Skip to main content

Advertisement

SpringerLink
Log in

Effects of melatonin supplementation on disease activity, oxidative stress, inflammatory, and metabolic parameters in patients with rheumatoid arthritis: a randomized double-blind placebo-controlled trial

  • Original Article
  • Published:
Clinical Rheumatology Aims and scope Submit manuscript

Abstract

Objective

Considering the pathologic significance of inflammation and oxidative stress in rheumatoid arthritis (RA) as well as the antioxidant, anti-inflammatory and hypolipidemic effects of melatonin, the current research is designed to investigate the effect of melatonin supplementation on disease activity, oxidative stress, inflammatory, and metabolic parameters in RA patients.

Methods

In this randomized double-blind, placebo-controlled trial, 64 RA cases were selected and randomly assigned into 2 groups to take 6 mg/day melatonin or placebo for 12 weeks. Before and after trial, serum malondialdehyde (MDA), total antioxidant capacity (TAC), erythrocyte sedimentation rate (ESR), lipid profile, fasting blood sugar (FBS), and insulin levels were measured and disease activity was determined by disease activity score-28 (DAS-28).

Results

Compared to the baseline, melatonin significantly decreased DAS-28, ESR, MDA, and LDL-C by 50.5%, 59%, 97%, and 13%, respectively (P<0.001) and significantly increased TAC by 89% (P=0.013) and HDL-C by 22% (P<0.001). After treatment, considerable differences were only seen between the two groups in serum MDA (P<0.001) and LDL-C (P=0.007) concentrations, adjusted for baseline measures. Moreover, there were no significant changes in DAS-28, ESR, TAC, triglyceride, total cholesterol, HDL-C, FBS, and insulin levels compared to placebo group (P>0.05).

Conclusions

Although melatonin supplementation had no beneficial effects on DAS-28, it could lower serum MDA and LDL-C levels. It seems that melatonin supplementation should not be used as a replace for routine drugs prescribed in RA treatment. Further investigations should be conducted to fully understand the effects of melatonin in RA.

Key Points

• Compared to baseline, melatonin significantly decreased DAS-28, ESR, MDA, and LDL-C and significantly increased TAC and HDL-C.

• After treatment, considerable differences were only seen between melatonin and placebo groups in serum MDA and LDL-C concentrations.

• After treatment, there were no significant changes in DAS-28, ESR, TAC, triglyceride, total cholesterol, HDL-C, FBS, and insulin levels compared to the placebo group.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Silman AJ, Pearson JE (2002) Epidemiology and genetics of rheumatoid arthritis. Arthritis Res 4(Suppl 3):S265–S272

    Article  Google Scholar 

  2. Alamanos Y, Drosos AA (2005) Epidemiology of adult rheumatoid arthritis. Autoimmun Rev 4(3):130–136

    Article  Google Scholar 

  3. McInnes IB, Schett G (2011) The pathogenesis of rheumatoid arthritis. N Engl J Med 365(23):2205–2219

    Article  CAS  Google Scholar 

  4. Mateen S, Moin S, Khan AQ, Zafar A, Fatima N (2016) Increased reactive oxygen species formation and oxidative stress in rheumatoid arthritis. PLoS One 11(4):e0152925

    Article  Google Scholar 

  5. Hadjigogos K (2003) The role of free radicals in the pathogenesis of rheumatoid arthritis. Panminerva Medica 45(1):7–13

    CAS  PubMed  Google Scholar 

  6. Venetsanopoulou AI, Pelechas E, Voulgari PV, Drosos AA (2020) The lipid paradox in rheumatoid arthritis: the dark horse of the augmented cardiovascular risk. Rheumatol Int 40(3):1181–1191

    Article  Google Scholar 

  7. Hardeland R, Pandi-Perumal S, Cardinali DP (2006) Melatonin. Int J Biochem Cell Biol 38(3):313–316

    Article  CAS  Google Scholar 

  8. Afkhamizadeh M, Sahebari M, Seyyed-Hoseini SR (2014) Morning melatonin serum values do not correlate with disease activity in rheumatoid arthritis: a cross-sectional study. Rheumatol Int 34(8):1145–1151

