Pharmacoepidemiological Data on Drug–Herb Interactions: Serotonin Syndrome, Arrhythmias and the Emerging Role of Artificial Intelligence
Open accessAbstract
Herbal medicinal products are increasingly used alongside conventional medicines, raising the risk of potential interactions such as pharmacodynamic drug–herb interactions (PD-DHIs) that can cause serious adverse drug reactions (ADRs). This review aims to present available pharmacological, clinical and pharmacoepidemiological literature regarding potential DHIs associated with serotonin syndrome or cardiac arrhythmias. Furthermore, it assesses the current evidence using the Oxford Centre for Evidence-Based Medicine (CEBM) 2009 framework. Serotonin syndrome most often results from combining serotonergic herbs (e.g., St. John’s wort) with antidepressants like serotonin reuptake inhibitors (SSRIs), as supported by repeated case reports and mechanistic plausibility (CEBM Level 3, Grade C). Other herbs such as black cohosh, ginseng, Syrian rue, turmeric, rhodiola, ashwagandha, and L-tryptophan/5-HTP have been linked to serotonin syndrome when used with SSRIs, serotonin-norepinephrine reuptake inhibitors (SNRIs), or monoamine oxidase inhibitors (MAOIs), but evidence is limited (Levels 4–5, Grade D). For cardiac arrhythmias, PD-DHIs arise when herbs interact with drugs that alter cardiac electrophysiology—such as QT-prolonging agents, psychotropics, antiarrhythmics or digoxin—thereby amplifying arrhythmogenic risk. Ephedra with sympathomimetics is strongly associated with arrhythmias (Level 2–3, Grade B). Licorice may potentiate digoxin and QT-prolonging drugs via hypokalemia (Level 4, Grade C). Other related PD-DHIs include aconite with antiarrhythmics, bitter orange or caffeine with QT-prolonging psychotropics, yohimbine with cardiovascular agents, and aloe or senna with digoxin. Overall, the evidence for PD-DHIs varies from moderate to weak but large-scale pharmacoepidemiological data is scarce. Future approaches, including artificial intelligence with explainable machine learning and network pharmacology, may integrate mechanistic, clinical, and real-world data to improve early detection or prediction of PD-DHIs. However, several specific challenges must be addressed. Therefore, it is crucial for healthcare providers in both clinical and community settings to increase their awareness of these interactions and ADRs to ensure the safe use of herbal remedies alongside conventional therapies.
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Berberine belongs to the broader group of drugs and supplements with a risk of induced arrhythmia, monitorable through pharmacovigilance, in which the pharmacist's assessment has a preventive role.
“This places berberine within the broader group of drugs and supplements with a risk of induced arrhythmia, monitorable through pharmacovigilance, in which the pharmacist’s assessment has a preventive role [91,93,94].”
From Berberine-Drug Interactions: Mechanisms, Clinical Relevance and Risk Stratification-A Narrative Review (2026) · cites this paper as [94]
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- Authors
- Spanakis, M., Bakaros, E., Papadopoulou, S.-N., Fournaraki, A., & Symvoulakis, E. K.
- Affiliations
- University of Crete (GR)
- University of Thessaly (GR)
- Community Pharmacists Association of Heraklion, 71201 Heraklion, Greece
- Community Pharmacists Association of Rethymno, 74132 Rethymno, Greece
- Corresponding author
- Spanakis, Marios
- Venue
- Pharmacoepidemiology
- Publisher
- MDPI AG
- Published
- 2025-10-09
- Volume
- 4
- Issue
- 4
- Pages
- 22
- ISSN
- 2813-0618 (ISSN-L)
- OpenAlex
- W4414989210
- Cited by
- 6
- References
- 189
- Citations by year
- 2026: 5 · 2025: 1
- FWCI
- 7.41
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Pharmacoepidemiology (publishedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Special Research Account of the UoC (KA 11903)
- Topics
- Health Sciences › Medicine › Complementary and alternative medicine › Complementary and Alternative Medicine Studies
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Pharmacovigilance and Adverse Drug Reactions
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Plant-based Medicinal Research
- Keywords
- herb-drug interactions, pharmacodynamic interactions, serotonin syndrome, cardiac arrhythmias, herbal medicinal products, adverse drug reactions, Hypericum perforatum, serotonin reuptake inhibitors, QT prolongation, digoxin, Ephedra, licorice, hypokalemia, artificial intelligence, network pharmacology, explainable machine learning, herbal medicine safety, pharmacovigilance
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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