Cannabidiol and Other Phytocannabinoids as Cancer Therapeutics

Abstract
Preclinical models provided ample evidence that cannabinoids are cytotoxic against cancer cells. Among the best studied
phytocannabinoids, cannabidiol (CBD) is most promising for the treatment of cancer as it lacks the psychotomimetic prop erties of delta-9-tetrahydrocannabinol (THC). In vitro studies and animal experiments point to a concentration- (dose-)
dependent anticancer efect. The efectiveness of pure compounds versus extracts is the subject of an ongoing debate. Actual
results demonstrate that CBD-rich hemp extracts must be distinguished from THC-rich cannabis preparations. Whereas
pure CBD was superior to CBD-rich extracts in most in vitro experiments, the opposite was observed for pure THC and
THC-rich extracts, although exceptions were noted. The cytotoxic efects of CBD, THC and extracts seem to depend not
only on the nature of cannabinoids and the presence of other phytochemicals but also largely on the nature of cell lines
and test conditions. Neither CBD nor THC are universally efcacious in reducing cancer cell viability. The combination
of pure cannabinoids may have advantages over single agents, although the optimal ratio seems to depend on the nature of
cancer cells; the existence of a ‘one size fts all’ ratio is very unlikely. As cannabinoids interfere with the endocannabinoid
system (ECS), a better understanding of the circadian rhythmicity of the ECS, particularly endocannabinoids and receptors,
as well as of the rhythmicity of biological processes related to the growth of cancer cells, could enhance the efcacy of a
therapy with cannabinoids by optimization of the timing of the administration, as has already been reported for some of the
canonical chemotherapeutics. Theoretically, a CBD dose administered at noon could increase the peak of anandamide and
therefore the efects triggered by this agent. Despite the abundance of preclinical articles published over the last 2 decades,
well-designed controlled clinical trials on CBD in cancer are still missing. The number of observations in cancer patients,
paired with the anticancer activity repeatedly reported in preclinical in vitro and in vivo studies warrants serious scientifc
exploration moving forward.