Background: Berberine, an isoquinoline alkaloid present in Berberis spp., Coptis chinensis and Hydrastis canadensis, is among the most widely consumed metabolic-health supplements, popularized as "nature's Ozempic". Concurrent, often undisclosed use with prescription drugs is common in older adults, yet berberine is far from inert. Objective: To synthesize the evidence on berberine as a perpetrator of supplement-drug interactions, propose a four-axis mechanistic taxonomy, with product quality treated separately as a modifier of exposure rather than as a mechanism, and derive a clinically actionable risk-stratification framework. Methods: Structured narrative review, prepared per the SANRA quality criteria; PubMed/MEDLINE, Scopus, Web of Science and Embase were searched up to May 2026. Results: Despite very low systemic exposure (oral bioavailability 0.68% in rats; low ng/mL plasma concentrations in humans), high luminal, enterocytic and hepatic concentrations generate interaction liability, documented in humans for a few pairs and mechanistic for most, along four mechanistic axes: inhibition, and transcriptional induction, of CYP3A4, with CYP2D6/CYP2C9 inhibition that is quasi-irreversible through a metabolite-intermediate complex; transporter modulation (P-glycoprotein, OCT1/OCT2, and MATE1); pharmacodynamic additivity (hypoglycemia, hypotension, and QT prolongation); and microbiome- and gut-barrier-mediated effects, the last of these being a candidate axis rather than a demonstrated one. Product-quality variability is treated separately, as a modifier of exposure. The clinical anchor is increased cyclosporine exposure in renal-transplant recipients (AUC +34.5%; trough 29.3% above control). These elements are integrated into a three-tier risk-stratification framework that combines perpetrator potency, victim-drug vulnerability, and patient vulnerability, with each tier being linked to a defined pharmacy action. Conclusions: In patients on multiple medications, and particularly when berberine is co-administered with drugs of narrow therapeutic index, it should be managed as an active pharmacological perpetrator rather than as an inert supplement. Unstandardized product quality and an unsettled European regulatory framework, under which national limits differ by more than an order of magnitude, further widen the uncertainty around the dose actually delivered. Berberine use should therefore be elicited routinely at medication reconciliation and stratified by mechanism, by victim-drug vulnerability, and by patient risk, with particular attention to metabolic self-medication in the GLP-1 era.

The global rise of antimicrobial resistance among Gram-negative hospital pathogens urgently demands new antibacterial candidates supported by both phenotypic activity and mechanistic evidence. Here, canadine (tetrahydroberberine), a principal alkaloid of Hydrastis canadensis L., was evaluated as an antibacterial lead against berberine. Target nomination via reverse pharmacophore mapping (PharmMapper), followed by bacterial-target filtering, prioritized DNA gyrase subunit B (GyrB) for mechanistic investigation. Whole-cell antibacterial activity, assessed by broth microdilution against a panel of pathogenic bacteria, revealed that canadine exhibited consistently superior activity to berberine, including enhanced inhibition of Acinetobacter baumannii. Structure-based docking against the A. baumannii GyrB crystal structure (PDB: 7PQL), validated by redocking of the co-crystallized inhibitor (RMSD = 1.68 Å), yielded a favorable docking score for canadine (-10.5 kcal/mol), approaching that of the co-crystallized ligand (-10.8 kcal/mol) and outperforming berberine. Molecular dynamics simulations (100 ns) demonstrated stable canadine-GyrB complexes with lower conformational deviation and reduced energetic fluctuation relative to berberine. Interaction-energy decomposition identified van der Waals forces as the primary stabilizing contributions, with electrostatic interactions serving as secondary modulators. Binding free-energy calculations further supported favorable canadine-GyrB association (ΔG = -9.57 kcal/mol). In vitro E. coli DNA gyrase inhibition assays confirmed greater inhibitory potency for canadine over berberine. Collectively, these findings establish canadine as a mechanistically credible GyrB-targeting antibacterial lead with superior performance to berberine across phenotypic, computational, and biochemical assessments, warranting further optimization through structure-activity relationship studies, selectivity profiling, and translational evaluation against multidrug-resistant A. baumannii.

