^ Ettefagh K.A., Burns J.T., Junio H.A., Kaatz G.W., Cech N.B., "Goldenseal (Hydrastis canadensis L.) Extracts Synergistically Enhance the Antibacterial Activity of Berberine via Efflux Pump Inhibition", Planta Medica 2010
Mechanism of action
Herbalist Paul Bergner investigated the research and has been unable to find case reports where the level of intestinal pathogens are lower after taking goldenseal. In fact, a study by Rabbani where men with E. coli induced diarrhea had 42–48% reduced symptoms after taking berberine showed unchanged levels of intestinal bacteria, pathogenic or otherwise.
It appears likely that goldenseal shares with Mahonia (Oregon grape) and Berberis (Barberry) the ability to inhibit the drug resistance efflux pumps (MDR pumps) of bacteria, as discussed below.
Constituents and modern pharmacology
Goldenseal contains the isoquinoline alkaloids: hydrastine, berberine, berberastine, hydrastinine, tetrahydroberberastine, canadine, and canalidine. A related compound, 8-oxotetrahydrothalifendine was identified in one study. One study analyzed the hydrastine and berberine contents of twenty commercial goldenseal and goldenseal-containing products and found they contained variously 0%-2.93% hydrastine and 0.82%-5.86% berberine. Berberine and hydrastine act as quaternary bases and are poorly soluble in water but freely soluble in alcohol. The herb seems to have synergistic antibacterial activity over berberine in vitro, possibly due to efflux pump inhibitory activity.
Multiple bacteria and fungi, along with selected protozoa and chlamydia are susceptible to berberine in vitro. Berberine alone has weak antibiotic activity in vitro since many microorganisms actively export it from the cell (although a whole herb is likely to work on the immune system as well as on attacking the microbes and hence have a stronger clinical effect than the antibiotic activity alone would suggest). Interestingly, there is some evidence for other berberine-containing species synthesizing an efflux pump inhibitor that tends to prevent antibiotic resistance, a case of solid scientific evidence that the herb is superior to the isolated active principle. However, it is not yet known whether goldenseal contains a drug resistance efflux pump inhibitor, although many antimicrobial herbs do.
Most of the research that is popularly attributed to goldenseal has actually been into the constituent berberine, which goldenseal has in common with a variety of other medicines including oregon-grape, coptis, phellodendron, barberry (Berberis vulgaris) and yellowroot. However, constituents frequently act differently in isolation than a whole herb acts in the body. In 1996, the committee of the European Union that regulates drugs placed barberry in a table of Herbal Drugs with Serious Risks without any Accepted Benefit because it contains berberine. Paul Bergner investigated the literature and was able to find only a single report of potential adverse effects of berberis species, berberine-containing plants, or berberine itself in a computer search of the MEDLINE and TOXLINE databases of the U.S. National Library of Medicine. This was a study in China that showed that berberine sulfate is inappropriate for the treatment of newborn infants with prenatal jaundice. However that is not a likely scenario in a country where babies born jaundiced are hospitalized, but it does lend credence to the traditional advice not to take goldenseal or other berberine herbs during pregnancy.
Research into the toxicology and pharmacology of goldenseal has focused on berberine and hydrastine, which are antimicrobial, chloretic and each have a variety of other properties helping immunity. But toxicity in a concentrated constituent does not translate to toxicity of the whole herb, which contains many other compounds. In one study, the lethal dose (LD50) for rats was 12 times lower with hydrastine than with goldenseal extract.
A study where pregnant rats fed were about 47 times the usual human dose of 26 mg/kg concluded, "Maternal liver weights were increased at ≥6250 ppm, suggesting possible enzyme induction. There was no definitive evidence of developmental toxicity in this study." Another study, where mice were fed ~300 times the estimated human intake from dietary supplements, concluded, "Maternal liver weights were increased at greater than 12,500 ppm, but in the absence of treatment-related histopathological lesions. At the high dose, definitive evidence of developmental toxicity was limited to a statistically significant (~8%) reduction in average fetal body weight per litter."
The lethal dose (LD50) of berberine isolates in humans is thought to be 27.5 mg/kg. Berberine is absorbed slowly orally; it achieves peak concentrations in 4 hours and takes 8 hours to clear Berberine is excreted in the urine and human studies of berberine show evidence it can be absorbed through the skin. Pharmacokinetic data is not available for hydrastine or goldenseal root powder. Berberine in humans can cause blocking of receptors in smooth muscle, blocking potassium channels in the heart and reducing ventricular tachycardia, inhibiting intestinal ion secretion and toxin formation in the gut and increasing bile secretion.
While goldenseal, like all alkaloid-rich herbs including coffee and tobacco should be avoided during pregnancy and given to very young children with care, it appears that goldenseal is unlikely to be toxic in normal doses. Interactions with drugs with narrow therapeutic windows like warfarin, ciclosporin, protease inhibitors and cardiac glycosides are potential concerns.
Side effects of goldenseal may include "digestive complaints, nervousness, depression, constipation, rapid heartbeat, diarrhea, stomach cramps and pain, mouth ulcers, nausea, seizures, vomiting, and central nervous system depression. High doses may cause breathing problems, paralysis, and even death. Long-term use may lead to vitamin B deficiency, hallucinations, and delirium." In addition, goldenseal may cause brain damage to newborn babies if given to them directly or if taken by their breastfeeding or pregnant mothers, and may affect blood pressure unpredictably because it contains several different compounds that have opposite effects on blood pressure.
Goldenseal has an affinity for mucosa, and is cooling so should not be used if an infection is at an early stage or there are more chills than fever. Goldenseal should be used with caution only while sick with illnesses that respond to hydrastine and berberine. It should generally not be taken for an early stage Upper Respiratory Infection (URI), but reserved for illnesses in which there is yellow or green phlegm. Generally a two-week maximum dosage is suggested. Taking goldenseal over a long period of time can reduce absorption of B vitamins. Avoid goldenseal during pregnancy and lactation, with gastrointestinal inflammation, and with proinflammatory disorders.A recent study (2011) found rats fed with Goldenseal constantly for two years had a greater tendency towards tumor formation.
Goldenseal has been found to have inhibited cytochrome P450 CYP2D6, CYP3A4, and CYP3A5 activity by approximately 40%, a statistically and clinically significant reduction. CYP2D6 specifically is a known metabolizer of many commonly used pharmaceuticals, such as antidepressants (including all SSRIs except for fluvoxamine), neuroleptics, and codeine. Combining Goldenseal with such medications should be done with caution and under the supervision of a doctor as it can lead to serious - perhaps fatal - toxicity. Those with a genetic deficiency in these enzymes are at particular risk.