    Article  CAS  Google Scholar 

  9. Maestroni GJ, Sulli A, Pizzorni C, Villaggio B, Cutolo M (2002) Melatonin in rheumatoid arthritis: synovial macrophages show melatonin receptors. Ann N Y Acad Sci 966:271–275

    Article  CAS  Google Scholar 

  10. Reiter RJ, Mayo JC, Tan DX, Sainz RM, Alatorre-Jimenez M, Qin L (2016) Melatonin as an antioxidant: under promises but over delivers. J Pineal Res 61(3):253–278

    Article  CAS  Google Scholar 

  11. Hosseinzadeh A, Kamrava SK, Joghataei MT, Darabi R, Shakeri-Zadeh A, Shahriari M, Reiter RJ, Ghaznavi H, Mehrzadi S (2016) Apoptosis signaling pathways in osteoarthritis and possible protective role of melatonin. J Pineal Res 61(4):411–425

    Article  CAS  Google Scholar 

  12. Galano A, Tan DX, Reiter RJ (2013) On the free radical scavenging activities of melatonin’s metabolites, AFMK and AMK. J Pineal Res 54(3):245–257

    Article  CAS  Google Scholar 

  13. Barlow-Walden L, Reiter R, Abe M, Pablos M, Menendez-Pelaez A, Chen L-D, Poeggeler B (1995) Melatonin stimulates brain glutathione peroxidase activity. Neurochem Int 26(5):497–502

    Article  CAS  Google Scholar 

  14. Rodriguez C, Mayo JC, Sainz RM, Antolin I, Herrera F, Martin V, Reiter RJ (2004) Regulation of antioxidant enzymes: a significant role for melatonin. J Pineal Res 36(1):1–9

    Article  CAS  Google Scholar 

  15. Tomás-Zapico C, Coto-Montes A (2005) A proposed mechanism to explain the stimulatory effect of melatonin on antioxidative enzymes. J Pineal Res 39(2):99–104

    Article  Google Scholar 

  16. Hussein MR, Ahmed OG, Hassan AF, Ahmed MA (2006) Intake of melatonin is associated with amelioration of physiological changes, both metabolic and morphological pathologies associated with obesity: an animal model. Int J Exp Pathol 88(1):19–29

    Article  Google Scholar 

  17. Cuzzocrea S, Reiter RJ (2002) Pharmacological actions of melatonin in acute and chronic inflammation. Curr Top Med Chem 2(2):153–165

    Article  CAS  Google Scholar 

  18. Radogna F, Diederich M, Ghibelli L (2010) Melatonin: a pleiotropic molecule regulating inflammation. Biochem Pharmaco 80(12):1844–1852

    Article  CAS  Google Scholar 

  19. Hussain SA (2007) Effect of melatonin on cholesterol absorption in rats. J Pineal Res 42(3):267–271

    Article  CAS  Google Scholar 

  20. Chan TY, Tang PL (1995) Effect of melatonin on the maintenance of cholesterol homeostasis in the rat. Endocr Res 21(3):681–696

    Article  CAS  Google Scholar 

  21. Müller-Wieland D, Behnke B, Koopmann K, Krone W (1994) Melatonin inhibits LDL receptor activity and cholesterol synthesis in freshly isolated human mononuclear leukocytes. Biochem Biophys Res Commun 203(1):416–421

    Article  Google Scholar 

  22. Dauchy RT, Blask DE, Sauer LA, Davidson LK, Krause JA, Smith LC, Dauchy EM (2003) Physiologic melatonin concentration, omega-3 fatty acids, and conjugated linoleic acid inhibit fatty acid transport in rodent hind limb skeletal muscle in vivo. Comp Med 53(2):186–190

    CAS  PubMed  Google Scholar 

  23. Tamura H, Nakamura Y, Narimatsu A, Yamagata Y, Takasaki A, Reiter RJ, Sugino N (2008) Melatonin treatment in peri- and postmenopausal women elevates serum high-density lipoprotein cholesterol levels without influencing total cholesterol levels. J Pineal Res 45(1):101–105

