Machado, J. A.; Araujo, D. B.; Lima-Maximino, M.; de Siqueira-Silva, D. H.; Tomchinsky, B.; Cueto-Escobedo, J.; Rodriguez-Landa, J. F.; Maximino, C.

Flavonoids are natural secondary compounds of plants with a basic composition derived from polyphenols that can produce a plethora of different neurochemical effects, some of which are relevant to anxiety disorders. As such, many flavonoids have been evaluated in behavioral screens in preclinical research on anxiolytics. Given the many different molecular subclasses of flavonoids, the many different molecular targets that have been proposed for these compounds, and the different research priorities that arise in preclinical research, we sought to map the potential of flavonoids as anxiolytics by bibliometric analysis and a meta-analysis of animal tests using these compounds. Bibliometric analysis suggest that the field is highly concentrated on few research groups that are 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 anxioselective effects and looking for dose-response patterns; this suggests that the field, as a whole, could benefit from more mechanistic and confirmatory research. 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 = -1.4398, 95%CI[-1.7319, -1.1477]). Subgroup analysis suggested that this effect is present in acute treatment (SMD = -1.14, 95%CI[-1.36, -0.93]), but not after chronic treatment (SMD = -1.96, 95%CI[-4.93; 1.01]). For all molecule subclasses included in the study, only isoflavones, glycoside derivatives, and flavanolignans did not show evidence of an anxiolytic-like effect, although the low number of studies including these subclasses is low. We finish with a set of recommendations for preclinical research on the anxiolytic potential of flavonoids.