Antidepressant effects of artemisinin and its derivatives: a systematic review and meta-analysis of randomized controlled animal studies.

Introduction: Depression imposes a substantial global disease burden. Current pharmacotherapies are often limited by a delayed onset of action, significant adverse effects, and high costs. Preclinical studies have indicated that artemisinin and its derivatives possess neuroprotective and anti-inflammatory properties and have demonstrated antidepressant-like effects in rodent models. However, no meta-analysis has yet been performed on these preclinical rodent studies. This study aimed to systematically evaluate the antidepressant efficacy of artemisinin in rodent models of depression-like behavior and to identify potential factors influencing the variability in treatment effects. Methods: This study systematically searched four databases (PubMed, Web of Science, Embase, and China National Knowledge Infrastructure), including randomized controlled trials (RCTs) published up to May 2026. All data were statistically analyzed using a random-effects model, yielding standardized mean differences (SMDs) with their 95% confidence intervals (CIs). Subgroup analyses were conducted based on rodent species, depression-like modeling methods, intervention timing, duration, and frequency. Publication bias was assessed using Egger's test, funnel plots, and trim-and-fill analyses. Sensitivity analyses were performed to evaluate result robustness. The risk of bias was evaluated using the Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE) tool, and the overall certainty of evidence was evaluated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework. Results: A total of 17 studies involving 402 rodents were included in the analysis. Compared with the control group, artemisinin reduced immobility in the TST and FST, increased sucrose preference in the SPT, alleviated anxiety-like behaviors in the OFT and EPM, and improved cognitive performance in the MWM, Y-maze, and NOR. Subgroup analyses identified intervention duration, frequency, species, modeling methods, and derivative type as impactful moderators. Sensitivity tests validated stable outcomes. While Egger's test hinted at publication bias in the OFT, TST, and FST datasets, trim-and-fill analyses imputed zero missing studies, although this does not fully exclude publication bias given the limited number of studies. Under the GRADE framework, the certainty of evidence was rated as very low for most outcomes due to high risk of bias, substantial heterogeneity, and indirectness. Discussion: Artemisinin can ameliorate depression-like and anxiety-like behaviors and improve cognitive function. These findings provide a basis for further investigation into artemisinin as an adjunctive therapeutic agent for depression. However, the certainty of evidence is very low due to methodological limitations in the included preclinical studies, and additional clinical trials are required to evaluate its efficacy in humans.