Herb-Drug Interactions: Valerian

Valeriana officinalis L. (Valerianaceae)

Synonym(s) and related species

All-heal, Belgian valerian, Common valerian, Fragrant valerian, Garden valerian.

Many other Valerian species are used in different parts of the world.

Pharmacopoeias

Powdered Valerian (The United States Ph 32); Powdered Valerian Extract (The United States Ph 32); Valerian (British Ph 2009, The United States Ph 32); Valerian Dry Aqueous Extract (European Ph 2008); Valerian Dry Hydroalcoholic Extract (British Ph 2009, European Ph, 6th ed., 2008 and Supplements 6.1, 6.2, 6.3 and 6.4); Valerian Root (European Ph, 6th ed., 2008 and Supplements 6.1, 6.2, 6.3 and 6.4); Valerian Tablets (The United States Ph 32); Valerian Tincture (British Ph 2009, European Ph, 6th ed., 2008 and Supplements 6.1, 6.2, 6.3 and 6.4).

Constituents

Valerian root and rhizome contains a large number of constituents which vary considerably according to the source of the plant material and the method of processing and storage. Many are known to contribute to the activity, and even those that are known to be unstable may produce active decomposition products. The valepotriates include the valtrates, which are active constituents, but decompose on storage to form other actives including baldrinal, and volatile constituents. The volatile oil is composed of valerenic acids and their esters, and other derivatives including isovaleric acid (which is responsible for the odour of valerian), and others. Other constituents present include: the free amino acids gamma-aminobutyric acid (GABA); the flavonoids flavone 6-methylapigenin, hesperidin and linarin; alkaloids of the pyridine type including valerianine and valerine; and sterols including beta-sitosterol.

Valerian dry hydroalcoholic extract is an extract produced from valerian root and contains a minimum of 0.25% sesquiterpenic acids, expressed as valerenic acid.

Use and indications

Valerian is used particularly for stress and insomnia. It has long been used as a hypnotic, sedative, anxiolytic, antispasmodic, carminative and antihypertensive, and for hypochondriasis, migraine, cramp, intestinal colic, rheumatic pains and dysmenorrhoea. Despite many pharmacological studies showing sedative and anxiolytic effects, and binding or modulation of constituents to GABA and other neuro-transmitter receptors, the clinical efficacy is not conclusively proven. A recent study suggested that it is safe, but not necessarily effective; however, many analytical reports also show that extracts and products of valerian vary greatly in both chemical composition and biological activity, and it may be that only certain preparations have any therapeutic benefit. Many commercial products use valerian in combination with hops, passiflora and other herbal extracts, and there is some evidence that these may be more efficacious, although again this is not clinically proven. The use of valerian as an aid to benzodiazepine withdrawal has been suggested on the basis of GABA-receptor binding effects, and there is a small study in mice which suggests that it may be useful to a limited extent; again this has not been shown clinically.

Pharmacokinetics

An in vitro study using a number of different valerian root preparations (capsules or tablets of the powdered extract, and teas) found that the products tested inhibited the cytochrome P450 isoenzyme CYP3A4. Other in vitro studies have found no effects, or an inductive effect at levels unlikely to be obtained clinically. Generally, studies suggest that any effect on CYP3A4 is unlikely to be of clinical importance, see benzodiazepines.

A further in vitro study suggests that valerian has no effect, or weak effects, on CYP1A2 (see also caffeine), CYP2C9 or CYP2C19. This study also suggests that valerian does not affect CYP2D6, although another in vitro study suggests that valerian may cause induction of CYP2D6, but this was at concentrations that are unlikely to be attained in vivo. These effects are unlikely to be clinically relevant because a study in 12 healthy subjects found that valerian root extract had no significant effects on the metabolism of debrisoquine, a probe substrate for CYP2D6, as did another clinical study using dextromethorphan). A further clinical study suggests that valerian also has no clinically relevant effect on CYP2E1, see chlorzoxazone.

In vitro investigations have suggested that valerian may inhibit P-glycoprotein, although the authors of one study concluded that this is unlikely to be clinically relevant, because the concentration at which this occurred is unlikely to be attained in vivo, and the findings of another study suggested that the effects were much weaker than those of verapamil, a known, clinically relevant P-glycoprotein inhibitor.

For information on the pharmacokinetics of individual flavonoids present in valerian, see under flavonoids.

