Usnea lichens and purified usnic acids have been used historically in traditional herbal medicine as bactericidal and antimicrobial agents. Usnea lichens contain 1%–3% (+/−)-usnic acid and extracts of these lichens are currently marketed in the United States as herbal antimicrobial agents. (+/−)-Usnic acid exhibits membrane proton uncoupling activity, which not only forms the mechanistic basis of its bactericidal action, but also has provided a rationale for its use as a fat burning, weight-loss agent. Purified (+)-usnic acid has been marketed in the United States for this purpose either alone or in combination with other chemical agents. Use of some of these fat burning products that contain (+)-usnic acid has resulted in serious liver damage. This study investigated the potential toxicity of ground Usnea lichens containing (+/−)-usnic acid in male and female Fischer 344/N Nctr rats and B6C3F1/Nctr mice that were exposed via feed for 3 months. F344/N Nctr rats were administered 0, 30, 60, 120, 360, or 720 ppm in feed, while B6C3F1/Nctr mice were administered 0, 15, 30, 60, 180, or 360 ppm in feed.
Exposure of F344/N Nctr rats to Usnea lichens containing (+/−)-usnic acid in feed for 3 months resulted in severe toxicity and morbidity at exposure levels equivalent to 720 ppm of (+/−)-usnic acid. Significant hepatotoxicity was observed in male rats at exposure levels of 120, 360, and 720 ppm, and in female rats at an exposure level of 720 ppm. Exposure of B6C3F1/Nctr mice to Usnea lichens containing (+/−)-usnic acid in feed for 3 months resulted in hepatotoxicity at an exposure level equivalent to 360 ppm (+/−)-usnic acid in both male and female mice, ovarian atrophy at 180 and 360 ppm, and extended estrous cycle at 360 ppm. The estrus stage was extended in both mice and rats at 360 ppm. Body weight was significantly reduced compared to vehicle control values at exposure levels of 360 and 720 ppm in rats and of 360 ppm in mice. Male and female B6C3F1/Nctr mice exposed to 600 ppm (+/−)-usnic acid for 2 weeks exhibited increased frequencies of erythrocyte micronuclei. A no-observed-adverse-effect level (NOAEL) of 60 ppm of (+/−) usnic acid in Usnea lichens administered in the feed was established for both F344/N Nctr rats and B6C3F1/Nctr mice on the basis of the results of these studies.
National Toxicology Program (NTP). 2022. NTP technical report on the toxicity studies of usnea lichens containing (+/−)-usnic acid (CASRN 125-46-2) administered in feed to F344/N Nctr rats and B6C3F1/Nctr mice. Research Triangle Park, NC: National Toxicology Program. Toxicity Report 105. https://doi.org/10.22427/NTP-TOX-105