Flavonoids as Anxiolytics in Animal Tests: Systematic Review, Meta‐Analysis, and Bibliometrical Analysis

Flavonoids are natural secondary metabolites of plants with a basic composition derived from polyphenols that can produce a plethora of different neurophysiological effects, some of which are relevant to anxiety disorders. As such, many flavonoids have been evaluated in behavioral screens in preclinical research on anxiolytics. We sought to map the potential of flavonoids as anxiolytics by bibliometric analysis and a systematic review and meta-analysis of animal tests using these compounds. Bibliometric analysis suggests that the field is highly concentrated on a few research groups mostly located in the Global South, suggesting the need to improve international collaborations. The themes which emerged in the bibliometric analysis are driven by the exploratory steps of pharmacological research, including finding anxio-selective effects and looking for dose-response patterns. This suggests that the field, as a whole, could benefit from more mechanistic and confirmatory research. The systematic review included 38 articles, with a total of k = 183 comparisons, comprising 43 different molecules. The meta-analysis showed strong evidence for an anxiolytic-like effect of flavonoids on animal tests, including assays made in rats, mice, and zebrafish (SMD = -1.457, 95% CI [-1.365 to -0.9264]). Subgroup analysis suggested that this effect is present in acute treatment (SMD = -1.0985 (95% CI: -1.31 to -0.88)), but not after chronic treatment (SMD = -1.96, 95% CI [-4.93; 1.01]). Study quality was overall moderate. We finish with a set of recommendations for preclinical research on the anxiolytic potential of flavonoids.