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Goldenseal (Hydrastis canadensis)


Goldenseal (Hydrastis canadensis) Image
Synonyms / Common Names / Related Terms
Berberine, berberine bisulfate, curcuma, eye balm, eye root, golden root, goldensiegel, goldsiegel, ground raspberry, guldsegl, hydrastis rhizoma, hydrophyllum, Indian dye, Indian paint, Indian plant, Indian turmeric, jaundice root, kanadische gelbwurzel, kurkuma, Ohio curcuma, orange root, Ranunculaceae (family), tumeric root, warnera, wild curcuma, wild turmeric, yellow eye, yellow Indian plant, yellow paint, yellow paint root, yellow puccoon, yellow root, yellow seal, yellow wort.

Note: Goldenseal is sometimes referred to as "Indian turmeric" or "curcuma," but should not be confused with turmeric.


Mechanism of Action

Pharmacology:

  • Constituents: The active ingredients of goldenseal include isoquinoline alkaloids, such as berberine, canadine, and hydrastine. Goldenseal has been reported to contain these alkaloids in the ranges of 1.5-4% hydrastine, 0.5-6% berberine, and 2-3% berberastine.23 Most of the actions of goldenseal have been attributed to hydrastine and berberine. Due to the lack of clinical evidence regarding the use of goldenseal itself, it is unclear whether the actions of its constituents are also attributable to goldenseal preparations.
  • Antibacterial effects: In vitro research assessing the antibacterial activity of berberine has found an aqueous extract containing berberine to have an MIC of 50mcg/mL for Clostridium tetani17, and an MIC <4mcg/mL for Candida krusei26. The MIC for Streptococcus pyogenes was found to be 30mcg/mL; berberine inhibits the adherence of S. pyogenes to epithelial cells possibly by immobilizing fibronectin and hexadecane at concentrations below the MIC.40 Berberine is bactericidal against Vibrio cholera at concentrations of 35mcg/mL, and against Staphylococcus aureus at 50mcg/mL.41 Berberine sulfate has been shown to possess antimicrobial activity against gram positive and gram negative organisms in vitro through inhibition of RNA and protein synthesis.41
  • Antiparasitic effects: Berberine sulfate has been shown to possess antimicrobial activity against protozoal organisms in vitro through inhibition of RNA and protein synthesis.41 In vitro, a methanol extract of berberine has demonstrated parasiticidal activity against T. vaginalis, G. lamblia, and E. histolytica.42 Subsequent in vitro study has found that berberine sulfate (1mg/mL) causes nuclear chromatin clumping in E. histolytica after 24 hours of exposure, irregular shaped vacuoles in G. lamblia after three hours of incubation, and an increased number of autophagic vacuoles in T. vaginalis.43 Berberine (0.5mg) injected into chick embryos reduced the mortality rate of the embryos due to the introduction of trachoma organisms into the yolk sac.11
  • In vitro study has demonstrated the ability of berberine to completely inhibit the growth of promastigotes at a concentration of 5mcg/mL, possibly by inhibiting endogenous respiration of the organism and inhibiting nucleic acid and protein synthesis.44 Subsequent study has shown berberine chloride to interact with Leishmania donovani nuclear DNA, inhibiting the multiplication of amastigotes in macrophage culture in vitro and decreasing parasitic load in animals.16
  • Anti-fungal effects: Berberine, at concentrations of 10mg/mL, has exhibited antifungal activity against Alternaria, Candida albicans, Curvularia, Drchslera, Fusarium, Mucor, and Rhizopus oryzae; concentrations of 25mg/mL have inhibited growth of Aspergillus flavus and Asp. fumigates in vitro.6 Berberine sulfate has been shown to possess antifungal activity in vitro through inhibition of RNA and protein synthesis.41
  • Anti-inflammatory effects: Berberine sulfate administered subcutaneously to the ears of mice in doses of 4-8mg/kg has significantly inhibited xylene-induced swelling.27 Berberine has inhibited edema and inflammation induced in guinea pig paw by carrageenan or zymosan solution.7 Rats treated with 6.6 grams of goldenseal extract in drinking water were repeatedly exposed to a known antigen (keyhole limpet hemocyanin); goldenseal was associated with increased production of IgM following antigen exposure.45 COX-2 regulation has been implicated as a possible mechanism.46,47
