Concomitant use of cannabis with other drugs may lead to cannabis-drug interactions, mainly due to the pharmacokinetic mechanism involving the family of CYP450 isoenzymes. This narrative systematic review aimed to systematize the available information regarding clinical relevance of cannabis-drug interactions. We utilized the PubMed/Medline database for this systematic review, using the terms drug interactions and cannabis, between June 2011 and June 2021. Articles with cannabis-drug interactions in humans, in English or Spanish, with full-text access were selected. Two researchers evaluated the article's inclusion. The level of clinical relevance was determined according to the severity and probability of the interaction. Ninety-five articles were identified and twenty-six were included. Overall, 19 pairs of drug interactions with medicinal or recreational cannabis were identified in humans. According to severity and probability, 1, 2, 12, and 4 pairs of cannabis-drug interactions were classified at levels 1 (very high risk), 2 (high risk), 3 (medium risk), and 5 (without risk), respectively. Cannabis-warfarin was classified at level 1, and cannabis-buprenorphine and tacrolimus at level 2. This review provides evidence for both the low probability of the occurrence of clinically relevant drug interactions and the lack of evidence regarding cannabis-drug interactions.