Pulegone

Spasmolytic activity is documented in isolated smooth muscle preparations. Toxicological data from pennyroyal oil (predominantly pulegone) inform the hepatotoxicity risk at high doses; isolated essential oil ingestion has caused fatal hepatotoxicity. At concentrations present in leaf infusions (low pulegone content relative to diosphenol), risk is considered negligible for short-term therapeutic use.

Animal studies demonstrate anxiolytic effects at low doses via GABAergic modulation (de Sousa et al., 2007). Hepatotoxicity of concentrated pulegone well-documented at doses far exceeding therapeutic range — basis for regulatory limits on pulegone in food products (EU maximum 25 mg/kg). Content in M. haplocalyx is variable (1–8% of volatile oil) and typically lower than in pennyroyal (M. pulegium).

The National Toxicology Program (NTP) 2-year carcinogenicity study in rodents (2011) found clear evidence of carcinogenic activity of pulegone, with hepatocellular adenomas and carcinomas in both rats and mice. Sullivan et al. (JAMA, 1979) documented fatal human hepatotoxicity from 15 mL pennyroyal oil. Anderson et al. (Annals of Internal Medicine, 1996) described a non-fatal case treated successfully with N-acetylcysteine, establishing the glutathione-depletion mechanism parallel to acetaminophen toxicity.