The Pharmacological Activity of Non-Cannabinoid Phytochemicals in Cannabis sativa L.: A Systematic Review

Cannabis sativa (C. sativa) is widely recognized for its therapeutic potential, historically attributed to its cannabinoid content. Some of the phytocannabinoid compounds of C. sativa are mediated through interactions with the endocannabinoid system, while some are able to modulate the interaction between cannabinoids and the endocannabinoid system. Additionally, the non-cannabinoid group exhibits a broad range of bioactive potential, also displaying pharmacological actions. However, the non-cannabinoid fraction of the plant has not been extensively studied. This review emphasizes the emerging pharmacological importance of non-cannabinoid phytochemicals such as terpenes, flavonoids, phenolic compounds, and alkaloids found within C. sativa. Scopus, Google Scholar, and PubMed were utilized as databases to search for relevant published literature. The search employed the keywords such as "Cannabis sativa phytochemicals, non-cannabinoid compounds of Cannabis sativa, pharmacological activity of non-cannabinoid compounds of Cannabis sativa". The total number of published articles initially retrieved between January 2010 and May 2025 was 187. From these, only 12 articles were selected according to the inclusion and exclusion criteria. The review highlights the structural diversity and functional significance of non-cannabinoid constituents. Terpenes and flavonoids were particularly well-characterized, with demonstrated synergistic interactions that enhanced therapeutic efficacy via mechanisms like the "entourage effect." Despite promising preclinical findings, the clinical translation of these compounds remains limited due to challenges in standardization, regulatory barriers, and a lack of well-defined analytical methods. This review concludes that non-cannabinoid phytochemicals are integral to the pharmacological complexity of C. sativa and warrant further investigation as potential candidates for drug development, especially in formulations that aim to optimize whole-plant therapeutic effects.