Herb-Drug Interactions: Goldenseal

Hydrastis canadensis L. (Ranunculaceae)

Synonym(s) and related species

Hidrastis, Hydrastis, Orange root, Yellow root. Xanthorhiza simplicissima Marsh.

Pharmacopoeias

Goldenseal (US Ph 32); Goldenseal Rhizome (European Ph 2008); Goldenseal Root (British Ph 2009); Powdered Goldenseal (US Ph 32); Powdered Goldenseal Extract (The United States Ph 32).

Constituents

The rhizome of goldenseal contains the isoquinoline alkaloids hydrastine and berberine, to which it may be standardised, and also berberastine, hydrastinine, canadine (tetrahydroberberine), canalidine and others.

Use and indications

Used for inflammatory and infective conditions, such as amoebic dysentery and diarrhoea; gastric and liver disease. The alkaloids are antibacterial, amoebicidal and fungicidal. For details on the uses of berberine, a major constituent of goldenseal, see berberine.

Pharmacokinetics

In several in vitro studies, goldenseal root has been identified as a potent inhibitor of the cytochrome P450 isoenzyme CYP3A4, but more modest inhibitory effects were seen clinically with the CYP3A4 probe substrate, midazolam. Two studies in healthy subjects, found that goldenseal, given for 14 to 28 days, reduced the metabolism or urinary clearance of debrisoquine, a probe substrate of CYP2D6, by 36% and 47%, respectively. In vitro studies using another CYP2D6 probe, dextromethorphan also found that goldenseal inhibits CYP2D6, and suggested that this may be, at least in part, due to berberine; hydrastine had no effects on CYP2D6.

Goldenseal has also been reported to possibly have some inhibitory effect on CYP2C8 (see paclitaxel) and CYP2C9 (see diclofenac). Another studysuggested that goldenseal had no significant effect on CYP2E1 (see chlorzoxazone), CYP1A2 (see caffeine) or CYP2C19. In addition, there is some in vitro evidence of P-glycoprotein inhibition, but no effect was seen on the levels of digoxin, which is used as a probe substrate of this transporter.

For information on the pharmacokinetics of the constituent berberine, see under berberine.

Interactions overview

Goldenseal appears to modestly decrease the metabolism of midazolam, but has no significant effects on the pharmacokinetics of indinavir or digoxin.

Goldenseal does not appear to affect the metabolism of caffeine or chlorzoxazone. The interaction between goldenseal and diclofenac, paclitaxel or tolbutamide is based on experimental evidence only.

For a possible interaction with ciclosporin, occurring as a result of the constituent berberine, see Berberine + Ciclosporin.

Goldenseal + Benzodiazepines

Goldenseal appears to modestly decrease the metabolism of midazolam.

Clinical evidence

A study in 12 healthy subjects investigated the effects of goldenseal 900 mg three times daily taken for 28 days on a single 8-mg dose of oral midazolam. Goldenseal reduced the metabolism of midazolam to hydroxymidazolam by about 40%. The supplement used had no standardisation information. Similarly, in a study in 16 healthy subjects given a single 8-mg dose of midazolam after goldenseal 1323 mg three times daily for 14 days, there was a significant increase in the maximum concentration and AUC of midazolam of 41% and 62%, respectively, and a reduction in the clearance of about 36%. These increases were considered moderate when compared with the effects of clarithromycin and rifampicin in the study, which produced a 448% increase and 93% decrease in the AUC of midazolam, respectively. The goldenseal product used gave an estimated daily dose of berberine of about 77 mg and of hydrastine of 132 mg.

Experimental evidence

Goldenseal appears to be a potent inhibitor of the cytochrome P450 isoenzyme CYP3A4 in vitro. See Pharmacokinetics.

Mechanism

A standardised goldenseal extract appears to modestly inhibit the cytochrome P450 isoenzyme CYP3A4, which is the major route of midazolam metabolism. Concurrent use therefore raises midazolam levels.

Importance and management

Evidence for an interaction between goldenseal and midazolam is based on clinical studies in healthy subjects. They suggest that some caution might be appropriate if patients taking goldenseal supplements are given oral midazolam; however, the effects were modest. Nevertheless, the clinical effects of this interaction do not appear to have been studied and so it may be prudent to be aware of the small possibility of increased sedation if midazolam is given to patients taking goldenseal supplements. Any interaction is unlikely to be significant in patients given a single dose of intravenous or oral midazolam pre-operatively.

