Cannabinoids and the endocannabinoid system in the regulation of cytochrome P450 metabolic activity-a review

Abstract

The use of cannabinoids has a history spanning thousands of years, and their pharmacological and toxicological properties, particularly those of THC and CBD, are well-documented. However, their potential to induce drug-drug interactions remains underexplored. This review aims to provide a comprehensive perspective by contextualizing the historical and pharmacological significance of cannabinoids while focusing on their capacity to modulate the metabolic activity of cytochrome P450 isoforms relevant to drug metabolism. Additionally, we look at the impact of cannabinoids in neuronal circuits impacting the hypothalamic-pituitary hormonal axis, such as the locus coeruleus and raphe nuclei and their possible consequences on the cytochrome P450 system. Recognising potential interactions between cannabinoids and other drugs could enhance understanding of their pharmacological effects, improve the efficacy and safety profiles of cannabinoid-based therapies, and encourage further exploration into this under-researched area of psychopharmacology, with implications for both preclinical research and clinical practice.

Keywords: cannabinoid-based therapies; cannabinoids; cytochrome P450; endocannabinoid system; hypothalamic-pituitary axis; metabolism.

FIGURE 1

Proposed influence of the different neurotransmitter systems in the regulation of P450 enzymes. Cannabinoids interaction with CB1 receptors influences the modulation of various neurotransmitter systems (NA, DA, 5-HT). Possible hypothalamic influence in the PVN and ARC interfering with the release of several hormones, which, in turn, interact with nuclear receptors (PPARα, GR, PXR, and CAR), thereby affecting the inhibition or induction of P450 enzymes. Created in BioRender (https://BioRender.com/j18d041).