Exogenous cannabinoids such as tetrahydrocannabinol (THC), cannabidiol (CBD) and cannabinol (CBN) are compounds that are nowadays known to be abused worldwide. The main goal of this study is to evaluate the inhibitory effect of these compounds on the human drug metabolizing enzymes CYP450. The Geneva Cocktail, composed of Phenacetine, Bupropion, Flurbiprofene, Omeprazole, Dextromethorphan, and Midazolam, was used to evaluate respectively the activity of CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 in the Human Liver Microsomes (HLMs). The substrates and their metabolites were analyzed by liquid chromatography-tandem mass spectrometry (MS/MS). In vivo studies show a contradiction concerning the inhibitory effect of CBD on Clobazam (CYP2C19 substrate). In vitro data reveals that CBD, unlike TCH and CBN, is a strong inhibitor of CYP3A4, 2D6 and 2C19, while all three components studied are inhibitors of CYP2C9. The results of the study were in agreement with the published in vitro data. In fact, the studied cannabis components do inhibit CYP450 activities. CBD significantly inhibits CYP3A4, 2D6, 2C9, 2C19, and 2B6 with IC50 respectively equal to7.58 μM, 19.5 μM, 9.24 μM, 1.14 μM, and 1.76 μM. Furthermore, THC significantly inhibits CYP2C9 and 2B6, with IC50 respectively equal to 14.12 μM and 21.8 μM. Finally, CBN inhibits CYP2C9 activity with an IC50 equal to 19.95 μM. In comparison to kinetics data found in the literature, much higher concentrations of THC, CBD and CBN, in both recreational and medicinal use, are needed to achieve concentrations responsible of a significant inhibition in vivo.