Study Protocol for Developing a Methodological Framework and a Theory-informed Dissemination Plan for Herb-drug Interactions-related Clinical Practice Guidelines: a Delphi Survey and a Semi-structured Interview Study

In recent decades, the combined use of conventional (Western) drugs and herbal medicines has become increasingly common. Numerous studies have reported the prevalence of combined use, ranging from approximately 14% to 45%. The prevalence may be higher in low- and middle-income countries (LIC/LMIC), as studies have indicated that Traditional and Complementary Medicine is more popular in these regions, with Palestine and China reporting the highest prevalence of herbal medicine use. Although the initial purpose of combining conventional drugs and herbal medicines is to improve health and reduce adverse reactions, these combinations may yield either beneficial or harmful interactions. Herb-drug interactions (HDIs) can occur at pharmacokinetic (PK) and pharmacodynamic (PD) levels. PK interactions are those that affect the processes of drug absorption, distribution, metabolism, or excretion (known as ADME interactions). For example, St. John's Wort can reduce plasma concentrations of concomitantly administered CYP3A substrates such as alprazolam by inducing CYP3A4 activity. PD interactions are those in which the effect of one drug is altered by the presence of another drug at its site of action. For instance, ginkgo combined with anticoagulants such as warfarin can produce an additive effect, increasing the risk of bleeding. A scoping review focusing on cancer patients estimated that approximately 45.4% of patients using herbal medicines were at risk of harmful HDIs, which can cause adverse reactions and even pose a threat to people's lives. Therefore, it is essential to prioritize safety alongside efficacy of integrated therapies.

I. Gaps in HDI-related clinical practice guidelines (CPGs) The World Health Organization (WHO), U.S. Food and Drug Administration (FDA), and European Medicines Agency (EMA) have issued technical documents and established regulatory frameworks to support safe concurrent use of conventional drugs and herbal medicines. However, these efforts have not led to a proliferation of HDI-related CPGs. HDI-related CPGs remain scarce. Existing CPGs normally lack specific management and monitoring strategies and may not be well aligned with real-world practice, limiting their utility for clinicians. For example, a 2001 guideline recommended avoiding the combined use of Korean Ginseng and Warfarin unless under medical supervision, without specifying the type of supervision required. Furthermore, information provided by existing clinical decision support systems is inconsistent, creating further challenges on implementation in this area. A study reported significant discrepancies in the direction and severity of interactions between warfarin and medicinal plants across four commonly used online clinical decision resources, which could compromise clinical decision-making.

Beyond these gaps, there is currently no methodological framework existing for translating HDI evidence into implementable CPGs. Although there are frameworks such as GRADE Evidence to Decision (EtD) assisting in synthesizing evidence into recommendations, they are primarily designed for interventions with clearly defined PICO questions. This intervention-oriented nature limits their applicability to HDI, where herbal medicines represent complex, heterogeneous exposures rather than standardized interventions. Therefore, it is urgent to develop a dedicated framework for HDI-related CPGs to bridge evidence and practice.

II. Gaps in dissemination of HDI-related CPGs Integrating CPG recommendations into clinical practice is often slow and challenging, with an average lag of 17 years for evidence to influence routine care. To mitigate time lag, dissemination planning should begin alongside CPG development, as recommended by the Scottish Interprofessional Guidelines Network (SIGN). Several guideline dissemination platforms, including MAGIC, ECRI Guidelines Trust, and the Guidelines International Network, have been developed to organize fragmented evidence or recommendations into structured, searchable, and updatable formats to facilitate adoption. However, these platforms are limited by narrow scope and poor accessibility, and often rely on external links. In the context of HDIs, clinicians often access information through software and online resources, yet encounter conflicting data, insufficient detail, and usability challenges. Patients also express a desire for reliable HDI information. Despite this demand, few studies have investigated barriers, facilitators or end-user preferences for disseminating HDI-related CPGs. Addressing these gaps is essential to improve the accessibility, clarity and uptake of HDI-related CPGs.

To address the scarcity of HDI-related CPGs and the lack of effective dissemination strategies, the specific objectives of this study are to: