Herb-Drug Interactions: Echinacea

Echinacea species (Asteraceae)

Synonym(s) and related species

Black sampson, Brauneria, Coneflower, Purple coneflower, Rudbeckia.

Echinacea angustifolia (DC) Heller, Echinacea pallida (Nutt.) Britt, Echinacea purpurea (L.) Moensch. Other names that have been used include Brauneria pallida (Nutt.) Britton, Echinacea intermedia Lindl., Rudbeckia hispida Hoffm, Rudbeckia pallida Nutt. Rudbeckia purpurea L. and Rudbeckia serotina (Nutt) Sweet.

Pharmacopoeias

Echinacea angustifolia: Powder and Powdered extract (US Ph 32); Root (British Pharmacopoeia 2009).

Echinacea pallida: Powder and Powdered extract (US Ph 32); Root (British Pharmacopoeia 2009).

Echinacea purpurea: Aerial Parts (US Ph 32); Herb (British Ph 2009); Powder and Powdered extract (US Ph 32); Root (British Ph 2009, The United States Ph 32).

Constituents

The constituents of the various species are slightly different and this leads to confusion as to the potential for drug interactions.

(a) Echinacea angustifolia

The root contains alkamides, mainly 2-monoene isobutyl-amides, and similar caffeic acid esters and glycosides to Echinacea purpurea, including the major component, echinacoside, and cynarin. Alkylketones, and the saturated pyrrolizidine alkaloids, tussilagine and isotussilagine, are also present (these are not the unsaturated hepatotoxic type).

(b) Echinacea pallida

The root contains similar caffeic acid esters and glycosides to Echinacea purpurea, including the major component, echinacoside. Polyenes and polyacetylenes, including a range of ketoalkenes and ketopolyacetylenes, have been reported and polysaccharides and glycoproteins are also present.

(c) Echinacea purpurea

The root contains alkamides, mainly 2,4-dienoic isobutyl-amides of straight-chain fatty acids, caffeic acid derivatives including the major component, cichoric acid, with echinacoside, verbascoside, caffeoylechinacoside, chlorogenic acid, isochlorogenic acid and caftaric acid. The saturated pyrrolizidine alkaloids tussilagine and isotussilagine are present.

The herb contains similar alkamides, and cichoric acid is the major caffeic acid derivative present. Polysaccharides PS1 (a methylglucuronoarabinoxylan), PS2 (an acidic rhamnoarabinogalactan), a xyloglucan and glycoproteins have been reported.

The pressed juice (from the aerial parts) contains heterogeneous polysaccharides, inulin-type compounds, arabinogalactan polysaccharides and glycoproteins.

Use and indications

Echinacea is mainly used for its immunostimulant (immunomodulatory) effects, particularly in the treatment and prevention of the common cold, influenza and other upper respiratory tract infections. It has a long history of medicinal use for infections, both bacterial and viral, especially in skin conditions such as acne and boils, and also in mild septicaemia.

Pharmacokinetics

Most work has been carried out using Echinacea purpurea, although other Echinacea species have been studied on selected isoenzymes. In vitro studies using non-drug probe substrates. suggest that Echinacea purpurea extracts (Echinacare and Echinagard) do not have any significant effects on the cytochrome P450 isoenzyme CYP2D6: a finding supported by in vitro and clinical studies using drugs as probe substrates, see dextromethorphan. Similarly, in vitro studies- suggest that Echinacea purpurea extracts (Echinacare, Echinagard and Echinaforce) either do not inhibit, or only weakly inhibit, CYP1A2, CYP2C9, and CYP2C19. These in vitro findings for CYP2C9 and CYP1A2 would be expected to be replicated in most patients, as suggested by clinical studies with the probe substrates tolbutamide, and caffeine, respectively.

The effects of echinacea on CYP3A4 are less clear. Some extracts of Echinacea angustifolia, Echinacea pallida and Echinacea purpura (Echinagard and Echinaforce) weakly.or moderately inhibited CYP3A4, whereas one extract of Echinacea purpura (Echinacare) caused both weak inhibition and induction of CYP3A4. However, in one study the inhibitory properties varied greatly (150-fold). This seemed to be related to the alkamide content of the extract, although Echinacea pallida contains only low concentrations of alkamides, so other constituents may also have a role in CYP3A4 inhibition. Indeed, one study found that the caffeic acid derivatives echinacoside and cichoric acid caused moderate and very weak CYP3A4 inhibition, respectively.The findings of a clinical study using midazolam (a probe substrate for CYP3A4) were also somewhat complex (see midazolam), but appears to suggest only a clinically modest effect of echinacea on CYP3A4.

