Category Archives: Rheumatoid Arthritis

Patient-Reported Outcomes of Pain, Stiffness, and Fatigue Reduction in Rheumatoid and Psoriatic Arthritis With Cannabinoid Use

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“Rheumatoid arthritis (RA) and psoriatic arthritis (PsA) are autoimmune conditions that can progressively destroy joints, causing chronic, often debilitating pain, and drastically affecting the quality of life. Novel pharmaceutical remedies have recently been developed, which allow for better symptom management. However, the complex pain experienced is challenging to control fully, leading this patient population to seek alternative treatments.

Though cannabis has been legalized for medical use in most states in the United States, the safety and efficacy of its use in inflammatory arthritis have still not been satisfactorily established. We conducted a cross-sectional study on patients with RA and PsA who visited a rheumatology outpatient clinic from October 2019 to March 2020.

We conducted a brief, voluntary, and anonymous Qualtrics survey of specific questions regarding their use of cannabinoids and their forms, sources, methods, side effects, and perceived efficacy. The survey initially involved 302 eligible candidates, but only 290 patients completed it. Among them, 84.9% (n, 247) reported a diagnosis of RA, while 15.1% (n, 44) reported PsA. Demographically, 82.3% (n, 238) were female, and 17.7% (n, 52) were male, with mean ages of 57.1 years for RA and 56.2 years for PsA.

Around 16.95% (n=40) of RA and 11.63% (n=5) of PsA patients reported cannabinoid use, primarily inhaled for RA and topical/liquid for PsA.

Post-cannabis use, a significant decrease in pain scale was noted (mean difference: 2.267, p < 0.001), with improvements in stiffness, fatigue, and swelling reported. Side effects were minimal, and most patients were willing to discuss cannabinoid treatment with their physician (80.9% RA [n=199], 86.4% PsA [n=38]).

In conclusion, our study indicates that a notable portion of the patients with inflammatory arthritis including RA and PsA reported a history of use or ongoing cannabinoid use. Furthermore, the patients reported a short-term reduction of pain, fatigue, and swelling, though it is unclear if these findings are related to a placebo effect.”

https://pubmed.ncbi.nlm.nih.gov/39583459/

“In summary, our study sheds light on the self-utilization and the reported effectiveness of cannabinoids in managing symptoms associated with RA and PsA. Our data indicate that the reduction in pain was statistically significant, suggesting cannabinoids may help alleviate the pain associated with these conditions.”

https://www.cureus.com/articles/204984-patient-reported-outcomes-of-pain-stiffness-and-fatigue-reduction-in-rheumatoid-and-psoriatic-arthritis-with-cannabinoid-use#!/

Cannabidiol regulates L-carnitine and butyric acid metabolism by modulating the gut microbiota to ameliorate collagen-induced arthritis

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“Background: Rheumatoid arthritis (RA) is one of the most common autoimmune diseases, affecting multiple systems in the body. Cannabidiol (CBD) is one of the most medically valuable active ingredients in cannabis. At present, CBD has been shown to alleviate the progression of RA; however, owing to its multiple targets, the mechanism of CBD is not clear.

Methods: On the basis of the gut microbiota, we explored the mechanism by which CBD inhibits RA progression. Metagenomic and nontargeted metabolomic analyses were used to determine the changes in the intestinal ecology and plasma metabolites of collagen-induced arthritis (CIA) rats after CBD treatment.

Results: CBD reversed gut dysbiosis in CIA rats, notably altering the abundances of Allobaculum_unclassified, Allobaculum_fili, and Prevotella_unclassified. In addition, metabolomic analysis confirmed that CBD increased the contents of butyric acid and L-carnitine. Allobaculum could produce butyric acid and Prevotella could accelerate the metabolism of L-carnitine. In addition, in vitro experiments demonstrated that L-carnitine participated in the regulation of neutrophils, macrophages and RA-fibroblast-like synoviocytes (RA-FLSs), which was consistent with the synovial changes in CIA rats caused by CBD.