  • Anti-proliferative effects: Berberine was shown in vitro to inhibit DNA fragmentation and apoptosis of thymocytes induced by etoposide and camptothecin 48, to affect cell cycle and apoptosis in HeLa/L1210 cells10, and to inhibit synthesis of DNA, RNA, protein, and lipids in ascitic tumor cell lines; however, this inhibition did not carry over to experiments performed in mice49. Berberine significantly inhibited the transformation of lymphocytes, despite the presence of known mitogens in vitro, as measured by [3H]thymidine uptake by lymphocytes.50 After three days of continuous exposure in vitro, berberine significantly inhibited hepatoma cell growth in a dose-dependent manner, and inhibited the release of alpha-fetoprotein after 18 hours of exposure.51 In concentrations of 25mcg/mL, berberine-induced apoptosis during the S-phase of the cell cycle in promyelocytic leukemia HL-60 cells.52 An in vitro study found that 9-ethoxycarbonyl berberine significantly inhibits topoisomerase II.53 Protoberberines are organic cations that are able to intercalate DNA and inhibit topoisomerase I.54 Berberine has also been found to activate macrophages to act against the growth of tumor cells at concentrations above 0.15mcg/mL.28 Additionally, at concentrations above 1.5mcg/mL, berberine has successfully inhibited DNA synthesis in tumor cells. Berberine was shown to induce differentiation of human teratocarcinoma cells into cells with neuronal cell morphology, beginning one day after the addition of 0.1mg/mL berberine to the culture medium.29 In an experiment on mouse skin, berberine inhibited activity of the tumor promoters teleocidin and 12-O-tetradecanoylphorbol-13-acetate.9 In a murine model of Lewis lung carcinoma, oral administration of berberine for two weeks significantly inhibited mediastinal lymph node metastases; however, there was no inhibition of tumor growth in lung parenchyma.55 The addition of berberine to a culture of human brain tumor cell lines resulted in a mean 91% rate of cell death.8 In a rat model of gliosarcoma, berberine administration resulted in a mean 80.9% rate of cell death.8
  • Anti-secretory effects: Berberine sulfate administered orally in doses of 60mg/kg, significantly decreases vascular permeability caused by 0.7% acetic acid in mice.27 Subcutaneous administration of berberine sulfate in doses of 20-50mg/kg decreases vascular permeability induced by histamine.27 Berberine significantly reduces the secretory response of pig jejunal segments to E. coli heat-stable enterotoxin or neostigmine.56,36,57
  • Bilirubin effects: Berberine was shown to increase the secretion of bilirubin in rats with hyperbilirubinemia acutely, although this effect diminished with continued berberine exposure.58 A subsequent study reported berberine to displace bilirubin from albumin both in vitro and in animals, resulting in an increase in serum total and direct bilirubin concentrations.21
  • Cardiovascular effects: A 30-minute infusion of berberine in 12 patients with congestive heart failure at a rate of 0.2mg/kg has been shown to significantly improve systemic and pulmonary vascular resistance, right atrial and left ventricular end-diastolic pressures, cardiac index, and left ventricular ejection fraction.18 Intravenous berberine at a concentration of 0.2mg/kg/min significantly raised left ventricular end-diastolic pressure in anesthetized dogs with embolized left main coronary arteries.59 Berberine has exhibited positive inotropic effects in dogs and prevents/reverses ouabain-induced ventricular arrhythmias.2,3 Berberine plasma concentrations greater than 0.11mg/L have been associated with a significant decrease in the occurrence of ventricular premature beats and a significant increase in left ventricular ejection fraction in patients with congestive heart failure vs. plasma concentrations less than 0.11mg/L.60 Animal experiments have reported berberine to restore ventricular arrhythmias and atrial fibrillation to normal sinus rhythm.4 Berberine 0.2-0.7mg/kg/min increases cardiac output and decreases total peripheral resistance and heart rate in animals; doses of 0.02mg/kg/min only increase cardiac output.61 Berberine sulfate bolus injection (1mg/kg), administered to rats one minute after undergoing coronary artery occlusion significantly reduced early mortality from ventricular fibrillation or complete atrioventricular block (36% mortality vs. 66% mortality in a control group).5 Berberine sulfate solution (5mg/mL) produced a dose-dependent decrease in blood pressure in anesthetized dogs, cats, frogs, and rats that was not inhibited by intravenous atropine, mepyramine maleate, pentolinium tartrate, propranolol or phenoxybenzamine.22 Intravenous berberine caused a significant decrease in systolic and diastolic blood pressure in rats at doses of 2-8mg/kg.24 Berberine has caused bradycardia in isolated right and left atria excised from guinea pigs, which was not reversible by atropine.35 An alcoholic extract of goldenseal has been shown in vitro to cause dose-dependent inhibition of epinephrine, serotonin, and histamine-induced aortic contraction.25 Dose-dependent vasoconstriction was observed beginning at a concentration of 50mcL/mL of goldenseal, although neither berberine nor hydrastine alone demonstrated this effect. Extracts of berberine alone showed inhibitory activity on adrenaline-induced aortic contraction. Hydrastine alone was ineffective. Berberine has been found to competitively inhibit the binding of yohimbine in a fashion similar to that of clonidine, suggesting that berberine may possess partial agonist activity at platelet alpha-2 receptors.39