A 16-year-old boy with severe obsessive-compulsive disorder (OCD), characterized by health-focused obsessions, intrusive ruminations, derealization, and significant functional impairment, failed to tolerate standard serotonergic agents (escitalopram, fluoxetine) and bupropion due to worsening anxiety, somatic concerns, or headaches. An oral glutamatergic regimen was initiated with dextromethorphan 30 mg/day for N-methyl-D-aspartate (NMDA) antagonism, piracetam 1,200 mg/day for AMPA modulation, and goldenseal (Hydrastis canadensis) root extract 600 mg/day as a botanical CYP2D6 inhibitor to prolong dextromethorphan exposure, alongside low-dose pregabalin, risperidone, and aripiprazole for ancillary support. Within four weeks of adding goldenseal, symptoms markedly improved, meeting remission thresholds: the Patient Health Questionnaire-9 (PHQ-9) score fell to 2, GAD-7 score to 3, obsessive thoughts and derealization resolved, headaches ceased, and full school attendance and functioning returned. These benefits lasted for two months, and there were no negative effects from goldenseal. This case indicates that a cost-effective, entirely oral amalgamation of a prevalent cough suppressant, a nootropic, and a botanical supplement may yield ketamine-like glutamatergic advantages for patients with OCD who are intolerant to conventional treatments; however, controlled studies are required to validate efficacy and safety.

Treating bipolar depression that comes with obsessive, looping thoughts can be tricky because standard antidepressants often help only a little and can sometimes push the mood too high. In this report, we followed a 32-year-old man whose low mood and health-related ruminations lingered despite mood stabilisers (valproate, low-dose aripiprazole, pregabalin, and Deanxit). Hoping to copy some of ketamine's brain-circuit effects, he tried an over-the-counter mix of dextromethorphan, piracetam, and L-glutamine; the result was modest at best. Ten days after he added 600 mg of the herbal CYP2D6 inhibitor goldenseal, thought to slow the breakdown of dextromethorphan, he reported a clear lift in energy, mood, and work performance, with no signs of hypomania; the improvement faded when he stopped the herb and returned when he restarted it, and he had no side effects. Although this single experience cannot show cause and effect, it hints that short courses of a well-standardised botanical CYP2D6 inhibitor might prolong the benefit some patients get from oral dextromethorphan-based combinations, an idea that would need careful study, including drug-level monitoring and checks for mood switches.

Antifungal resistance is growing increasingly more common due to the widespread use of limited number of antifungal compounds classes. Plant extracts have been used and studied for thousands of years as antifungal therapeutics alone or in combination with other natural products. This study investigated the synergistic effects of combining ethanolic extracts from nine plants with documented antifungal activity to identify natural and more powerful antifungal treatments against Candida albicans. Using checkerboard microdilution assays, 11 out of 15 combinations exhibited additive or synergistic interactions (fractional inhibitory concentration index, FICI < 1). The strongest synergy was observed between Alpinia officinarum and Hydrastis canadensis with MIC90 FICI = 0.08 and MIC50 FICI = 0.05. Combinations involving H. canadensis, Eucalyptus globulus, and Punica granatum produced the most synergistic effects with other tested extracts and with each other. Combining putative active compounds from each of these three extracts demonstrated synergistic antifungal activity, with the strongest synergy observed with berberine (from H. canadensis) and punicalagin (from P. granatum) with MIC90 FICI = 0.31 and MIC50 FICI = 0.13. Eucalyptol did not produce any significant antifungal activity so E. globulus extract was fractionated to identify its main antifungal compounds. UPLC-MS analysis determined that the most active fractions were primarily made up of hydrolysable tannins which produced strong synergy when combined to berberine with MIC90 FICI = 0.31 and MIC50 FICI = 0.25. The combinations of berberine with punicalagin and berberine with the E. globulus high tannin fraction F5 displayed antifungal activity against C. albicans with MIC90 concentrations of 2-16 µg/mL, which are comparable to MIC90 concentration for econazole of 0.5-8 µg/mL. These results suggest that phytochemical mixtures containing different classes of antifungal compounds can approach the efficacy of commercial antifungals and may serve as effective alternatives.