Conclusion: In summary, CBD increased the plasma contents of butyric acid and L-carnitine by altering the abundances of gut microbiota, thereby inhibiting inflammation in neutrophils, macrophages and RA-FLSs. Our study is the first to explain the mechanism by which CBD alleviates progression in CIA rats from the perspective of gut microbes and metabolites, providing new views into CBD mechanisms, which warrants clinical attention.”

https://pubmed.ncbi.nlm.nih.gov/39591767/

“Cannabidiol (CBD) is one of the most medically valuable active ingredients in cannabis and has various pharmacological effects, such as neuroprotective, anxiolytic, antipsychotic, antiemetic, antitumor, anti-inflammatory, and antioxidant effects.”

https://www.sciencedirect.com/science/article/abs/pii/S0944711324009267?via%3Dihub

Cannabinoids in the Inflamed Synovium Can Be a Target for the Treatment of Rheumatic Diseases

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“The management of rheumatic diseases has noticeably changed in recent years with the development of targeted therapeutic agents, namely, biological disease-modifying antirheumatic drugs. Identifying essential signaling pathways and factors crucial for the development and progression of these diseases remains a significant challenge.

Therapy could be used to delay the onset or reduce harm. The endocannabinoid system’s presence within the synovium can be identified as a suggested target for therapeutic interventions due to its role in modulating pain, inflammation, and joint metabolism.

This review brings together the most pertinent information concerning the actions of the endocannabinoid system present in inflamed synovial tissue and its interaction with phytocannabinoids and synthetic cannabinoids, which can be used from a therapeutic perspective to minimize the inflammatory and pain processes typical of osteoarthritis and rheumatoid arthritis.”

https://pubmed.ncbi.nlm.nih.gov/39273304/

https://www.mdpi.com/1422-0067/25/17/9356

Cannabis therapy in rheumatological diseases: A systematic review

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“Cannabis has been used in rheumatic diseases as therapy for chronic pain or inflammatory conditions. Herein, the authors systematically review the rheumatological diseases in which cannabis has been studied: systemic sclerosis, fibromyalgia, osteoarthritis, rheumatoid arthritis, osteoporosis, polymyalgia rheumatica, gout, dermatomyositis, and psoriatic arthritis. We systematically searched PubMed for articles on cannabis and rheumatic diseases between 1966 and March 2023. Twenty-eight articles have been selected for review.

Most of them (n=13) were on fibromyalgia and all of them but one showed important reduction in pain; sleep and mood also improved. On rheumatoid arthritis, two papers displayed decrease in pain and in one of them a reduction in inflammatory parameters was found. In scleroderma there was a case description with good results, one study on local use for digital ulcers also with good outcomes and a third one, that disclosed good results for skin fibrosis. In dermatomyositis a single study showed improvement of skin manifestations and in osteoarthritis (3 studies) this drug has demonstrated a good analgesic effect. Several surveys (n=5) on the general use of cannabis showed that rheumatological patients (mixed diseases) do use this drug even without medical supervision. The reported side effects were mild.

In conclusion, cannabis treatment is an interesting option for the treatment of rheumatological diseases that should be further explored with more studies.”

https://pubmed.ncbi.nlm.nih.gov/39165706/

https://northclinist.com/jvi.aspx?un=NCI-43669&volume=11&issue=4

The Impact of the CB2 Cannabinoid Receptor in Inflammatory Diseases: An Update

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“The emergence of inflammatory diseases is a heavy burden on modern societies.

Cannabis has been used for several millennia to treat inflammatory disorders such as rheumatism or gout.

Since the characterization of cannabinoid receptors, CB1 and CB2, the potential of cannabinoid pharmacotherapy in inflammatory conditions has received great interest. Several studies have identified the importance of these receptors in immune cell migration and in the production of inflammatory mediators.