    Article  CAS  Google Scholar 

  24. Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO, Birnbaum NS, Burmester GR, Bykerk VP, Cohen MD, Combe B, Costenbader KH, Dougados M, Emery P, Ferraccioli G, Hazes JM, Hobbs K, Huizinga TW, Kavanaugh A, Kay J, Kvien TK, Laing T, Mease P, Ménard HA, Moreland LW, Naden RL, Pincus T, Smolen JS, Stanislawska-Biernat E, Symmons D, Tak PP, Upchurch KS, Vencovský J, Wolfe F, Hawker G (2010) 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum 62(9):2569–2581

    Article  Google Scholar 

  25. Hansson I, Holmdahl R, Mattsson R (1992) The pineal hormone melatonin exaggerates development of collagen-induced arthritis in mice. J Neuroimmunol 39:23–30

    Article  CAS  Google Scholar 

  26. Forrest CM, Mackay GM, Stoy N, Stone TW, Darlington LG (2007) Inflammatory status and kynurenine metabolism in rheumatoid arthritis treated with melatonin. Br J Clin Pharmacol 64(4):517–526

    Article  CAS  Google Scholar 

  27. Cutolo M, Maestroni G (2005) The melatonin–cytokine connection in rheumatoid arthritis. Ann Rheum Dis 64:1109–1111

    Article  CAS  Google Scholar 

  28. Cutolo M, Villaggio B, Otsa K et al (2005) Altered circadian rhythms in rheumatoid arthritis patients play a role in the disease’s symptoms. Autoimmun Rev 4:497–502

    Article  CAS  Google Scholar 

  29. El-Awady HM, El-Wakkad AS, Saleh MT, Muhammad SI, Ghaniema EM (2007) Serum melatonin in juvenile rheumatoid arthritis: correlation with disease activity. Pak J Biol Sci 10(9):1471–1476

    Article  CAS  Google Scholar 

  30. Jamilian M, Foroozanfard F, Mirhosseini N, Kavossian E, Aghadavod E, Bahmani F, Ostadmohammadi V, Kia M, Eftekhar T, Ayati E, Mahdavinia M, Asemi Z (2019) Effects of melatonin supplementation on hormonal, inflammatory, genetic, and oxidative stress parameters in women with polycystic ovary syndrome. Front Endocrinol 10:273

    Article  Google Scholar 

  31. Raygan F, Ostadmohammadi V, Bahmani F, Reiter RJ, Asemi Z (2019) Melatonin administration lowers biomarkers of oxidative stress and cardio-metabolic risk in type 2 diabetic patients with coronary heart disease: a randomized, double-blind, placebo-controlled trial. Clin Nutr 38(1):191–196

    Article  CAS  Google Scholar 

  32. Kedziora-Kornatowska K, Szewczyk-Golec K, Kozakiewicz M, Pawluk H, Czuczejko J, Kornatowski T, Bartosz G, Kedziora J (2009) Melatonin improves oxidative stress parameters measured in the blood of elderly type 2 diabetic patients. J Pineal Res 46(3):333–337

    Article  CAS  Google Scholar 

  33. Koziróg M, Poliwczak AR, Duchnowicz P, Koter-Michalak M, Sikora J, Broncel M (2011) Melatonin treatment improves blood pressure, lipid profile, and parameters of oxidative stress in patients with metabolic syndrome. J Pineal Res 50(3):261–266

    Article  Google Scholar 

  34. Alamdari NM, Mahdavi R, Roshanravan N, Yaghin NL, Ostadrahimi A, Faramarzi E (2015) A double-blind, placebo-controlled trial related to the effects of melatonin on oxidative stress and inflammatory parameters of obese women. Horm Metab Res 47(07):504–508

