Paradoxical Patterns of Sinusoidal Obstruction Syndrome-Like Liver Injury in Aged Female CD-1 Mice Triggered by Cannabidiol-Rich Cannabis Extract and Acetaminophen Co-Administration

Molecules. 2019 Jun 17;24(12):2256. doi: 10.3390/molecules24122256.


The goal of this study was to investigate the potential for a cannabidiol-rich cannabis extract (CRCE) to interact with the most common over-the-counter drug and the major known cause of drug-induced liver injury-acetaminophen (APAP)-in aged female CD-1 mice. Gavaging mice with 116 mg/kg of cannabidiol (CBD) [mouse equivalent dose (MED) of 10 mg/kg of CBD] in CRCE delivered with sesame oil for three consecutive days followed by intraperitoneally (i.p.) acetaminophen (APAP) administration (400 mg/kg) on day 4 resulted in overt toxicity with 37.5% mortality. No mortality was observed in mice treated with 290 mg/kg of CBD+APAP (MED of 25 mg/kg of CBD) or APAP alone. Following CRCE/APAP co-administration, microscopic examination revealed a sinusoidal obstruction syndrome-like liver injury-the severity of which correlated with the degree of alterations in physiological and clinical biochemistry end points. Mechanistically, glutathione depletion and oxidative stress were observed between the APAP-only and co-administration groups, but co-administration resulted in much greater activation of c-Jun N-terminal kinase (JNK). Strikingly, these effects were not observed in mice gavaged with 290 mg/kg CBD in CRCE followed by APAP administration. These findings highlight the potential for CBD/drug interactions, and reveal an interesting paradoxical effect of CBD/APAP-induced hepatotoxicity.

Keywords: acetaminophen; cannabidiol; liver injury; natural products; phytochemical; sinusoidal obstruction syndrome.

MeSH terms

  • Acetaminophen / adverse effects*
  • Animals
  • Biomarkers
  • Cannabidiol / adverse effects*
  • Cannabidiol / chemistry
  • Cannabis / chemistry
  • Chemical and Drug Induced Liver Injury / diagnosis
  • Chemical and Drug Induced Liver Injury / etiology
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Drug Synergism
  • Female
  • Hepatic Veno-Occlusive Disease / diagnosis*
  • Hepatic Veno-Occlusive Disease / etiology*
  • Liver / drug effects
  • Liver / metabolism
  • Liver / pathology
  • Mice
  • Mice, Inbred Strains
  • Phytochemicals / adverse effects
  • Phytochemicals / chemistry
  • Plant Extracts / adverse effects


  • Biomarkers
  • Phytochemicals
  • Plant Extracts
  • Cannabidiol
  • Acetaminophen