Written by Keely Puchalski, ND. Results from this study suggest that adjunctive silymarin supplementation may improve joint symptoms, physical function, fatigue, and mood in patients with active rheumatoid arthritis receiving conventional DMARD therapy, though without significant changes in inflammatory markers CRP or ESR.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent synovial inflammation, joint pain, and progressive disability¹. Despite conventional treatments, many patients continue to experience fatigue, mood disorders, and high disease burden^1,2. Oxidative stress and inflammatory cytokine activity are central to RA pathogenesis³. Silymarin, a flavonolignan complex extracted from the fruits of Silybum marianum (L.) Gaertn., also known as milk thistle, is well known for its hepatoprotective, regenerative, antioxidant, and anti-inflammatory effects and is widely used as an herbal medication or nutritional supplement^4-6. Previous clinical studies have suggested potential benefits in joint disease^4,7-9.

To evaluate silymarin’s therapeutic potential in RA, Zugravu et al. (2024) conducted a randomized, controlled, parallel-group trial of 122 enrolled Romanian adults with active RA, defined as DAS28-CRP >3.2 (a disease activity score that measures the number of swollen and tender joints, CRP levels, and patient-reported symptoms; a score above 3.2 indicates moderate to high disease activity). Patients were diagnosed using the 2010 ACR/EULAR criteria and had RA for an average of 5 years. Inclusion criteria required that all participants had ceased steroid and NSAID use at least one month prior and were taking conventional DMARDs (methotrexate, leflunomide, sulfasalazine, hydroxychloroquine, or azathioprine) as monotherapy or in two- or three-drug combinations. Participants were randomized to receive either a standardized silymarin extract called Silymarin Forte (Zenyth Pharmaceuticals) with 375 mg of extract containing 300 mg silymarin, once daily for 8 weeks (intervention arm), or continue DMARD therapy alone (control arm).

After 7 patients withdrew (5 control, 2 intervention), a total of 115 patients completed the study. Primary outcomes were changes in disease activity scores (DAS28-ESR/CRP, CDAI, SDAI) and disability physical function (HAQ-DI). Secondary outcomes included changes in fatigue (VAS-F), depression (BDI-II), and anxiety (GAD-7). Tender joint count (TJC28), swollen joint count (SJC28), morning stiffness time (min), and pain (VAS) were also assessed. Both physician (PhGA) and patient (PtGA) global assessments were included. The control and intervention groups did not differ significantly in baseline characteristics including age, gender, BMI, smoking status, RA duration/stage, functional capacity, comorbidities, or RF positivity (p > 0.05). However, pain intensity, PtGA, and PhGA were significantly higher in the intervention group at baseline (p < 0.05). No significant baseline differences were found in CRP, ESR, TJC28, SJC28, or morning stiffness (p > 0.05). Statistical analysis was done with SPSS 25. Normality was tested using Kolmogorov–Smirnov. Independent and paired t-tests compared groups and time points, Chi-square tested categorical variables, and Pearson’s correlation assessed relationships between disease activity and symptom scores. A two-step cluster analysis was also used. Significance was set at p ≤ 0.05.

Key findings from the study at 8 weeks included:

• Tender and swollen joint counts significantly reduced in the silymarin group compared to both baseline and control (p < 0.001).
• Morning stiffness duration showed modest but significant improvement in the intervention group compared to both baseline (p < 0.002) and control (p < 0.001).

• Pain severity improved significantly in the intervention group compared to both baseline and control (p < 0.001).
• Disease activity scores (DAS28-ESR, DAS28-CRP, SDAI, CDAI) significantly decreased in the silymarin group compared to both baseline and control (p < 0.001).
• HAQ-DI scores improved significantly versus both baseline and control (p < 0.001). The intervention group still reported moderate to severe disability at the end of the study, but their scores had improved while those in the control group had worsened compared to baseline (p < 0.05), demonstrating severe to very severe disability.
• Fatigue (VAS-F), depression (BDI-II), and anxiety (GAD-7) scores improved significantly in the silymarin group compared to both baseline and control (p < 0.001). The correlations between the above disease activity indices and mood scores were weak and not statistically significant.
• CRP and ESR levels did not change significantly in either group.