Cholera, a life-threatening diarrheal disease caused by Vibrio cholerae, remains a global health concern. Traditional medicinal plants such as Berberis vulgaris (barberry) and Hydrastis canadensis (goldenseal) have long been used for their antimicrobial properties. This study employed integrated computational approaches to identify potential anti-cholera compounds from these plants by targeting sodium-pumping NADH-ubiquinone oxidoreductase (Na⁺-NQR). Virtual screening identified compounds 122623, 197835, and 638024, along with the control Korormicin, exhibiting favorable binding affinities and hydrogen bonding interactions. Machine learning-based prediction models were further applied to assess functional activity and binding affinity. The study incorporated ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) profiling and density functional theory (DFT) calculations to evaluate physicochemical properties and electronic characteristics of the compounds. Molecular dynamics (MD) simulations demonstrated stable RMSD values for the ligands, with 122623 exhibiting the lowest RMSD (0.3-0.5 nm), closely resembling the control (0.3-0.4 nm), suggesting stable binding. Principal component analysis (PCA) showed tight conformational clusters for complexes with 122623 and 197835, while free energy landscape (FEL) analysis revealed deep energy minima, supporting complex stability. MM/GBSA calculations showed that 122623 had the lowest binding free energy (-38.71 kcal/mol), followed by 638024 (-35.14 kcal/mol) and 197835 (-30.68 kcal/mol). Per-residue energy decomposition identified key residues (Phe137, Val155, Phe159, Phe160) involved in ligand binding. Network pharmacology analysis predicted additional gene targets for the selected compounds, providing insights into their broader therapeutic relevance. Collectively, compounds 122623, 197835, and 638024 derived from Hydrastis canadensis and Berberis vulgaris demonstrated promising inhibitory interactions with the Na⁺-NQR enzyme, suggesting their potential as anti-cholera agents.

Unique from Gram-positive bacteria, Gram-negative bacteria have an outer membrane containing lipopolysaccharide. This distinction has important implications for antibiotic therapies where this complex outer cell membrane presents a significant barrier to the entry of drugs, such as antibiotics, into the cell. Many botanical extracts are purported for their antibacterial properties. In this study, several botanical extracts were compared for their antibacterial activity against various Gram-positive and Gram-negative bacteria. Gram-positive bacteria were found to be more sensitive to the antibacterial effects of these botanical extracts, including Larrea tridentata, Eucalyptus glabra, Hypericum perforatum, Coptis chinensis and Hydrastis canadensis. For Gram-negative bacteria, various permeabilizers including EDTA, spermidine and polyethyleneimine, have been identified which facilitate the passage of the antibiotics through the outer membrane. These permeabilizers were tested to improve the efficacy of botanical extracts against Gram-negative bacteria where an increase in antibacterial activity was observed but was dependent on the type of permeabilizer used (EDTA being most effective) and the botanical extract (primarily observed with Larrea tridentata, Eucalyptus glabra, Coptis chinensis, and Salvia officinalis). These results characterize the spectrum of antibacterial activity of several commonly used botanical extracts in the presence and absence of membrane permeabilizers. The research performed supports the use of permeabilizers to potentially improve the antibacterial efficacy of botanical extracts and therapeutics.

Multidrug-resistant (MDR) bacteria have become a significant global concern in recent years, necessitating the development of innovative strategies to combat these pathogens. Berberine, a bioactive alkaloid found in Berberis vulgaris, Berberis aquifolium, Coptis chinensis, Coptis japonica, and Hydrastis canadensis, exhibits a broad spectrum of biological activities, including antibacterial effects. However, its low aqueous solubility limits its bioavailability, restricting its therapeutic potential. Poly(2-hydroxyethyl methacrylate) (pHEMA)-based cryogel membranes, known for their biocompatibility and ease of synthesis, have been widely utilized in biomedical applications, particularly in wound healing. In this study, berberine was successfully incorporated into pHEMA cryogel membranes and characterized using FT-IR spectroscopy. Biocompatibility assessments were conducted using L929 fibroblast cells, and MTT assay results confirmed that cell viability remained above 88 %, indicating good biocompatibility. The antibacterial properties of the prepared membranes against MDR E. coli and MRSA were evaluated using the disk diffusion and time-kill methods. According to the time-kill assay, high-dose berberine-loaded cryogel membranes (BM2) exhibited inhibition rates of 87.2 % against MRSA and 96.8 % against MDR E. coli. The antibacterial and antibiofilm effects of the membranes were further validated by SEM imaging, which revealed that berberine effectively disrupted bacterial biofilms. To gain insight into the molecular mechanisms underlying antibacterial activity, molecular docking studies were performed on key bacterial proteins involved in essential physiological processes, including the OmpA transmembrane domain (PDB ID: 1BXW), E. coli DNA gyrase B (PDB IDs: 4WUB, 6KZX, 6KZV), E. coli hydrogenase (PDB ID: 5LMM), penicillin-binding protein 3 (PBP3; PDB ID: 3VSL), and PBP2a from MRSA (PDB IDs: 1MWT, 4CJN, 5M18, 6Q9N). The strongest interaction was observed between berberine and 6KZX, with a docking score of -7.898 kcal/mol, whereas the weakest interaction was noted with 4CJN, with a docking score of -3.743 kcal/mol. These findings highlight the potential of berberine-loaded pHEMA cryogel membranes as a promising antibacterial platform for combating MDR bacterial infections, particularly for wound healing applications.