Midazolam is used as a probe drug for CYP3A4 activity, and therefore these results also suggest that a modest pharmacokinetic interaction between goldenseal and other CYP3A4 substrates is possible. See the table Drugs and herbs affecting or metabolised by the cytochrome P450 isoenzyme CYP3A4, for a list of known CYP3A4 substrates.

For mention of an animal study of the possible anxiolytic effect of high-dose berberine and its interaction with diazepam, see Berberine + Anxiolytics.

Goldenseal did not affect caffeine metabolism in one study.

Clinical evidence

A study in 12 healthy subjects found that a goldenseal supplement 900 mg three times daily taken for 28 days had no significant effects on the metabolism of a single 100-mg oral dose of caffeine. The supplement used had no standardisation information.

Experimental evidence

See under Mechanism, below.

Mechanism

A standardised goldenseal extract did not inhibit CYP1A2 in vitro, nor did goldenseal have a clinically relevant effect on the cytochrome P450 isoenzyme CYP1A2 activity using caffeine as a probe substrate.

Importance and management

This study suggests that goldenseal does not have any clinically relevant effect on caffeine metabolism in healthy subjects.

Caffeine is used as a probe substrate for CYP1A2 activity, and therefore these results also suggest that a pharmacokinetic interaction as a result of this mechanism between goldenseal and other CYP1A2 substrates is unlikely.

Goldenseal + Chlorzoxazone

Goldenseal did not affect chlorzoxazone metabolism in one study.

Clinical evidence

In a study in 12 healthy subjects, a goldenseal supplement 900 mg three times daily taken for 28 days had no significant effects on the metabolism of a single oral dose of chlorzoxazone 250 mg. The supplement used had no standardisation information.

Experimental evidence

See under Mechanism, below.

Mechanism

A standardised goldenseal extract did not inhibit CYP2E1 in vitro, nor did goldenseal have a clinically relevant effect on the cytochrome P450 isoenzyme CYP2E1 activity using chlorzoxazone as a probe substrate.

Importance and management

Evidence from the clinical study suggests that goldenseal is unlikely to affect the metabolism of chlorzoxazone. Chlorzoxazone is used as a probe substrate for CYP2E1 activity, and therefore these results also suggest that a pharmacokinetic interaction as a result of this mechanism between goldenseal and other CYP2E1 substrates is unlikely.

Goldenseal + Diclofenac

The interaction between goldenseal and diclofenac is based on experimental evidence only.

Evidence, mechanism, importance and management

An in vitro study investigated the effects of a goldenseal extract, (containing equal amounts of the active constituents hydrastine and berberine) on the activity of the cytochrome P450 isoenzyme CYP2C9 in human liver microsomes, using diclofenac as a probe drug. Goldenseal 0.98% inhibited the hydroxylation of diclofenac by about 50%. When berberine and hydrastine were tested separately, hydrastine inhibited CYP2C9 to a greater extent than berberine.However, note that another in vitro study found that goldenseal had little effect on the metabolism of tolbutamide, another probe drug for CYP2C9 activity.

The general relevance of this is unknown as there are no clinical studies reporting the effects of goldenseal on CYP2C9. However, note that in the study cited here, goldenseal was about five times more potent as an inhibitor of CYP3A4 than CYP2C9, and clinically, goldenseal has only a modest effect on the CYP3A4 substrate midazolam. This provides some indication that CYP2C9 inhibition by goldenseal might not be clinically relevant. However, a clinical study is needed to confirm this.

Goldenseal + Digoxin

Goldenseal has only very small effects on the pharmacokinetics of digoxin.

Clinical evidence

A study in 20 healthy subjects given a single 500-microgram dose of digoxin before and on the last day of treatment with standardised goldenseal root extract 1070 mg three times daily for 14 days, found a 14% increase in the maximum digoxin plasma levels, but no other changes in the pharmacokinetics of digoxin. The product gave an estimated daily dose of berberine of about 77 mg and of hydrastine of about 132mg.

Experimental evidence

See under Mechanism, below.

