Clin Exp Pharmacol Physiol. 2021;48:1059–1069. wileyonlinelibrary.com/journal/cep | 1059 © 2021 John Wiley & Sons Australia, Ltd Received: 25 December 2020 | Revised: 6 March 2021 | Accepted: 21 April 2021 DOI: 10.1111/1440-1681.13510 REVIEW ARTICLE Spirulina supplementation and oxidative stress and pro- inflammatory biomarkers: A systematic review and meta- analysis of controlled clinical trials Sara Mohiti 1 | Meysam Zarezadeh 2,3 | Fatemeh Naeini 4 | Helda Tutunchi 3 | Alireza Ostadrahimi 3 | Zohreh Ghoreishi 3 | Mehrangiz Ebrahimi Mamaghani 1 Abbreviations: BDNF, brain-derived neurotrophic factor; BMI, body mass index; COPD, chronic obstructive pulmonary disease; COX-2, cyclooxygenase-2; H 2 O 2 , hydrogen peroxide; HO, hydroxyl radical; HOO, peroxyl radicals; IkB, inhibitor of nuclear factor kappa B; IL-2, interleukin-2; IL-6, interleukin-6; iNOS, inducible nitric oxide synthase; JNK, c-Jun N-terminal kinase; MCP-1, monocyte chemoattractant protein--1; MDA, malondialdehyde; NADPH, nicotinamide adenine dinucleotide phosphate hydrogen; NF- κB, nuclear transcription factor κB; NO, nitric oxide; O 2 , superoxide anion radical; Pc, phytocyanin; p-CREB, p-cAMP response element-binding protein; RNS, reactive nitrogen species; ROS, reactive oxygen species; SMD, standardized mean difference; TBARS, thiobarbituric acid reactive substances; TNF- α, tumour necrosis factor- α. 1 Nutrition Research Center, Department of Biochemistry and Diet Therapy, School of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran 2 Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran 3 Nutrition Research Center, Department of Clinical Nutrition, School of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran 4 Department of Clinical Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Science, Tehran, Iran Correspondence Meysam Zarezadeh, Nutritional Sciences, School of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Attar-Neishaburi St., Golgasht Alley, Azadi Blvd., Tabriz, Iran. Email: meysam.za93@gmail.com Funding information Student Research Committee, Tabriz University of Medical Sciences, Grant/ Award Number: 66477 Abstract Studies investigating the effects of spirulina on inflammation and oxidative stress status are controversial. Therefore, the current systematic review and meta-analysis aimed to evaluate the impacts of spirulina supplementation on oxidative stress indica- tors and inflammatory markers. PubMed-Medline, SCOPUS, Web of Science, Embase databases and Google Scholar were searched up to 1 October 2020. Random-effect analysis was applied to perform meta-analysis. Subgroup analyses and multivariate meta-regression were performed to find heterogeneity sources. Quality assessment was conducted using Cochrane Collaboration’s tool. A total of 11 studies that enrolled 465 subjects were included in our meta-analysis. Pooled results demonstrated a sig- nificant increase in interleukin-2 (IL-2) concentrations [Standardized mean difference (SMD = 2.69 pg/mL; 95% CI: 0.26, 5.11; P = .03)]; however this result changed to insignificant (SMD = 0.54 pg/mL; 95% CI: −1.29, 2.27; P > .05) when sensitivity analy- sis performed. A marginal decreasing effect were also found on interleukin-6 (IL-6) (SMD = −0.72 mg/dL; 95% CI: −1.50, 0.07; P = .073) and thiobarbituric acid reactive substances (TBARS) levels (SMD = −0.65; 95% CI: −1.37, 0.08; P = .08). In addition, results of subgroup analysis revealed a significant reduction in IL-6 and TBARS con- centrations when the baseline body mass index (BMI) of participants was lower than 25 kg/m 2 . Moreover, spirulina had no significant effect on tumour necrosis factor- α (TNF- α) (SMD = −0.07 mg/dL; 95% CI: −0.33, 0.18; P = .56) and malondialdehyde (MDA) concentrations (SMD = −0.42; 95% CI: −0.98, 0.14; P = .14). Spirulina con- sumption contributed to a significant increase in IL-2 concentrations changing to insig- nificant after sensitivity analysis and marginal decreasing effects on IL-6 and TBARS levels. No considerable impacts were observed on TNF- α and MDA concentrations. KEYWORDS inflammation, meta-analysis, oxidative stress, spirulina, systematic review