Interactions overview

Theoretically, echinacea may antagonise the effects of immunosuppressants. The use of echinacea has been studied with a number of drugs that are used as probe substrates for cytochrome P450 activity or P-glycoprotein. With the possible exceptions of midazolam and caffeine, no clinically relevant interactions have been identified. Echinacea seems to present a low risk for interactions occurring as a result of these mechanisms.

Echinacea + Caffeine

Echinacea appears to have a variable effect on the pharmacokinetics of caffeine. In most patients, echinacea is unlikely to raise caffeine levels.

Clinical evidence

In a pharmacokinetic study, 12 healthy subjects were given an 8-day course of Echinacea purpurea root 400 mg four times daily, with a single 200-mg oral dose of caffeine on day 6. The maximum serum concentration and AUC of caffeine were increased by about 30%. There was a large variation between subjects, with some having a 50% increase in caffeine clearance, and some a 90% decrease. However, the paraxanthine-to-caffeine ratio (a measure of CYP1A2 activity) was reduced by just 10%.’ In another study in 12 healthy subjects given Echinacea purpurea 800 mg twice daily for 28 days, the paraxanthine-to-caffeine ratio was not significantly affected when a single 100-mg dose of caffeine was given at the end of the treatment with Echinacea purpurea.

Experimental evidence

No relevant data found.

Mechanism

Echinacea is an inhibitor of the cytochrome P450 isoenzyme CYP1A2, which is involved in caffeine metabolism. Echinacea was therefore expected to raise caffeine levels. Although the studies found that caffeine levels were modestly raised by caffeine this did not appear to be due to an effect of echinacea on CYP 1A2 (effects found were mild).

Importance and management

Evidence appears to be limited to the two studies cited, which suggest that in most patients echinacea is unlikely to raise caffeine levels by inhibiting CYP1A2. However, some patients did experience a decrease in caffeine clearance, which suggests that, rarely, caffeine levels may be raised. Some patients may therefore experience some increase in the adverse effects of caffeine, such as headache, tremor and restlessness, particularly if they have a high caffeine intake. Should this occur, advise the patient to either stop taking echinacea and/or reduce their caffeine intake.

Caffeine is used as a probe drug for CYP1A2 activity, and therefore these results also suggest that a pharmacokinetic interaction between echinacea and other CYP1A2 substrates is unlikely.

Echinacea + Dextromethorphan

Echinacea does not appear to have a clinically relevant effect on the pharmacokinetics of dextromethorphan.

Clinical evidence

In a study, 12 healthy subjects were given Echinacea purpurea root 400 mg four times daily for 8 days with a single 30-mg dose of dextromethorphan on day 6. In the 11 subjects who were of the cytochrome P450 isoenzyme CYP2D6 extensive metaboliser phenotype there were no changes in the pharmacokinetics of dextromethorphan. In contrast, the one subject who was a poor metaboliser had a 42% increase in the AUC of dextromethorphan and a 31% increase in its half-life. In another study, in 12 healthy subjects given Echinacea purpurea 800 mg twice daily for 28 days, there was no change in the debrisoquine urinary ratio after a single 5-mg dose of debrisoquine.

Experimental evidence

In vitro studies found that an ethanol-based extract of Echinacea purpura (Echinagard) produced a slight, non-significant inhibition of dextromethorphan metabolism, a marker for CYP2D6 activity. Similar effects have been found with other probe substrates of CYP2D6.S

Mechanism

In vitro studies suggest that echinacea has weak inhibitory effects on the cytochrome P450 isoenzyme CYP2D6; however, the in vivo study using debrisoquine (another probe substrate of CYP2D6) suggests that this is not of clinical relevance.

Importance and management

The available evidence seems to reliably suggest that in most patients echinacea does not affect the pharmacokinetics of dextromethorphan. Those who are lacking, or are deficient, in CYP2D6 may experience a modest increase in dextromethorphan levels. However, dextromethorphan is generally considered to have a wide therapeutic range and the dose is not individually titrated. Therefore, the interaction is probably unlikely to be clinically relevant.

Dextromethorphan is used as a probe drug for CYP2D6 activity, and therefore these results (along with those for debrisoquine) also suggest that a clinically relevant pharmacokinetic interaction between echinacea and other CYP2D6 substrates is unlikely.

Echinacea + Digoxin

Echinacea does not appear to have a clinically relevant effect on the pharmacokinetics of digoxin.