Interactions overview

Valerian does not appear to affect the metabolism of alprazolam, caffeine, chlorzoxazone, dextromethorphan or midazolam to a clinically relevant extent. Valerian may increase the sleeping time in mice in response to alcohol and barbiturates. Case reports describe possible interactions with ginkgo, see Ginkgo + Herbal medicines; Valerian, and St John’s wort and/or loperamide, see St John’s wort + Loperamide. For information on the interactions of individual flavonoids present in valerian, see under flavonoids.

Valerian + Alcohol

The interaction between valerian and alcohol is based on experimental evidence only.

Clinical evidence

No interactions found.

Experimental evidence

In a study in mice, a valepotriate extract of valerian, given in high doses, almost doubled the sleeping time in response to alcohol. In contrast, in a separate experiment, the extract appeared to antagonise the effects of alcohol on motor activity.

Mechanism

Additive CNS depressant effects.

Importance and management

The evidence of an interaction between valerian and alcohol appears to be limited to a study in mice. However, valerian is said to have sedative effects, and is used for insomnia, and so additive effects on sedation seem possible. The manufacturers of two herbal products containing valerian that are registered by the MHRA in the UK advise against excessive alcohol intake while taking valerian because the sedative effect of valerian may be potentiated by alcohol. It seems reasonable to suggest that additive sedative effects are possible. It would be prudent to warn patients that they may be more sedated if they drink alcohol while taking valerian and, if this occurs, to avoid undertaking skilled tasks. Note that, in the study in mice, the sedative effects of valepotriates, even in large doses, were more modest than those of diazepam and chlordiazepoxide. Remember that not all the indications of valerian are as an anxiolytic/hypnotic.

Valerian + Barbiturates

The interaction between valerian and barbiturates is based on experimental evidence only.

Clinical evidence

No interactions found.

Experimental evidence

In a study in mice, valerenic acid (an active constituent of valerian) 50 or 100 mg/kg was found to increase sedation (measured by balance tests), but only at the highest doses. The effect was strongest 10 to 15 minutes after administration. Pentobarbital 60mg/kg also sedated the mice, but the effects were more pronounced than those with valerenic acid. When both substances were given together, valerenic acid prolonged the sleeping time in response to pentobarbital. The effect was dose dependent, with the higher valerenic acid dose approximately doubling the pentobarbital sleeping time.

Mechanism

Valerenic acid has non-specific central nervous depressant properties, which appear to enhance the effects of pentobarbital.

Importance and management

Evidence for an interaction between valerenic acid and pentobarbital appears to be limited to this study in mice; however, the effects are in line with the known activities of both substances. It is unclear whether the use of valerian would result in an effect of similar magnitude, but some additive sedation seems likely. Other barbiturates do not appear to have been studied, but it seems likely that they will interact similarly. It may therefore be prudent to consider the potential additive sedative effects in any patient taking barbiturates with valerian. This seems most likely to be of importance with the use of phenobarbital (or other barbiturates) for epilepsy, when sedative effects are less desirable. It would be prudent to warn patients that they may be more sedated and, if this occurs, to avoid undertaking skilled tasks. Remember that not all the indications of valerian are as an anxiolytic/hypnotic.

Valerian + Benzodiazepines

Valerian does not affect the pharmacokinetics of alprazolam or midazolam to a clinically relevant extent However, additive sedative effects are a possibility.

Clinical evidence

In a crossover study, 12 healthy subjects were given valerian root extract 1 g each night for 14 days, with a single 2-mg dose of alprazolam on the morning of day 15. Valerian increased the maximum plasma concentration of alprazolam by 20%, but there were no other statistically significant changes in the pharmacokinetics of alprazolam. The valerian extract used in this study contained 11 mg of valerenic acid per gram.

In another study, 12 healthy subjects were given valerian root extract 125 mg three times daily for 28 days before receiving a single dose of midazolam. Valerian root extract caused no significant changes in the metabolism of midazolam.

Experimental evidence

No relevant data found.

Mechanism

Valerian has been found in some in vitro studies to be an inhibitor of the cytochrome P450 isoenzyme CYP3A4. See Pharmacokinetics. Alprazolam and midazolam are metabolised by this isoenzyme. The minor pharmacokinetic changes reported therefore suggest that, clinically, valerian has only slight effects on CYP3A4.