This study has several strengths, including a defined population and use of both subjective and objective measures. However, key limitations include its small sample size, single-center design, short duration, and lack of a placebo group—making it hard to attribute effects directly to silymarin. While the authors cite anti-inflammatory effects, neither CRP nor ESR decreased, which is unexpected given how quickly these markers typically respond to treatment¹⁰. Other issues include reporting inconsistencies, misleading p-values (e.g., p = 0.000), and limited statistical rigor for such a small sample. Despite improvements in disease activity and mood scores, correlations between them were weak, suggesting individual variability. Additional time points might have better captured mood shifts. Silymarin was generally well tolerated, though adverse event data were not clearly reported.

Overall, this pilot study offers promising evidence that silymarin may be a helpful adjunct to conventional DMARDs in active RA by improving disease activity and quality of life measures, including mood and fatigue. Further large-scale, placebo-controlled trials of longer duration, ideally with mid-point assessments, will be needed to validate these findings and assess trajectory of change more clearly.

Source: Zugravu, Georgeta Stefanovici, Carmen Pintilescu, Carmen-Marinela Cumpat, Sorin Dan Miron, and Anca Miron. “Silymarin supplementation in active rheumatoid arthritis: Outcomes of a pilot randomized controlled clinical study.” Medicina 60, no. 6 (2024): 999.

© 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/
4.0/).

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Posted July 23, 2025.

Keely Puchalski, ND, is a naturopathic physician and natural products expert specializing in integrative psychiatry, gut health, and chronic illness. She earned her ND from Sonoran University of Health Sciences (formerly Southwest College of Naturopathic Medicine) in 2020. She co-founded Restored Counseling & Wellness Center in Gilbert, AZ where she practices with a team of therapists and naturopathic doctors:  https://restoredcw.com

References:

1. Smolen JS, Aletaha D, McInnes IB. Rheumatoid arthritis. Lancet. Oct 22 2016;388(10055):2023-2038. doi:10.1016/s0140-6736(16)30173-8
2. Radu AF, Bungau SG. Management of Rheumatoid Arthritis: An Overview. Cells. Oct 23 2021;10(11)doi:10.3390/cells10112857
3. Choudhary M, Kumar V, Malhotra H, Singh S. Medicinal plants with potential anti-arthritic activity. J Intercult Ethnopharmacol. Apr-Jun 2015;4(2):147-79. doi:10.5455/jice.20150313021918
4. Shavandi M, Moini A, Shakiba Y, et al. Silymarin (Livergol®) Decreases Disease Activity Score in Patients with Rheumatoid Arthritis: A Non-randomized Single-arm Clinical Trial. Iran J Allergy Asthma Immunol. Apr 2017;16(2):99-106.
5. Scapagnini G, Davinelli S, Drago F, De Lorenzo A, Oriani G. Antioxidants as antidepressants: fact or fiction? CNS Drugs. Jun 1 2012;26(6):477-90. doi:10.2165/11633190-000000000-00000
6. Hussain G, Zhang L, Rasul A, et al. Role of Plant-Derived Flavonoids and Their Mechanism in Attenuation of Alzheimer’s and Parkinson’s Diseases: An Update of Recent Data. Molecules. Apr 2 2018;23(4)doi:10.3390/molecules23040814
7. Numan IT, Hussain SA-R, Abdullah TA, Jasim NA. Evaluation of the clinical use of silymarin in knee osteoarthritis: application of the dual inhibitory concept of cyclooxygenase and 5-lipoxygenase. IPMJ. 2007;6:333-40.
8. Hussain SA, Jassim NA, Numan IT, Al K, II, Abdullah TA. Anti-inflammatory activity of silymarin in patients with knee osteoarthritis. A comparative study with piroxicam and meloxicam. Saudi Med J. Jan 2009;30(1):98-103.
9. Shavandi M, Yazdani Y, Asar S, Mohammadi A, Mohammadi-Noori E, Kiani A. The Effect of Oral Administration of Silymarin on Serum Levels of Tumor Necrosis Factor-α and Interleukin-1ß in Patients with Rheumatoid Arthritis. Iran J Immunol. Dec 2022;19(4):427-435. doi:10.22034/iji.2022.90456.2007
10. Aletaha D, Smolen JS. Diagnosis and Management of Rheumatoid Arthritis: A Review. Jama. Oct 2 2018;320(13):1360-1372. doi:10.1001/jama.2018.13103