Comprehensive review on cannabis seed phenolic compounds from extraction to functional applications

Cannabis sativa L. seeds have long been regarded as a by-product of cannabis cultivation. Beyond their nutritional value, cannabis seeds are increasingly recognized as a source of specialized phenolic compounds with potential biological relevance. However, research on seed phenolics remains fragmented, often receiving only marginal attention, and a dedicated synthesis focused specifically on these compounds is still lacking. This review provides a focused and up-to-date synthesis of phenolic compounds reported in cannabis seeds, critically examining their chemical diversity, extraction and analytical strategies, and key factors influencing phenolic recovery and composition. Cannabis seeds exhibit a diverse phenolic profile dominated by hydroxycinnamic acid amides (mainly N-trans-caffeoyltyramine) and lignanamides (particularly Cannabisins A and B). Their extraction remains largely reliant on conventional solvent-based approaches, with limited adoption of innovative and green technologies, except for ultrasound assisted extraction. Advances in high-resolution analytical tools for phenolic separation and identification enabled comprehensive profiling and a deeper understanding of phenolic diversity. The extractability and final content of phenolic compounds result from a complex interplay between extraction-related parameters, biological variability, and seed processing conditions. Biological activities associated with cannabis seed phenolics include antioxidant, anticancer, neuroprotective, anti-inflammatory, dermo-protective, antibacterial, and metabolic regulatory effects. These activities are discussed with reference to reported mechanisms, such as free radical scavenging, modulation of inflammatory mediators, and inhibition of cancer cell proliferation. Current evidence highlights cannabis seeds as a promising yet underexploited source of phenolic compounds with potential applications in nutraceutical, pharmaceutical, and dermato-cosmetic fields. Nevertheless, important challenges remain, such as methodological heterogeneity, limited in-vivo and clinical validation, and insufficient data on bioavailability and formulation. Addressing these limitations and gaps through standardized protocols, mechanistic studies, and translational research will be essential to support the effective valorization of cannabis seed phenolics in industrial and health-related applications.