A Systematic review of β-caryophyllene and Piperine as Multitarget Phytochemicals: Integrated Phytochemical Profiling and Mechanistic Insights into their Biological Activities

β-Caryophyllene, a dietary sesquiterpene and selective CB2 receptor agonist, and piperine (PIP), a bioavailability-enhancing alkaloid, represent two potent phytochemicals with extensive, complementary biological activities. This systematic review synthesizes the current scientific evidence on their integrated phytochemical profiling, pharmacokinetics, and pharmacological properties, with a focus on their synergistic potential as a multitarget therapeutic combination. Rigorous analysis confirms that BCP exhibits pronounced anti-inflammatory, antioxidant, analgesic, and cytoprotective effects, largely mediated through CB2 activation and Nrf2 pathway induction. PIP, beyond its intrinsic pharmacological merits, acts as a potent bioenhancer by inhibiting drug-metabolizing enzymes (CYP450, UGT) and efflux transporters (P-glycoprotein). Critically, co-administration demonstrates a dual synergy: pharmacokinetically, PIP significantly enhances the oral bioavailability and systemic exposure of BCP; pharmacodynamically, their actions converge on shared pathways (e.g., NF-κB inhibition, Nrf2 activation), yielding superior efficacy in preclinical models of neuropathic pain, neurodegeneration, metabolic syndrome, and hepatotoxicity compared to monotherapies. This synergy enables dose-sparing effects and an improved therapeutic index. The findings underscore the BCP-PIP pair as a paradigm of natural product synergy, transitioning from traditional spice constituents to a promising, evidence-based multitarget strategy for managing complex chronic diseases. However, clinical translation requires standardized formulations and rigorous human trials to validate safety and efficacy.