Mechanism

It was suggested that constituents of goldenseal may alter digoxin pharmacokinetics by affecting P-glycoprotein, since goldenseal alkaloids are modulators of P-glycoprotein in vitro. However, the clinical study showed that goldenseal does not cause clinically relevant changes in digoxin pharmacokinetics.

Importance and management

Evidence from the clinical study suggests that goldenseal has only very modest effects on the pharmacokinetics of digoxin, which would not be expected to be clinically relevant. No dosage adjustment would be expected to be necessary if patients taking digoxin also wish to take goldenseal.

Digoxin is used as a probe substrate for P-glycoprotein activity and therefore this study also suggests that goldenseal is unlikely to have a clinically relevant effect on the transport of other drugs by P-glycoprotein.

Goldenseal + Food

No interactions found.

Goldenseal + Herbal medicines

No interactions found.

Goldenseal + Indinavir

Goldenseal does not appear to affect the pharmacokinetics of indinavir.

Clinical evidence

In a study in 10 healthy subjects, goldenseal root (Nature’s Way) 1.14g twice daily for 2weeks did not alter the mean peak plasma level, half-life or oral clearance of a single 800-mg dose of indinavir. Eight of the subjects had less than a 20% increase or decrease in oral clearance, but one subject had a 46% increase and one a 46% decrease.

Experimental evidence

No relevant data found.

Mechanism

Studies using the probe substrate midazolam have suggested that goldenseal is a modest inhibitor of CYP3A4, and it was therefore predicted to inhibit the metabolism of indinavir, which is a substrate for CYP3A4. However, the study here suggests that goldenseal does not have a significant effect on indinavir metabolism. The contrasting results might be explained by indinavir having a relatively high oral bioavailability compared with midazolam. Alternatively, because indinavir is also a potent inhibitor of CYP3A4, as well as a substrate of CYP3A4, the inhibitory effects of indinavir may have negated the minor inhibitory effects of goldenseal.

Importance and management

The clinical study suggests that goldenseal root has no clinically significant effects on indinavir metabolism, and may be taken without any undue concern in patients also taking this protease inhibitor. However, confirmation may be required in light of the midazolam probe study and the two subjects who experienced a relatively greater change in indinavir oral clearance. Further study is needed before firm clinical recommendations can be made.

Goldenseal + Paclitaxel

The interaction between goldenseal and paclitaxel is based on experimental evidence only.

Evidence, mechanism, importance and management

In an in vitro study using human liver microsomes, an aqueous and ethanolic goldenseal extract inhibited CYP2C8 activity by about 50 to 60% when used at a concentration of 20 micromol alkaloids (sum of hydrastine and berberine), and had a lesser effect at 1 micromol (40%). However, because of wide confidence intervals, only the 60% decrease with the ethanolic extract was statistically significant. Paclitaxel was used as a probe cytochrome P450 isoenzyme CYP2C8 substrate, and therefore this study also suggests that goldenseal has the potential to inhibit the metabolism of other CYP2C8 substrates. When studied individually, both berberine and hydrastine had some CYP2C8 inhibitory activity (also not statistically significant).

The general relevance of the effect of goldenseal on paclitaxel metabolism is unknown as there are no clinical studies reporting the effects of goldenseal on CYP2C8 substrates. Note that high-dose berberine blocked the anticancer effects of paclitaxel in one in vitro study, see Berberine + Paclitaxel0, and therefore, until more data are available, some caution may be prudent.

Goldenseal + Tolbutamide

The interaction between goldenseal and tolbutamide is based on experimental evidence only.

Evidence, mechanism, importance and management

An in vitro study investigated the effects of aqueous and alcoholic extracts of goldenseal on the cytochrome P450 isoenzyme CYP2C9 as measured by the activity of tolbutamide hydroxylase. The activity of CYP2C9 was increased by about 35% when incubated with the extract with an alkaloid concentration of 1 micromol, but this was only statistically significant for the ethanolic extract. Moreover, the higher alkaloid concentration of 20 micromol had no effect. Note that another in vitro study found that goldenseal inhibited the metabolism of diclofenac, a probe drug for CYP2C9.

The clinical relevance of these results is unknown, and the disparate findings of goldenseal on CYP2C9 are not easily explained, but any effect was modest. Therefore goldenseal would be expected to have only modest, if any, effects on the response to tolbutamide. Further study is needed to assess these effects.