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Context: Saffron, a natural remedy with potential antidepressant and anxiolytic properties, has gained attention as a potential therapeutic option., Objective: This systematic review and meta-analysis aimed to evaluate the comparative effectiveness of saffron versus selective serotonin reuptake inhibitors (SSRIs) in treating depression and anxiety., Data Source: Electronic databases, including PubMed, Embase, Scopus, Web of Science, and the Cochrane database, were searched from inception to April 31, 2023., Data Extraction: Randomized controlled trials (RCTs) comparing saffron intervention with SSRIs in adults with depression or anxiety were included., Data Analysis: Random-effects meta-analysis using standardized mean differences (SMDs) and risk ratio (RRs) with their 95% CIs calculated continuous and binary outcomes, respectively. Meta-analysis of 8 studies assessing depression outcomes revealed a nonsignificant difference between saffron and SSRIs in reducing depressive symptoms (SMD = 0.10l 95% CI: -0.09 to 0.29). Four studies reporting anxiety outcomes showed a nonsignificant difference between saffron and SSRIs in reducing anxiety symptoms (SMD = 0.04; 95% CI: -0.22 to 0.29). With regard to safety, participants receiving saffron had fewer adverse events than the SSRI group (risk difference: -0.06; 95% CI: -0.09, -0.04; I2: 0%)., Conclusion: Saffron could be a potential SSRI alternative to reduce depressive and anxiety symptoms with fewer adverse events. Further research with larger sample sizes and in diverse populations is warranted to validate these findings and explore potential moderators of treatment response., Systematic Review Registration: PROSPERO registration no. CRD42023443236., (© The Author(s) 2024. Published by Oxford University Press on behalf of the International Life Sciences Institute. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)