Abstract
Herbal medicines are used worldwide alongside conventional drugs, often for chronic conditions and frequently without clinician oversight. This reality makes herb–drug interactions (HDIs) more than a niche pharmacology topic: they are a recurring, clinically relevant feature of modern polypharmacy. When Natural Products Communications invited us to launch this Special Issue on Advances in Herb–Drug Interactions in Phytotherapy, our aim was to encourage contributions that move beyond “botanical anecdote” and current reductive HDI paradigms (i.e. absorption-metabolism) towards wider mechanistic understanding, better experimental and reporting standards (i.e. standardisation of plant materials), and clearer translational pathways (i.e. systems biology) that can support clinical decision-making.
The eight papers assembled in this issue collectively reinforce a key point: “interaction” is not synonymous with “harm.” HDIs can involve adverse events, but they can also produce synergy, antagonism, protection, or altered therapeutic response. This concept of “positive/beneficial HDI” have been explored in several works1,2 and could be defined as “ any interaction yielding a positive therapeutic outcome for the patient, driven by herb-mediated changes to the drug’s pharmacokinetic or pharmacodynamic profile”. The scientific task is to make these effects measurable, reproducible, and clinically interpretable, especially in a domain where botanical complexity, variable product quality, and heterogeneous usage patterns can easily obscure signals with noise. A clinical benefit, however, remains provisional and requires further validation through adequate exposure, safety, and outcome data.
A first theme across the collection is the careful study of combination effects, particularly where botanicals may modulate conventional therapies. Gao and colleagues examine Juniperus indica extract combined with 5-fluorouracil in esophageal squamous cell carcinoma models, reporting synergistic growth suppression and mechanistic signals consistent with pathway-level modulation (including AKT/mTOR-related biology). 3 Studies like this are valuable not because they “prove” an integrative regimen, but because they demonstrate how synergy claims should be approached: quantified, mechanism-informed, and anchored in experimental design that anticipates resistance, context dependence, and safety constraints.
Booranasubkajorn and colleagues analyse the Thai Herbal Wattana Formula and its constituent ingredients in HepG2 cells, 4 illustrating a second theme: multi-component formulations can produce effects that are not reducible to a single “active” ingredient. Their work distinguishes between formula-level findings (including effects on migration and intracellular glutathione) and ingredient-driven cytotoxicity, and then further dereplicates candidate constituents. This layered approach (testing the whole formulation, mapping ingredient contributions, and separating phenotypes) offers a pragmatic template for studying complex botanicals while avoiding both oversimplification and “black box” conclusions.
A third theme is the growing recognition of the medicine–food continuum as a major driver of real-world interaction risk and opportunity. Jiao and colleagues review progress on the dual use of Angelica sinensis as food and medicine in gastrointestinal tumours, summarizing reported anti-tumour mechanisms and discussing its potential role in supportive care contexts, including toxicity mitigation and chemosensitisation. 5 Whether every proposed mechanism holds up under future clinical testing is an open question, but the framing is important: botanicals used as foods or supplements can be taken chronically and informally, expanding exposure beyond the clinic and making interaction science a population-level concern.
Hu and colleagues provide a systematic review and bibliometric analysis of mulberry, mapping bioactive classes and applications across nutrition, food technology, and medicine. 6 This work highlights a practical clinical implication: when a “functional food” has pharmacologically relevant effects (for example, on glucose handling), additive or unexpected interactions with hypoglycaemics and other therapies become plausible. Here, HDI science overlaps with counselling, labelling, and surveillance, areas where evidence quality and communication matter as much as mechanistic sophistication.
The issue also emphasizes “positive interactions” to prevent iatrogenic organ injury in situations where patients’ vulnerability is high and medication burden is substantial. Leão and colleagues investigate hepatoprotective potential of extracts from Brazilian savanna species against acetaminophen-induced injury in a HepG2 model, 7 adding experimental grounding to a common patient behaviour: using botanicals to “protect the liver” in the setting of drug exposure or underlying disease. We hope that these types of studies motivate the next translational steps, chemical characterization, pharmacodynamic, toxicological, and pharmacokinetic considerations.
Two contributions focus on systems-level pharmacology of traditional formulas in cardiovascular and renal disease contexts. Dr Xiangjun Yang and colleagues (Shaosha-7) report cardioprotective effects in acute myocardial infarction models and propose links to metabolic regulation, including sucrose-related pathways. 8 On the other hand, Dr Sicheng Yang and colleagues (Nourishing Blood Diuretic Formula) investigate chronic renal failure and fibrosis, highlighting antifibrotic mechanisms consistent with modulation of the TGF-β/Smad axis. 9 These papers sit slightly outside the classic “CYP inhibition/induction” HDI narrative, and that is innovation: many clinically meaningful interactions are pharmacodynamic, network-level, or disease-context mediated. As more botanicals are studied for pathway-level effects in metabolism, inflammation, fibrosis, and stress responses, the clinical exploitation of “positive HDI” with conventional therapies gets more feasible.
Finally, Soulaimani’s review on essential oil mixtures and synergistic antimicrobial activity provides a useful methodological mirror for HDI research. 10 Antimicrobial synergy work has long suffered from variability in methods, interpretation of different types of checkerboard and time-kill data, and poor reproducibility across strains and conditions. The same issues (standardization, clear reporting, and mechanistic accountability) are central to HDI science.
Across the collection, several practical priorities emerge. First, rigorous botanical characterization (identity, preparation, chemical profiling, batch variability) is not optional; without it, the field cannot accumulate comparable evidence. Second, exposure realism must guide interpretation: in vitro findings are valuable for hypothesis generation, but clinical relevance depends on plausible concentrations, bioavailability, and metabolism. Third, synergy and modulation claims should be quantified and validated, not inferred. Fourth, the most impactful HDI research aligns with clinical needs: it helps clinicians and patients answer whether a combination is likely risky, potentially beneficial, or uncertain, and why.
We thank the authors for contributing thoughtful work to this Special Issue and the reviewers for strengthening each manuscript through careful critique. We also thank the editorial team at Natural Products Communications for their enthusiastic support with this timely special issue. Our hope is that this collection supports a more mature HDI science: one that respects botanical complexity while insisting on reproducible methods, transparent reporting, and translational accountability. Done well, herb–drug interaction research does not merely warn; it clarifies, and sometimes it enables safer and more effective integration of phytotherapy into contemporary care.