Importance and management

Evidence from two well-designed clinical studies suggest that valerian does not have a clinically relevant effect on the pharmacokinetics of either alprazolam or midazolam (the 20% rise in alprazolam levels seen in one study would not be expected to be clinically relevant). Therefore no dosage adjustment of either benzodiazepine would appear to be needed if valerian is also given. However, note that valerian is said to have sedative effects, and is used for insomnia, and so additive effects on sedation seem possible. There seems to be no reason to avoid the concurrent use of valerian with alprazolam or midazolam, but, as with any combination of CNS depressant drugs, warn patients that they be more drowsy, and caution against undertaking skilled tasks if this occurs. Midazolam is used as a probe drug for CYP3A4 activity, and therefore these results also suggest that a pharmacokinetic interaction between valerian and other CYP3A4 substrates is unlikely.

Valerian + Caffeine

Valerian does not affect the pharmacokinetics of caffeine to a clinically relevant extent. However, the stimulant effects of caffeine may oppose the hypnotic effects of valerian.

Clinical evidence

In a study, 12 non-smoking healthy subjects were given valerian root extract 125 mg three times daily for 28 days with a single 100-mg dose of oral caffeine at the end of supplementation. Valerian root extract caused no significant changes in the metabolism of caffeine.

Experimental evidence

No relevant data found.

Mechanism

Opposing pharmacological effects.

Importance and management

Although the evidence is limited to one study, it was a well-designed study in healthy subjects. It suggests that the use of valerian will not alter the pharmacokinetics of caffeine. However, the effects of caffeine (a stimulant) are likely to be in direct opposition to the effects of valerian (a hypnotic) and, although this does not appear to have been studied, caffeine has been shown to diminish the effects of other known hypnotic drugs. Therefore patients requiring valerian for its hypnotic properties should probably also consider their caffeine intake.

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

Valerian + Chlorzoxazone

Valerian does not affect the pharmacokinetics of chlorzoxazone to a clinically relevant extent. However, additive sedative effects are a possibility.

Clinical evidence

In a study, 12 healthy subjects were given valerian root extract 125 mg three times daily for 28 days with a single 250-mg dose of oral chlorzoxazone at the end of supplementation. Valerian root extract caused no significant changes in the metabolism of chlorzoxazone.

Experimental evidence

No relevant data found.

Mechanism

Additive pharmacological effects.

Importance and management

Although the evidence is limited to one study, it was a well-designed study in healthy subjects. It suggests that the use of valerian will not alter the pharmacokinetics of chlorzoxazone. However, note that chlorzoxazone has sedative effects and, although this was not studied, it may be prudent to consider the possibility of additive sedation when valerian is also given.

Chlorzoxazone is used as a probe drug for CYP2E1 activity, and therefore these results also suggest that a pharmacokinetic interaction between valerian and other CYP2E1 substrates is unlikely.

Valerian + Dextromethorphan

Valerian does not affect the pharmacokinetics of dextromethorphan to a clinically relevant extent.

Clinical evidence

In a crossover study, 12 healthy subjects were given valerian root extract 1 g each night for 14 days, with a single 30-mg dose of dextromethorphan on the morning of day 15. Valerian extract caused no significant changes in the pharmacokinetics of dextromethorphan. The valerian extract used in this study contained 11 mg of valerenic acid per gram.

Experimental evidence

See Pharmacokinetics, for in vitro studies of the possible inducing effects of valerian on the cytochrome P450 isoenzyme CYP2D6.

Mechanism

Although in vitro study suggests that valerian may induce the cytochrome P450 isoenzyme CYP2D6, this effect only occurred at high dose, and the clinical study suggests that this effect does not occur in humans.

Importance and management

Although the evidence is limited to one study, it was a well-designed study in healthy subjects. It suggests that the use of valerian will not alter the pharmacokinetics of dextromethorphan.

Dextromethorphan is used as a probe drug for CYP2D6 activity, and therefore these results also suggest that a pharmacokinetic interaction between valerian and other CYP2D6 substrates is unlikely.

Valerian + Food

No interactions found.

Valerian + Herbal medicines

For a report of a possible interaction between valerian and ginkgo, see Ginkgo + Herbal medicines; Valerian. For a case describing delirium in a patient taking St John’s wort, valerian and loperamide, see St John’s wort + Loperamide.