A new study published by the journal International Immunopharmacology found that combining cannabidiol (CBD) with methotrexate may improve treatment outcomes for rheumatoid arthritis while also reducing some of methotrexate’s harmful side effects.

Researchers from the Chinese Academy of Medical Sciences and Peking Union Medical College examined whether CBD could work alongside methotrexate, a commonly used treatment for rheumatoid arthritis that can cause dose-dependent adverse effects including liver damage, gastrointestinal issues and reproductive toxicity.

Using a mouse model of rheumatoid arthritis, the researchers compared methotrexate alone at low, medium and high doses with combinations of CBD and methotrexate at the same dosing levels. They found that the CBD-methotrexate combinations produced dose-dependent improvements, with the combined treatment reducing joint swelling, inflammation and bone erosion more effectively than methotrexate alone.

Notably, the medium-dose combination came close to matching the effects of high-dose methotrexate by itself. That suggests CBD may have a dose-sparing effect, potentially allowing for lower doses of methotrexate while maintaining similar therapeutic benefits.

The study also found that CBD appeared to protect against methotrexate-induced testicular toxicity and spermatogenic failure, a finding that could prove important given concerns over the drug’s impact on reproductive health.

According to the researchers, the combination worked by reducing M1 macrophage polarization and lowering levels of key inflammatory cytokines including TNF-α, IL-6 and IL-1β. The treatment did this by suppressing STAT3 and NF-κB signaling, two pathways strongly associated with inflammation.

Although the findings are limited to animal research and do not establish the same effects in humans, the results provide early evidence that CBD could enhance methotrexate’s anti-arthritis activity while offsetting some of its toxicity. The researchers say this supports further investigation into the combination as a potential treatment strategy for rheumatoid arthritis.