Evidence and Tradition in Dialogue: Biological Sex Variability in Phytomedicine Research as a Foundation for Safety, Efficacy, and Robust Evidence Standards

Background: Incorporating sex as a biological variable (SBV) is recognized as essential for improving the reliability, reproducibility, and generalizability of pharmacological research. This principle is codified in international policies and guidelines, yet implementation remains uneven, especially in phytomedicine. Phytomedicines are a major component of healthcare worldwide, with 65% of the global population relying on them in both regulated and traditional contexts. Globally, phytomedicines are used by males, females, intersex and non-cis gender persons, all of whom may present specific safety and efficacy considerations and warrant full inclusion in pre-clinical to clinical research pipelines. However, in contemporary settings, phytomedicine lags in SBV best practices relative to Western allopathic standards for research design. Methods: We conducted a non-systematic review and in silico data mining to quantify sex/gender representation in recent preclinical and clinical phytomedicine studies, complemented by targeted case studies of sexually dimorphic safety/efficacy. We also summarize the historical role of women and gender-diverse people as users and providers within Traditional and Integrative Medical Systems (TIMSs). Results: Across rodent and human studies, females are under-represented relative to males, and sex is rarely reported for cell lines. Intentional inclusion of intersex and other gender-diverse populations is largely absent. Case studies illustrate plausible sex-associated differences in pharmacokinetics, pharmacodynamics, and adverse event profiles. TIMSs historically address women’s health needs and include substantial participation by female practitioners; however, contemporary SBV practices remain less standardized than in Western allopathic pipelines. Conclusions: SBV integration in phytomedicine is needed to strengthen safety, efficacy, and regulatory-grade evidence. Practical barriers include legacy datasets without sex metadata, limited intersex animal models, and uneven resources across settings. We outline feasible, stepwise practices to improve SBV adoption in a manner compatible with TIMS contexts and recommend expanding current guidelines to better support diverse research environments while maintaining scientific rigor.