Continued growth in global sales of natural products has led to an increased risk of natural product-drug interactions that can compromise drug efficacy and safety. One such natural product, goldenseal, was shown to decrease systemic exposure to a subtherapeutic dose of oral metformin in healthy adults. A follow-up study involving therapeutic metformin doses and adults with type II diabetes demonstrated a metformin dose-dependent pharmacokinetic interaction with goldenseal. These results, along with no change in metformin half-life or renal clearance in both studies, suggested that the goldenseal-metformin interaction occurred in the gut via inhibition of an unidentified saturable intestinal transport process. We used enteroid monolayers derived from the duodenum of 4 healthy human adult donors to recapitulate the goldenseal-metformin interaction in vitro and identify the transporters involved in the observed in vivo interaction. Our results implicate thiamine transporter (ThTr) 2 as the predominant transporter involved in metformin uptake through the apical membrane, accounting for approximately 45% of total metformin intracellular accumulation. Additionally, goldenseal inhibited ThTr-2, but only under subsaturating metformin dosing concentrations. The goldenseal-metformin interaction mediated under therapeutic metformin dose conditions involves a low-affinity basolateral transporter, ThTr-1, which accounts for approximately 50% of inhibitable metformin apical to basolateral flux. However, a substantial fraction of metformin flux appears to involve paracellular transport. These results further elucidate the mechanism underlying the goldenseal-metformin interaction and suggest that enteroid monolayers are a promising model to study intestinal natural product-drug interactions. SIGNIFICANCE STATEMENT: The research presented in this article demonstrates the utility of enteroid monolayers to predict and ascertain the mechanisms of drug-drug and natural product-drug interactions. Using this model, the study was able to identify the transporters (thiamine transporter-1 and thiamine transporter-2) involved in metformin absorption that are inhibited by the natural product, goldenseal, which were previously unidentified.

Goldenseal (Hydrastis canadensis) root contains berberine and other isoquinoline alkaloids. Goldenseal has traditionally been used as an anti-infective both systemically and topically, although high-quality studies of its efficacy and safety are lacking. It has also been used to mask illicit drugs in the urine, although it appears to be ineffective with modern laboratory methods. Goldenseal has been used topically by nursing mothers to treat sore nipples.[1] No data exist on the excretion of any components of goldenseal into breastmilk or on the safety and efficacy of goldenseal in nursing mothers. Berberine can displace bilirubin from serum albumin, causing concern about exposure of newborn infants, because bilirubin can build up in the infant's brain, causing brain damage.[2] However, the extent of berberine's passage from the mother to the infant is unknown. Most sources recommend avoiding exposure of neonates to goldenseal via breastfeeding or otherwise.[3-5] Dietary supplements do not require extensive pre-marketing approval from the U.S. Food and Drug Administration. Manufacturers are responsible to ensure the safety, but do not need to prove the safety and effectiveness of dietary supplements before they are marketed. Dietary supplements may contain multiple ingredients, and differences are often found between labeled and actual ingredients or their amounts. A manufacturer may contract with an independent organization to verify the quality of a product or its ingredients, but that does not certify the safety or effectiveness of a product. Because of the above issues, clinical testing results on one product may not be applicable to other products. More detailed information about dietary supplements is available elsewhere on the LactMed Web site.