β-sitosterol reduces anxiety and synergizes with established anxiolytic drugs in mice

[nerd]

Highlights

1. In silico screen identifies β-sitosterol as a candidate anxiolytic drug
2. β-sitosterol is anxiolytic in both naive and chronically stressed mice
3. β-sitosterol alters the expression of immediate early genes
4. Sub-efficacious doses of β-sitosterol and fluoxetine synergize when combined

Abstract

Anxiety and stress-related conditions represent a significant health burden in modern society. Unfortunately, most anxiolytic drugs are prone to side effects, limiting their long-term usage. Here, we employ a bioinformatics screen to identify drugs for repurposing as anxiolytics. Comparison of drug-induced gene-expression profiles with the hippocampal transcriptome of an importin α5 mutant mouse model with reduced anxiety identifies the hypocholesterolemic agent β-sitosterol as a promising candidate. β-sitosterol activity is validated by both intraperitoneal and oral application in mice, revealing it as the only clear anxiolytic from five closely related phytosterols. β-sitosterol injection reduces the effects of restraint stress, contextual fear memory, and c-Fos activation in the prefrontal cortex and dentate gyrus. Moreover, synergistic anxiolysis is observed when combining sub-efficacious doses of β-sitosterol with the SSRI fluoxetine. These preclinical findings support further development of β-sitosterol, either as a standalone anxiolytic or in combination with low-dose SSRIs.

Nicolas Panayotis, Philip A. Freund, Letizia Marvaldi, Tali Shalit, Alexander Brandis, Tevie Mehlman, Michael M. Tsoory, Mike Fainzilber,
β-sitosterol reduces anxiety and synergizes with established anxiolytic drugs in mice, Cell Reports Medicine, Volume 2, Issue 5, 2021, 100281, ISSN 2666-3791, doi: 10.1016/j.xcrm.2021.100281

 

[nerd]

The dose for full anxiolytic efficacy was 100mg/kg. This is more than normally recommended to take. I'm not sure if it's proven to be safe for humans to take this much.

The dose for synergistic efficacy was 10 to 50 mg per kg. This is partially within the recommended margins for humans.