This review proposes the hypothesis that the effectiveness of
irinotecan chemotherapy might be impaired by high doses of concomitantly administered Δ9-tetrahydrocannabinol (
THC). The most important features shared by
irinotecan and
THC, which might represent sources of potentially harmful interactions are: first-pass hepatic metabolism mediated by
cytochrome P450 (CYP)
enzyme CYP3A4; glucuronidation mediated by
uridine diphosphate glycosyltransferase (UGT)
enzymes,
isoforms 1A1 and 1A9; transport of parent compounds and their metabolites via canalicular
ATP-binding cassette (
ABC) transporters ABCB1 and ABCG2; enterohepatic recirculation of both parent compounds, which leads to an extended duration of their pharmacological effects; possible competition for binding to
albumin;
butyrylcholinesterase (BChE) inhibition by
THC, which might impair the conversion of parent
irinotecan into the
SN-38 metabolite; mutual effects on
mitochondrial dysfunction and induction of oxidative stress; potentiation of hepatotoxicity; potentiation of genotoxicity and cytogenetic effects leading to
genome instability; possible neurotoxicity; and effects on
bilirubin. The controversies associated with the use of highly concentrated
THC preparations with
irinotecan chemotherapy are also discussed. Despite all of the limitations, the body of evidence provided here could be considered relevant for human-risk assessments and calls for concern in cases when
irinotecan chemotherapy is accompanied by preparations rich in
THC.