Herb-Drug Interactions: Turmeric

Curcuma longa L. (Zingiberaceae)

Synonym(s) and related species

Indian saffron.

Curcuma domestica Valeton is generally accepted to be the same species as Curcuma longa.

The related species Curcuma aromatica Salisb. is known as wild or aromatic turmeric and Curcuma xanthorrhiza D. Dietr. is known as Javanese turmeric.

Not to be confused with Curcuma zedoaria (Christmann) Roscoe, which is zedoary.

Pharmacopoeias

Javanese Turmeric (British Ph 2009, European Ph 2008); Turmeric (US Ph 32); Powdered Turmeric (US Ph 32); Powdered Turmeric Extract (The United States Ph 32).

Constituents

The active constituents are curcuminoids, and include a mixture known as curcumin which contains diferuloylmethane (sometimes referred to as curcumin or curcumin I), desmethoxycurcumin (curcumin II), bisdesmethoxycurcumin (curcumin III) and cyclocurcumin (curcumin IV). Most commercially available preparations of ‘curcumin’ are not pure, but also contain desmethoxycurcumin and bisdesmethoxycurcumin. The related species Curcuma aromatica and Curcuma xanthorrhiza also contain curcuminoids.

The essential oil contains mainly turmerones, including zingiberene.

Use and indications

Turmeric has many biological activities, which are mainly attributed to the curcuminoids that it contains. It is widely used as an anti-inflammatory and liver protecting agent, and its chemopreventive effects for cancer (inhibition of tumour formation, promotion, progression and dissemination in many animal models) are the subject of much research. Turmeric is also used for disorders related to the ageing process. Curcumin has an anti-oxidant and anti-inflammatory activity, and has been proposed as a treatment for many degenerative diseases with an inflammatory or oxidative basis, such as cardiovascular diseases, type 2 diabetes, arthrosis and arthritis, among others. Turmeric is also used as a spice in food.

Pharmacokinetics

An in vitro study suggested that curcumin-containing extracts from Curcuma longa may inhibit intestinal CYP3A4; this finding is supported by a study in rats, see midazolam. A study in rats fed curcumin, found that even large amounts of curcumin (5 g/kg) did not alter the activity of hepatic cytochrome P450 isoenzymes.

Several in vitro studies have suggested that curcumin inhibits or alters the effects of P-glycoprotein. See also beta blockers. Further study using individual curcumin constituents extracted from turmeric powder found that curcumin I has a greater inhibitory action on P-glycoprotein than curcumin II or curcurmin III, although curcumin III has been shown to have a greater influence on the multidrug resistance gene (of which P-glycoprotein is a product).

Interactions overview

Turmeric or its constituent curcumin affects the absorption of some beta blockers, increases the absorption of midazolam, but does not affect the absorption of iron. Pipeline, from pepper, enhances the bioavailability of curcumin.

Turmeric + Beta blockers

In a clinical study, curcumin, a major constituent of turmeric, decreased the absorption of talinolol, a P-glycoprotein substrate. Curcumin increased the absorption of celiprolol, another P-glycoprotein substrate, in rats.

Clinical evidence

In a randomised study, 12 healthy subjects were given a single 50-mg dose of talinolol after taking curcumin, a major constituent of turmeric, 300 mg daily for 6 days. Curcumin was found to reduce the AUC and maximum plasma level of talinolol by 33% and 28%, respectively, but no clinically significant changes in heart rate or blood pressure occurred.

Experimental evidence

In a study, rats were given curcumin 60 mg/kg daily for 5 days. Thirty minutes after the last dose of curcumin, a single 30-mg/kg dose of celiprolol was given. Curcumin increased the AUC and maximum plasma concentration of celiprolol by 30% and 90%, respectively. In a parallel single-dose study in rats curcumin 60 mg/kg, given 30 minutes before a single 30-mg/kg dose of celiprolol, had no effect on the pharmacokinetics of celiprolol.

Mechanism

It was thought that curcumin inhibits P-glycoprotein and therefore increases the absorption of P-glycoprotein substrates such as talinolol. This appears to be the case in a rat study, where curcumin had effects similar to (but weaker than) other known, clinically relevant P-glycoprotein inhibitors, that is, it increased the absorption of celiprolol, another P-glycoprotein substrate. However, in a clinical study the absorption of talinolol was unexpectedly decreased by curcumin, although, clinically, the known P-glycoprotein inhibitor verapamil also decreases talinolol absorption. This suggests that there may be other mechanisms involved in talinolol absorption. Differential effects on hepatic and intestinal P-glycoprotein may also be of relevance.

