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.