As the presence of the CB2 receptor was documented to be more predominant in immune cells, several pharmacological agonists and antagonists have been designed to treat inflammation. To better define the potential of the CB2 receptor, three online databases, PubMed, Google Scholar and clinicaltrial.gov, were searched without language restriction. The full texts of articles presenting data on the endocannabinoid system, the CB2 receptor and its role in modulating inflammation in vitro, in animal models and in the context of clinical trials were reviewed. Finally, we discuss the clinical potential of the latest cannabinoid-based therapies in inflammatory diseases.”

https://pubmed.ncbi.nlm.nih.gov/39064959/

https://www.mdpi.com/1420-3049/29/14/3381

Anti-Inflammatory Effects of Cannabigerol in Rheumatoid Arthritis Synovial Fibroblasts and Peripheral Blood Mononuclear Cell Cultures Are Partly Mediated by TRPA1

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“Since its medical legalization, cannabis preparations containing the major phytocannabinoids (cannabidiol (CBD) and δ9-tetrahydrocannabinol (THC)) have been used by patients with rheumatoid arthritis (RA) to alleviate pain and inflammation. However, minor cannabinoids such as cannabigerol (CBG) also demonstrated anti-inflammatory properties, but due to the lack of studies, they are not widely used. CBG binds several cellular target proteins such as cannabinoid and α2-adrenergic receptors, but it also ligates several members of the transient potential receptor (TRP) family with TRPA1 being the main target. TRPA1 is not only involved in nnociception, but it also protects cells from apoptosis under oxidative stress conditions. Therefore, modulation of TRPA1 signaling by CBG might be used to modulate disease activity in RA as this autoimmune disease is accompanied by oxidative stress and subsequent activation of pro-inflammatory pathways. Rheumatoid synovial fibroblasts (RASF) were stimulated or not with tumor necrosis factor (TNF) for 72 h to induce TRPA1 protein. CBG increased intracellular calcium levels in TNF-stimulated RASF but not unstimulated RASF in a TRPA1-dependent manner. In addition, PoPo3 uptake, a surrogate marker for drug uptake, was enhanced by CBG. RASF cell viability, IL-6 and IL-8 production were decreased by CBG. In peripheral blood mononuclear cell cultures (PBMC) alone or together with RASF, CBG-modulated interleukin (IL)-6, IL-10, TNF and immunoglobulin M and G production which was dependent on activation stimulus (T cell-dependent or independent). However, effects on PBMCs were only partially mediated by TRPA1 as the antagonist A967079 did inhibit some but not all effects of CBG on cytokine production. In contrast, TRPA1 antagonism even enhanced the inhibitory effects of CBG on immunoglobulin production. CBG showed broad anti-inflammatory effects in isolated RASF, PBMC and PBMC/RASF co-cultures. As CBG is non-psychotropic, it might be used as add-on therapy in RA to reduce IL-6 and autoantibody levels.”

https://pubmed.ncbi.nlm.nih.gov/36614296/

“Therefore, CBG might be suited as an adjunct therapy for RA to reduce cytokine and autoantibody production.”

https://www.mdpi.com/1422-0067/24/1/855

Application of Oil-in-Water Cannabidiol Emulsion for the Treatment of Rheumatoid Arthritis

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“Introduction: Rheumatoid arthritis (RA) is a chronic autoimmune disease with unknown cause. It mainly affects joints and, without proper treatment, negatively impacts their movement, causes painful deformities, and reduces the patients’ quality of life. Current treatment options consist of various types of disease-modifying antirheumatic drugs (DMARDs), however 20-30% of patients are partially resistant to them. Therefore, development of new drugs is necessary. Possible option are compounds exhibiting their action via endocannabinoid system, which plays an important role in pain and inflammation modulation. One such compound – cannabidiol (CBD) has already been shown to attenuate synovitis in animal model of RA in in vivo studies. However, it has low bioavailability due to its low water solubility and lipophilicity. This issue can be addressed by preparation of a lipid containing formulation targeting lymphatic system, another route of absorption in the body. 

