The comparative toxicity of a reduced, crude comfrey (Symphytum officinale) alkaloid extract and the pure, comfrey-derived pyrrolizidine alkaloids, lycopsamine and intermedine in chicks (Gallus gallus domesticus)

J Appl Toxicol. 2016 May;36(5):716-25. doi: 10.1002/jat.3205. Epub 2015 Jul 14.


Comfrey (Symphytum officinale), a commonly used herb, contains dehydropyrrolizidine alkaloids that, as a group of bioactive metabolites, are potentially hepatotoxic, pneumotoxic, genotoxic and carcinogenic. Consequently, regulatory agencies and international health organizations have recommended comfrey be used for external use only. However, in many locations comfrey continues to be ingested as a tisane or as a leafy vegetable. The objective of this work was to compare the toxicity of a crude, reduced comfrey alkaloid extract to purified lycopsamine and intermedine that are major constituents of S. officinale. Male, California White chicks were orally exposed to daily doses of 0.04, 0.13, 0.26, 0.52 and 1.04 mmol lycopsamine, intermedine or reduced comfrey extract per kg bodyweight (BW) for 10 days. After another 7 days chicks were euthanized. Based on clinical signs of poisoning, serum biochemistry, and histopathological analysis the reduced comfrey extract was more toxic than lycopsamine and intermedine. This work suggests a greater than additive effect of the individual alkaloids and/or a more potent toxicity of the acetylated derivatives in the reduced comfrey extract. It also suggests that safety recommendations based on purified compounds may underestimate the potential toxicity of comfrey.

Keywords: N-oxide; comfrey; intermedine; lycopsamine; pyrrolizidine alkaloid; tisane.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Aspartate Aminotransferases / blood
  • Bile Acids and Salts / blood
  • Chickens
  • Cholesterol / blood
  • Comfrey / chemistry
  • Comfrey / toxicity*
  • Creatine Kinase / blood
  • L-Iditol 2-Dehydrogenase / blood
  • L-Lactate Dehydrogenase / blood
  • Liver / drug effects
  • Liver / metabolism
  • Male
  • Plant Extracts / toxicity*
  • Pyrrolizidine Alkaloids / chemistry
  • Pyrrolizidine Alkaloids / toxicity*
  • Triglycerides / blood
  • gamma-Glutamyltransferase / blood


  • Bile Acids and Salts
  • Plant Extracts
  • Pyrrolizidine Alkaloids
  • Triglycerides
  • Cholesterol
  • intermedine
  • L-Iditol 2-Dehydrogenase
  • L-Lactate Dehydrogenase
  • gamma-Glutamyltransferase
  • Aspartate Aminotransferases
  • Creatine Kinase
  • indicine