(+)‑Usnic acid is a secondary metabolite of lichens belonging to the Usnea genus. Usnea lichens and purified usnic acids have been used historically in traditional herbal medicine as bactericidal and 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 (+)‑usnic acid in male and female F344/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 and B6C3F1/Nctr mice to (+)‑usnic acid in feed for 3 months resulted in hepatotoxicity in male rats at exposure levels above 120 ppm. Mild toxicity as demonstrated by increased serum enzyme activity was observed in female rats at exposure levels of 720 ppm. In male mice, moderate but significant increases in alanine aminotransferase and alkaline phosphatase were observed at exposure levels of 360 ppm, moderate significant increases in blood urea nitrogen were observed at exposure levels of 180 and 360 ppm, whereas moderate significant increases in serum creatinine were observed at exposure levels of 60, 180, and 360 ppm. There were significantly fewer female rats cycling in the 720 ppm group than in the control group, due to extended diestrus. Significant body weight decreases were achieved at exposure levels of 720 ppm in male and female rats. Exposure to 600 ppm (+)‑usnic acid for 14 days significantly increased the incidence of micronuclei in erythrocytes or reticulocytes from both male and female B6C3F1/Nctr mice; exposure to 1,200 ppm significantly increased the incidence of micronuclei in reticulocytes in male B6C3F1/Nctr mice. No-observed-adverse-effect levels (NOAELs) of 120 ppm and 30 ppm of (+)‑usnic acid administered in feed were established for F344/N Nctr rats and B6C3F1/Nctr mice, respectively, on the basis of the results of these subchronic studies.National Toxicology Program (NTP). 2022. NTP technical report on the toxicity studies of (+)-Usnic acid (CASRN 7562-61-0) administered in feed to F344/N Nctr rats and B6C3F1/Nctr mice. Research Triangle Park, NC: National Toxicology Program. Toxicity Report 104. https://doi.org/10.22427/NTP-TOX-104