Clinical evidence

In a study, 18 healthy subjects were given an extract containing Echinacea purpurea 195 mg and Echinacea angustifolia 72 mg three times daily for 14 days with a single 250-microgram dose of digoxin before and after the course of echinacea. No significant effects on the pharmacokinetics of digoxin were reported for echinacea, suggesting that echinacea does not have any significant effects on P-glycoprotein. No adverse effects were reported when digoxin was given with echinacea.

Experimental evidence

An in vitro study found that Echinacea purpurea extract had no significant effect on the pharmacokinetics of digoxin, a substrate for P-glycoprotein.

Mechanism

No mechanism expected.

Importance and management

The available evidence suggests that echinacea does not significantly affect the pharmacokinetics of digoxin, and therefore no digoxin dosage adjustments appear necessary if echinacea is also taken.

Digoxin is used as a probe substrate for P-glycoprotein, and therefore these results also suggest that a clinically relevant pharmacokinetic interaction between echinacea and other P-glycoprotein substrates is unlikely.

Echinacea + Food

No interactions found.

Echinacea + Herbal medicines

No interactions found.

Echinacea + Immunosuppressants

The interaction between echinacea and immunosuppressants is based on a prediction only.

Evidence, mechanism and importance and management

Echinacea has immunostimulating effects. Theoretically therefore, echinacea may antagonise the effects of immunosuppressant drugs. The manufacturers of three echinacea products licensed by the MHRA in the UK advise against concurrent use with immunosuppressants and specifically name ciclosporin and methotrexate. There do not appear to be any clinical reports of an interaction, but, until more is known, it may be prudent to follow this advice.

Echinacea + Midazolam

Echinacea does not appear to alter the AUC and clearance of oral midazolam, although the bioavailability may be increased. Clearance of intravenous midazolam may be modestly increased in patients taking echinacea.

Clinical evidence

In a pharmacokinetic study, 12 healthy subjects were given Echinacea purpurea root (Nature’s Bounty, USA) 400mg four times daily for 28 days, with a single 50-microgram/kg intravenous dose of midazolam on day 6 and, 24 hours later, a single 5-mg oral dose of midazolam. The clearance of intravenous midazolam was increased by 42%, and its AUC was reduced by 23%. In contrast, the clearance and AUC of oral midazolam were not significantly altered; however, the oral bioavailability of midazolam was increased by 50% but the oral bioavailability was still relatively low. In another study in 12 healthy subjects given Echinacea purpurea 800 mg twice daily for 28 days with a single 8-mg oral dose of midazolam, there was no difference in the ratio of midazolam to its 1-hydroxy metabolite.

Experimental evidence

No relevant data found.

Mechanism

Midazolam is predominantly metabolised by the cytochrome P450 isoenzyme CYP3A4. It was suggested the echinacea may have exerted opposing effects on the cytochrome P450 isoenzyme CYP3A in the liver and the intestine, which resulted in this difference in its effects on oral and intravenous midazolam.

Importance and management

Direct evidence about an interaction between midazolam and echinacea appears to be limited to these two clinical studies. Their findings suggest that echinacea is unlikely to interact with oral midazolam, as even though the oral bioavailability was increased this did not affect the maximum levels or AUC. The interaction of echinacea with intravenous midazolam is, at best, modest. As the dose of intravenous midazolam is usually tapered to the individual’s response, the potential for a reduced effect should be accommodated. The authors of one of the studies suggest that the effect of echinacea on CYP3A4 substrates may depend on whether they have high oral bioavailability and the degree of hepatic extraction, and is not easily predicted. More study is needed to establish if echinacea has any clinically relevant effects on a range of CYP3A4 substrates. See the table Drugs and herbs affecting or metabolised by the cytochrome P450 isoenzyme CYP3A4, for a list of known CYP3A4 substrates.

Echinacea + Tolbutamide

Echinacea does not appear to have a clinically relevant effect on the pharmacokinetics of tolbutamide.

Clinical evidence

In a pharmacokinetic study, 12 healthy subjects were given Echinacea purpurea root 400 mg four times daily for 8 days with a single 500-mg dose of tolbutamide on day 6. The AUC of tolbutamide was increased by 14%, and the time to maximum levels was increased from 4 to 6 hours. The oral clearance was decreased by a mean of 11%, although 2 subjects had a 25% or greater reduction.

Experimental evidence

No relevant data found.

Mechanism

No mechanism expected.

Importance and management

This one study suggests that echinacea does not significantly affect the pharmacokinetics of tolbutamide, and therefore no tolbutamide dosage adjustments appear necessary if echinacea is also taken.

Tolbutamide is used as a probe substrate for CYP2C9, and therefore these results also suggest that a clinically relevant pharmacokinetic interaction between echinacea and other CYP2C9 substrates is unlikely.