Importance and management

Evidence for an interaction between curcumin (a major constituent of turmeric) and beta blockers is sparse, but the available evidence does suggest that curcumin can modify the absorption of beta blockers that are P-glycoprotein substrates. The findings with talinolol were similar to the effects seen clinically with other P-glycoprotein inhibitors (see Mechanism above). However, the effects on absorption were modest, and beta blockers are generally accepted to have a wide therapeutic margin, so these findings would not be expected to be clinically relevant. It is unclear whether the effects of curcumin on celiprolol in rats will be replicated in humans. However, as with talinolol the effects were modest and are therefore unlikely to be clinically relevant.

Turmeric + Food

Consider Turmeric + Herbal medicines; Pepper, below. Turmeric is used as a spice in food.

Turmeric + Herbal medicines; Pepper

Piperine, a major constituent of pepper, increases the bioavailability of curcumin, a major constituent of turmeric.

Clinical evidence

In a crossover study, 8 healthy subjects were given a single 2-g dose of curcumin, a major constituent of turmeric, powder alone, or with piperine, a major constituent of pepper, powder 20 mg. When curcumin was given alone, its serum levels were either very low or undetectable. The addition of piperine increased curcumin levels 30-fold over the first 45 minutes, and the relative bioavailability of curcumin was increased 20-fold. Concurrent use was well tolerated.

Experimental evidence

In an experimental study, rats were given a single 2-g/kg dose of curcumin alone, or with piperine 20 mg/kg. Although piperine modestly increased the maximum levels and AUC of curcumin, these changes were not statistically significant. Note that curcumin was reasonably well absorbed in rats, in contrast to humans, where absorption is poor, but this may have been due to the much greater doses given.

Mechanism

Unknown. It was suggested that piperine may inhibit the metabolism of curcumin.

Importance and management

In general the evidence supports the suggestion that piperine (a constituent of pepper) increases the bioavailability of curcumin (a major constituent of turmeric). This interaction may be beneficial because the effects of curcumin may be increased; however, it may also increase the potential for curcumin to interact with other medicines. The effect of piperine on the absorption of curcumin from turmeric extracts does not appear to have been studied, but it seems reasonable to expect a similar increase in bioavailability.

Turmeric + Iron compounds

Turmeric does not appear to affect the bioavailability of dietary levels of iron.

Clinical evidence

In a randomised, crossover study, 30 healthy women were given a standard Thai meal (fortified with about 4 mg of isotopically labelled ferrous sulfate), with rice, to which 500 mg of ground turmeric had been added. Turmeric was found to have no effect on the absorption of iron.

Experimental evidence

No relevant data found.

Mechanism

It was thought that polyphenols in turmeric may inhibit iron absorption.

Importance and management

The study cited suggests that turmeric does not inhibit the absorption of dietary levels of iron. However, the authors note that the amount of turmeric used was relatively low, when compared with the intake from some Asian diets. Furthermore, the effects of turmeric on iron supplementation (e.g. ferrous sulfate in doses of 200 mg) does not appear to have been studied, so it is difficult to predict the effect of the use of turmeric as a herbal medicine on iron replacement therapy.

However, what is known suggests that an interaction would not be expected.

Turmeric + Midazolam

The interaction between curcumin, a major constituent of turmeric, and midazolam is based on experimental evidence only.

Clinical evidence

No interactions found.

Experimental evidence

In a study, rats were given curcumin, a major constituent of turmeric, 60 mg/kg daily for 5 days. Thirty minutes after the last dose of curcumin, a single 20-mg/kg dose of midazolam was given. Curcumin increased the AUC of midazolam 3.8-fold and, although the maximum plasma level was approximately doubled, this was not statistically significant.

Mechanism

Midazolam is a substrate of the cytochrome P450 subfamily CYP3A (specifically the isoenzyme CYP3A4). The authors of the study suggest that curcumin inhibited intestinal CYP3A, resulting in a decrease in the metabolism of midazolam by this route, which led to an increase in its bioavailability.

Importance and management

Evidence appears to be limited to this study in rats, which demonstrated a large increase in the bioavailability of midazolam. These findings are difficult to reliably extrapolate to humans, but, as the effect was so large, it would seem reasonable to assume that curcumin could cause a clinically relevant increase in the bioavailability of midazolam, which may lead to an increase in the sedative effects of midazolam. It is not clear whether turmeric, of which curcumin is a major constituent, would have similar effects, but if large doses are given an effect seems possible. It would seem prudent to warn patients taking curcumin, and turmeric, about the possible increase in sedative effects.

Midazolam is used as a probe drug for CYP3A4 activity, and therefore these results also suggest that a pharmacokinetic interaction between curcumin (and therefore possibly turmeric) 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.