Influence of the Cannabinoids Anandamide and Cannabidiol on Cytokine Production by CD4+ T Cells and Th17 Differentiation in Patients with Rheumatoid Arthritis

This work is based on investigations into the effects of cannabinoids such as cannabidiol (CBD) and anandamide (AEA) on phenotypic changes in cluster of differentiation 4-positive (CD4+) T cells from patients suffering from rheumatic autoimmune diseases, particularly rheumatoid arthritis (RA). Cannabinoids such as CBD are becoming increasingly prevalent in society and are often recommended for the treatment of various conditions, including RA. This is further underscored by the new German Cannabis Act (CanG), which regulates the handling of cannabis as of April 1, 2024, and, among other changes, eased access to medicinal cannabis. This is expected to further increase public acceptance and unsupervised use of cannabis and its derivatives. Additionally, the anticipated analgesic properties of CBD have led to increased use among RA patients seeking alternatives or supplements to their existing pain management plans. Given this growing prevalence of CBD use, often without medical supervision, it is clear that a better understanding of the full spectrum of CBD effects is necessary. Only in this way can patients be adequately informed about the benefits and risks associated with incorporating CBD into their existing medication plans. Alongside the increasing prevalence of cannabinoid use, our understanding of RA as a disease is also advancing. While the focus of RA research was initially on T helper 1 (Th1) cells, T helper 17 (Th17) cells and their interplay with regulatory T (Treg) cells are gaining importance as potential key players in the pathogenesis of RA. This enables a more precise investigation of potential therapeutics like CBD and their effects on RA-specific pathomechanisms. Our knowledge regarding the influence of CBD on Th17 cells and its significance in the context of RA is still incomplete. The aim of this work is to gain a deeper understanding of the effects of cannabinoids on Th17 differentiation and Interleukin-17A (IL-17A) positivity. With this objective, comprehensive in vitro studies were conducted to establish direct relationships between cannabinoid exposure and CD4+ T cell properties. Analysis of cannabinoid receptors 1 and 2 (CB1, CB2) showed no significant differences between RA patients and healthy controls, though a notable trend toward increased G-protein coupled receptor 55 (GPR55) expression was observed in RA and psoriatic arthritis patients. The results demonstrate that CBD significantly reduced CD4+ T cell viability while paradoxically increasing the proportion of IL-17A-positive cells, particularly in RA patients. This effect persisted even under Th17-polarizing conditions. Gene expression analysis revealed that CBD significantly upregulated serum glucocorticoid-regulated kinase 1 (SGK1) while downregulating colony stimulating factor 2 (CSF2) in RA patients, suggesting complex modulation of inflammation-related pathways. Despite increased cellular IL-17A positivity, ELISA analysis showed reduced secretion of IL-17A, interferon gamma (IFN-γ), and tumor necrosis factor alpha (TNF-α) in culture supernatants, potentially due to the substantial cytotoxic effects observed. Importantly, preliminary observational data from patients self-reporting non-standardized CBD use showed both increased IL-17A-positive CD4+ T cell percentages and elevated disease activity scores, aligning with our in vitro findings. Although CBD was able to reduce TNF-α- and IFN-γ-positive CD4+ T cells, our understanding of RA as an increasingly Th17 cell-mediated disease suggests that CBD use in RA patients could be detrimental from an autoimmunity perspective. This is primarily due to the finding that CBD led to an increased proportion of IL-17A-positive cells among CD4+ T cells, which should be taken into account when considering recommending CBD as a therapy supplement. However, further studies are required to understand the mechanism of action leading to the effects observed here. In vivo mouse studies should also be conducted to better understand the effects of CBD consumption in relation to the multiple and complex interactions within the body. It is also essential to analyze the extent to which the in vitro results presented here can be translated directly to patients given the high doses of CBD used in these experiments. So far, the data is not sufficient to unreservedly recommend CBD as a treatment approach for RA patients. Further studies are necessary to evaluate the potential and risks of cannabinoids in RA therapy and to make a recommendation for RA therapy.