted in a significant reduction of leukocyte levels in the blood, primarily through the suppression of neutrophil and monocyte populations, which play a central role in RA pathogenesis. Additionally, CBD-X reduced neutrophil migration to the joints in the CAIA model, highlighting its potential to alleviate joint inflammation. Furthermore, it modulated the neutrophil-to-macrophage ratio (NMR), an important marker of RA progression, an effect that was not observed with dexamethasone treatment, suggesting a distinct mechanism of immune regulation. Notably, CBD-X promoted the pro-resolving macrophages to the rheumatic joints. Importantly, CBD-X exerted its anti-inflammatory effect by downregulating TNF-α and MCP-1 while upregulating IL-10, a key anti-inflammatory cytokine involved in immune homeostasis.

Discussion: These findings indicate that CBD-X has a significant potential as a therapeutic agent for RA, offering a promising approach to modulate immune responses and reduce inflammation in RA patients.”

https://pubmed.ncbi.nlm.nih.gov/40709173/

“Cannabinoids, including CBD, have demonstrated anti-inflammatory effects in conditions like severe COVID-19 and may help prevent disease progression from mild to severe stages.”

“These results demonstrate that CBD-X treatment exerts an anti-inflammatory effect by reducing pro-inflammatory cytokines also enhances anti-inflammatory IL-10 levels highlighting its therapeutic potential in RA management.”

https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1599109/full