Balancing efficacy and risk: A toxicological review and safety transformation of Berberis plants and their alkaloids.

BACKGROUND: Berberis plants are widely distributed medicinal herbs with a long history of traditional use worldwide. Their primary active constituents are isoquinoline alkaloids, including berberine, palmatine, jatrorrhizine, and berbamine, which exhibit promising pharmacological activities in anti-inflammation, antibacterial, hypoglycemic, lipid-regulating, and antitumor effects. However, under specific doses, routes of administration, or individual conditions, these constituents may also induce multi-system toxic reactions, making the safety profile of Berberis plants a critical concern that warrants serious attention. PURPOSE AND METHODS: We systematically reviewed literature from PubMed, Web of Science, and Google Scholar to evaluate the toxicity profiles and adverse reaction characteristics of Berberis plants and their primary alkaloid constituents. We further analyzed contributing factors to toxicity and reviewed current detoxification strategies. Finally, we provided clinical recommendations for the safe use of Berberis plants. RESULTS: A total of 145 studies published between 1979 and 2026 were included, covering 38 Berberis species and their six representative alkaloids. Under specific doses and conditions, Berberis plants and their alkaloids exhibited multi-system toxicity, primarily affecting the liver, kidney, cardiovascular and immune systems, embryonic development, and genetic integrity. The observed toxicity was modulated by drug-related factors, host-related characteristics, and drug-drug interactions. Key determinants included dosage, pharmacokinetic properties, genetic variability, pregnancy status, hepatic and renal function, gut microbiota composition, as well as interactions involving CYP450 enzymes and P-glycoprotein. Current detoxification strategies encompass precise dose control, rational herbal compatibility, structural optimization, and nanodelivery to modify pharmacokinetic behavior. Based on the available evidence, the clinical use of Berberis species should emphasize indication-specific administration, individualized dosing in vulnerable populations, and careful assessment of potential drug-drug interactions. CONCLUSIONS: This review moves beyond descriptive toxicity accounts to establish a systematic rationale for the safe use of Berberis alkaloids. By linking specific toxicities to their contributing factors, it provides an evidence-based framework for individualized risk assessment. Integrating current detoxification strategies holds great promise for advancing Berberis plants into safer clinical applications.