    Google Scholar 

  35. Szewczyk-Golec K, Rajewski P, Gackowski M, Mila-Kierzenkowska C, Wesołowski R, Sutkowy P, Pawłowska M, Woźniak A (2017) Melatonin supplementation lowers oxidative stress and regulates adipokines in obese patients on a calorie-restricted diet. Oxid Med Cell Longev 2017:1–11

  36. Adamczyk-Sowa M, Pierzchala K, Sowa P, Polaniak R, Kukla M, Hartel M (2014) Influence of melatonin supplementation on serum antioxidative properties and impact of the quality of life in multiple sclerosis patients. J Physiol Pharmacol 65(4):543–550

    CAS  PubMed  Google Scholar 

  37. Sánchez-López AL, Gabriel Ortiz G, Pacheco-Moises F, Mireles-Ramírez MA, Bitzer-Quintero OK, Delgado-Lara DLC, Ramírez-Jirano LJ, Velázquez-Brizuela IE (2018) Efficacy of melatonin on serum pro-inflammatory cytokines and oxidative stress markers in relapsing remitting multiple sclerosis. Arch Med Res 49(6):391–398

    Article  Google Scholar 

  38. Zhao CN, Wang P, Mao YM, Dan YL, Wu Q, Li XM, Wang DG, Davis C, Hu W, Pan HF (2019) Potential role of melatonin in autoimmune diseases. Cytokine Growth Factor Rev 48:1–10

    Article  CAS  Google Scholar 

  39. MRM M, Abbasian S, Khazaie M (2018) Melatonin and exercise: their effects on malondialdehyde and lipid peroxidation. In: Melatonin-Molecular Biology. Clinical and Pharmaceutical Approaches, IntechOpen

    Google Scholar 

  40. Longoni B, Salgo MG, Pryor WA, Marchiafava PL (1998) Effects of melatonin on lipid peroxidation induced by oxygen radicals. Life Sci 62(10):853–859

    Article  CAS  Google Scholar 

Download references

Funding

The current study was funded by a grant from the Vice-chancellor for Research, Kashan University of Medical Sciences, Kashan, Iran.

Author information

Author notes

  1. Alireza Khabbazi and Aida Malek Mahdavi contributed equally to this work.

Authors and Affiliations

  1. Autoimmune Diseases Research Center, Kashan University of Medical Sciences, Kashan, Iran

    Kamal Esalatmanesh, Amirhossein Loghman & Roozbeh Esalatmanesh

  2. Infectious Diseases Research Center, Kashan University of Medical Sciences, Kashan, Iran

    Zahra Soleimani

  3. Connective Tissue Diseases Research Center, Tabriz University of Medical Sciences, Golgasht St, P.O Box 5166614756, Tabriz, Iran

    Alireza Khabbazi & Aida Malek Mahdavi

  4. Department of Statistics and Public Health, Faculty of Health, Kashan University of Medical Sciences, Kashan, Iran

    Seyed Gholam Abbas Mousavi

Authors
  1. Kamal Esalatmanesh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Amirhossein Loghman
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Roozbeh Esalatmanesh
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zahra Soleimani
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Alireza Khabbazi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Aida Malek Mahdavi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Seyed Gholam Abbas Mousavi
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

KE, AL, RE, ZS, and AKH designed the study; KE, RE, AL, ZS, and AKH were involved in the data acquisition and/or management; KE, AKH, and AMM analyzed the data and critically interpreted the results; KE, AL, RE, AKH, and AMM were involved in drafting the manuscript. All authors revised the manuscript critically for important intellectual content and approved the final manuscript.

Corresponding authors

Correspondence to Alireza Khabbazi or Aida Malek Mahdavi.

Ethics declarations

Disclosures

None.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Esalatmanesh, K., Loghman, A., Esalatmanesh, R. et al. Effects of melatonin supplementation on disease activity, oxidative stress, inflammatory, and metabolic parameters in patients with rheumatoid arthritis: a randomized double-blind placebo-controlled trial. Clin Rheumatol 40, 3591–3597 (2021). https://doi.org/10.1007/s10067-021-05670-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10067-021-05670-2

Keywords

Search

Navigation