  • Coagulation effects: The effects of goldenseal on coagulation are not clear. In vitro study has found that berberine inhibits platelet-activating factor and aggregation of platelets with a reported 50% inhibition at a concentration of 38mcg/mL, and inhibits the binding of platelet-activating factor to rabbit platelets with 50% inhibition seen at a concentration of 480mcg/mL.19 Other animal research has reported that berberine inhibits platelet aggregation caused by ADP, arachidonic acid, and collagen, and decreases thromboxane-B2 in rats with ischemic cerebral artery occlusion at doses of 20mg/kg for 1-5 days.20 It has also been noted that goldenseal may reduce the anticoagulant effects of warfarin due to antagonist properties.
  • Cytochrome P450 effects: Goldenseal has been found to inhibit cytochrome P450 3A (4,5) and 2D6 enzyme.33,34
  • CNS effects: In animals, berberine produced sedation and potentiated the sedative effects of pentobarbitone when administered via intraperitoneal or intraventricular routes.37 Berberine has been shown to reduce spontaneous motor activity and prolong hexobarbitone-induced sleeping time when administered to mice.22 The administration of berberine (0.1-0.5g/kg) for 14 days was effective in improving scopolamine-induced amnesia in rats, an effect that was augmented by physostigmine and neostigmine.38
  • Gastrointestinal effects: Oral berberine sulfate (40-80mg/kg) has significantly decreased the occurrence of diarrhea induced by ingestion of castor oil and Cassia angustifolia in mice.27 In 20 healthy subjects, the oral administration of 1.2g of berberine significantly delayed small intestinal transit time of a meglucamine diatrizoate and sorbitol test mixture (71.10 ±22.04 minutes in control vs. 98.25 ±29.03 minutes with berberine, p<0.01).62 In animal study, berberine significantly potentiated emesis in dogs.63
  • Endocrine effects: Berberine was reported to improve insulin resistance and liver glycogen levels similarly to metformin in rats fed a high-fat diet.12 Diabetic rats treated with berberine had significantly lower blood sugar concentrations than control rats.13 Goldenseal has also reduced hyperphagia and polydipsia associated with streptozotocin-induced diabetes mellitus in animals.14 In vitro study reports that berberine decreased glucose absorption by Caco-2 cells.15
  • Berberine, an active component of goldenseal, has been shown to inhibit parathyroid hormone-stimulated bone resorption in animal study.64 Berberine, in doses of 30-50mg/kg daily, has demonstrated an ability to prevent a decrease in bone mineral density of lumbar vertebra in ovariectomized rats and to induce apoptosis of osteoclastic cells.64
  • Muscle relaxant effects: Goldenseal extract, at a cumulative dose of 5mcg/mL, caused complete relaxation of carbachol-precontracted guinea pig trachea in vitro and a significant increase in cAMP levels.65 Berberine sulphate (20mcg/mL) pretreatment blocked the response of ileum, trachea, and rectal muscles to acetylcholine in animals.1 Similarly, an ethanol extract of goldenseal induced relaxation in rabbit bladder muscle in vitro.66 This relaxation was partly blocked by the addition of propranolol to the medium, suggesting a mechanism partially mediated through β-adrenoreceptors. An alcoholic extract of goldenseal inhibited acetylcholine, oxytocin, and serotonin-induced contractions of rat uterus cells in a dose dependent fashion in vitro.30 Berberine inhibited muscle contractions of guinea pig ileum and rat uterus induced by acetylcholine, carbachol, histamine, potassium chloride, and bradykinin.22 Berberine increased the amplitude of slow-response action potentials induced by histamine by 6.2%, increased the maximum rate of depolarization by 21.1%, increased the action potential duration (APD) by 50.1% (APD 50) and 47.2% (APD 100), and effective refractory period by 92.2%.31

Pharmacodynamics/Kinetics:

  • Goldenseal is traditionally believed to be poorly absorbed from the gastrointestinal tract.
  • Berberine plasma concentrations greater than 0.11mg/L have been associated with a significant decrease in the occurrence of ventricular premature beats and a significant increase in left ventricular ejection fraction in patients with congestive heart failure vs. plasma concentrations less than 0.11mg/L.60
  • In vitro, goldenseal extract has been shown to weakly inhibit CYP 3A432; however, this interaction has not been sufficiently evaluated in humans.

References

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  2. Krol R, Zalewski A, Cheung W, and et al. Additive effects of berberine and ouabain on myocardial contractility. Clin Res 1982;30(3):673A.
  3. Krol R, Zalewski A, and Maroko PR. Beneficial effects of berberine, a new positive inotropic agent, on digitalis-induced ventricular arrhythmias. Circulation 1982;66(suppl 2):56.
  4. Ksiezycka E, Cheung W, and Maroko PR. Antiarrhythmic effects of berberine on aconitine-induced ventricular and supraventricular arrhythmias. Clinical Research 1983;31(2):197A.
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