Materials and Methods: CBD-containing emulsion was prepared by high-shear homogenization and its droplet size distribution was analysed by optical microscopy. The relative oral bioavailability compared to oil solution as well as total availability of CBD were assessed in a cross-over study in rats and absorption of CBD via lymphatic system was observed. The effect of CBD on the animal model of RA was determined. 

Results: Compared to oil solution, the emulsion exhibited higher absolute oral bioavailability. Significant lymphatic transport of CBD was observed in all formulations and the concentrations in lymph were calculated. The therapeutic effect of CBD on RA was confirmed as an improvement in clinical symptoms as well as morphological signs of disease activity were observed during the study. 

Conclusion: In this work, we prepared a simple stable emulsion formulation, determined the pharmacokinetic parameters of CBD and calculated its absolute bioavailability in rats. Moreover, we successfully tested the pharmaceutical application of such a formulation and demonstrated the positive effect of CBD in an animal model of RA.”

https://pubmed.ncbi.nlm.nih.gov/36342775/

https://www.liebertpub.com/doi/10.1089/can.2022.0176

Cannabidiol as a treatment for arthritis and joint pain: an exploratory cross-sectional study

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“Introduction: An estimated 54 million Americans currently suffer from debilitating arthritis. Patients who have exhausted conservative measures can be subject to chronic pain and resort to symptomatic management with anti-inflammatories, acetaminophen, and opioids. Cannabidiol (CBD) is a non-psychoactive cannabinoid that has shown promise in preclinical studies to reduce inflammation and pain associated with arthritis. The purpose of this study was to explore patient perceived effects of cannabidiol on symptoms of arthritis.

Methods: A novel anonymous questionnaire was created to evaluate perceived efficacy of cannabidiol for the treatment of arthritis. A self-selected convenience sample (N=428) was recruited through online methods including social media accounts and newsletters (The Arthritis Foundation and Savvy Cooperative) between May 5, 2020, and November 5, 2020. Statistical analysis was performed to determine differences between types of arthritis and improvements in quality-of-life symptoms. Furthermore, a regression analysis was performed to identify variables associated with decreasing or discontinuing other medications.

Results: CBD use was associated with improvements in pain (83%), physical function (66%), and sleep quality (66%). Subgroup analysis by diagnosis type (osteoarthritis, rheumatoid, or other autoimmune arthritis) found improvements among groups for physical function (P=0.013), favoring the osteoarthritis group. The overall cohort reported a 44% reduction in pain after CBD use (P<0.001). The osteoarthritis group had a greater percentage reduction (P=0.020) and point reduction (P<0.001) in pain compared to rheumatoid arthritis and other autoimmune arthritis. The majority of respondents reported a reduction or cessation of other medications after CBD use (N=259, 60.5%): reductions in anti-inflammatories (N=129, 31.1%), acetaminophen (N=78, 18.2%), opioids (N=36, 8.6%) and discontinuation of anti-inflammatories (N=76, 17.8%), acetaminophen (N=76, 17.8%), and opioids (N=81, 18.9%).

Conclusion: Clinicians and patients should be aware of the various alternative therapeutic options available to treat their symptoms of arthritis, especially in light of the increased accessibility to cannabidiol products. The present study found associations between CBD use and improvements in patient’s arthritis symptoms and reductions in other medications. Future research should focus on exploring the benefits of CBD use in this patient population with clinical trials.”

https://pubmed.ncbi.nlm.nih.gov/35999581/

“The present study, while exploratory in nature, suggests there may be therapeutic benefits to CBD use and highlights the need for research in a field where the science lags behind popular use.”

https://jcannabisresearch.biomedcentral.com/articles/10.1186/s42238-022-00154-9

Cannabidiol: Influence on B Cells, Peripheral Blood Mononuclear Cells, and Peripheral Blood Mononuclear Cell/Rheumatoid Arthritis Synovial Fibroblast Cocultures

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“Background: Cannabidiol (CBD), one major nonintoxicating phytocannabinoid from Cannabis sativa demonstrated anti-inflammatory effects in animal models of several inflammatory conditions, including arthritis. However, it is still unknown which cell types mediate these anti-inflammatory effects of CBD, and, since CBD binds to a plethora of receptors and enzymes, it is complicated to pinpoint its mechanism of action. In this study, we elucidate the effects of CBD on B cells and peripheral blood mononuclear cells (PBMCs) in respect to survival, calcium mobilization, drug uptake, and cytokine (IL-6, IL-10, and TNF) and immunoglobulin production. 

