CBD's Anti-Inflammatory Effects and Arthritis

Medical marijuana can currently be recommended to treat rheumatoid arthritis in multiple states. However, a new study published in Cell Death & Disease reports that the anti-inflammatory effects of cannabidiol (CBD) may also be beneficial in treating arthritis due to a previously unknown mechanism of action.


According to the authors of the paper, “CBD increases intracellular calcium levels, reduces cell viability and IL-6/IL-8/MMP-3 production of rheumatoid arthritis synovial fibroblasts (RASF).” Subsets of RASF have been found to be major contributors to join destruction via the secretion of pro-inflammatory cytokines (interleukin-6 (IL-6) and interleukin-8 (IL-8)) and matrix degrading enzymes (matrix metalloproteinase-3 (MMP-3)).


The primary therapeutic target of this mechanism of action has been identified as the TRPA1 receptor. CBD is a known TRPA1 agonist. By increasing TRPA1 protein via TNF pre-stimulation, the researchers were able to augment CBD's effects.


The authors propose the following mechanism of how CBD influences RASF functionality and promotes cell death when pro-inflammatory conditions are induced:


TNF increases TRPA1 protein, which is located in intracellular compartments. CBD activates TRPA1 and Ca2+ is released into the cytosol. Elevations in cytosolic Ca2+ are reduced through uptake into mitochondria. In addition, increased cytosolic Ca2+ might enhance the activity of organic cation transporters (OCT) which might mediate the uptake of the fluorescent dye PoPo3. Additionally, OCT might mediate the uptake of CBD itself. By binding to VDAC1, CBD increases Ca2+ flux through the outer mitochondrial membrane. Ca2+ is then taken up into the matrix by the mitochondrial Ca2+ uniporter (MCU) and, if mitochondria are depolarized, by the Na+/Ca2+ exchanger (NCLX), which operates in reverse mode under these conditions. Ca2+ overload occurs, the mitochondrial permeability transition pore (mPTP) assembles and cell death occurs.


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