Methods: Modulation of intracellular calcium and drug uptake in B cells was determined by using the fluorescent dyes Cal-520 and PoPo3, respectively. Cytokine and immunoglobulin production was evaluated by enzyme-linked immunosorbent assay. PBMC composition and B cell survival after CBD treatment was assessed by flow cytometry. 

Results: B cells express two major target receptors for CBD, TRPV2 (transient receptor potential vanilloid 2) and TRPA1 (transient receptor potential ankyrin 1), which are not regulated by B cell activation. CBD increased intracellular calcium levels in mouse and human B cells, which was accompanied by enhanced uptake of PoPo3. These effects were not dependent on transient receptor potential channel activation. CBD increased the number of early apoptotic B cells at the expense of viable cells and diminished interleukin (IL)-10 and tumor necrosis factor (TNF) production when activated T cell independently. In PBMCs, CBD increased IL-10 production when B cells were activated T cell dependent, while decreasing TNF levels when activated T cell independently. In PBMC/rheumatoid synovial fibroblast cocultures, CBD reduced IL-10 production when B cells were activated T cell independently. Immunoglobulin M production was augmented by CBD when B cells were activated with CpG. 

Conclusion: CBD is able to provide pro- and anti-inflammatory effects in isolated B cells and PBMCs. This is dependent on the activating stimulus (T cell dependent or independent) and concentration of CBD. Therefore, CBD might be used to dampen B cell activity in autoimmune conditions such as rheumatoid arthritis, in which B cells are activated by specific autoantigens.”

https://pubmed.ncbi.nlm.nih.gov/35920857/

https://www.liebertpub.com/doi/10.1089/can.2021.0241

Impact of Δ 9-Tetrahydrocannabinol on Rheumatoid Arthritis Synovial Fibroblasts Alone and in Co-Culture with Peripheral Blood Mononuclear Cells

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“δ9-Tetrahydrocannabinol (THC) has demonstrated anti-inflammatory effects in animal models of arthritis, but its mechanism of action and cellular targets are still unclear. The purpose of this study is to elucidate the effects of THC (0.1-25 µM) on synovial fibroblasts from patients with rheumatoid arthritis (RASF) and peripheral blood mononuclear cells (PBMC) from healthy donors in respect to proliferation, calcium mobilization, drug uptake, cytokine and immunoglobulin production. Intracellular calcium and drug uptake were determined by fluorescent dyes Cal-520 and PoPo3, respectively. Cytokine and immunoglobulin production were evaluated by ELISA. Cannabinoid receptors 1 and 2 (CB1 and CB2) were detected by flow cytometry. RASF express CB1 and CB2 and the latter was increased by tumor necrosis factor (TNF). In RASF, THC (≥5 µM) increased intracellular calcium levels/PoPo3 uptake in a TRPA1-dependent manner and reduced interleukin-8 (IL-8) and matrix metalloprotease 3 (MMP-3) production at high concentrations (25 µM). Proliferation was slightly enhanced at intermediate THC concentrations (1-10 µM) but was completely abrogated at 25 µM. In PBMC alone, THC decreased interleukin-10 (IL-10) production and increased immunoglobulin G (IgG). In PBMC/RASF co-culture, THC decreased TNF production when cells were stimulated with interferon-γ (IFN-γ) or CpG. THC provides pro- and anti-inflammatory effects in RASF and PBMC. This is dependent on the activating stimulus and concentration of THC. Therefore, THC might be used to treat inflammation in RA but it might need titrating to determine the effective concentration.”

https://pubmed.ncbi.nlm.nih.gov/35625855/

https://www.mdpi.com/2227-9059/10/5/1118