Valerian for Insomnia: The "Natural" Valium

By David Kiefer, MD, Dr. Kiefer is a Clinical Instructor, Family Medicine, University of Washington in Seattle; Clinical Assistant Professor of Medicine, University of Arizona, Tucson, and Adjunct Faculty at Bastyr University in Seattle; Dr. Kiefer reports no financial relationships relevant to this field of study.

For many people who have trouble sleeping, valerian is one of the herbal medicines first thought of as a sleep aid. Perhaps they started by trying an infusion of chamomile (Matricaria recutita), with some effect, but the insomnia lingered, and word of mouth or internet research led invariably to products containing valerian.

Valerian has an aroma that has been likened to smelly sport socks steeping for a week on the back porch, so do you counsel your patients to stick with the infusion, switch to capsules, try a tincture, use a conventional medical pharmaceutical aid, or move on to the other sleep aids you have learned about in past issues of Alternative Medicine Alert? The details behind valerian's sedative effects, and clinical trials for insomnia, as detailed below, will help you make this important decision.

History and Traditional Use

Since the time of ancient Greece, valerian has been used for a variety of psychiatric and medical conditions, including insomnia, epilepsy, stress, anxiety, depression, and for "nervous headache" and "shell shock."1,2 In Ayurvedic medicine, valerian is used for hysteria and neurosis. The German Commission E mentions valerian root as a bath additive for mild sedation, and valerian oil as a treatment used for cholera during World War II.1 Various valerian species are used as spasmolytics for the gastrointestinal tract, as well as for hypertension, angina, asthma, menstrual cramps, biliary colic, and palpitations.2

Botany and Pharmacology

In Western herbal medicine, the Latin scientific name for valerian, or European valerian, is Valeriana officinalis, one of about 250 species of Valeriana.2 Herbal medicine sources also mention Mexican valerian (V. edulis) and Indian valerian (V. wallichii, V. jatamansi).1,3,4 These plants may grow to 3 feet in height, and are a part of the family Valerianaceae.

The active ingredients thought to account for the medicinal activity of V. officinalis are valepotriates (iridoid compounds), essential oil (monoterpenes, sesquiterpenes, esters of valerianic and isovaleric acid), and valerenic acid (cyclopentane sesquiterpenes).1 Different proportions of these compounds are extracted, each having different stabilities based on the type of solution. For example, different percentages of alcohol used in extractions of valerian root affect the amount of valerenic acid and valepotriates in the final product; the clinical significance of this is still unknown, as the exact physiological effects of the individual phytochemicals continues to be elucidated.3 Also, whereas ethanolic extracts contain both valepotriates and valerenic acids, according to one analysis, there is a limited presence of valepotriates in aqueous extracts.2

The strong smelly sock odor? It comes from isovaleric acid produced when the unstable valepotriate compounds decompose.1

Mechanism of Action

Animal studies on valerian root extract have shown a prolongation of barbiturate-induced sleeping time, anticonvulsant effects, decreased neuronal activity, and displacement of GABA from rat brain cortex tissue, but no interaction with benzodiazepine or opiate receptors.4 In rats, a 70% ethanolic valerian extract was shown to decrease sleep latency without affecting sleep quality (as represented by delta wave sleep), total time of wakefulness, non-REM sleep, or REM sleep.5

Both a valerian extract standardized to 0.3% valerenic acid and purified valerenic acid have been shown to inhibit neurons via GABA-A receptors in an in vitro rat brainstem preparation, possibly either by direct GABA receptor action or increasing the availability of GABA.6,7

Valerenic acid appears to inhibit GABA breakdown, leading to sedation and decreased CNS activity, whereas the valepotriates may bind to dopamine receptors, thereby decreasing central dopamine excitation.4

Also, valerenic acid and the valepotriates act as spasmolytics, the latter by transformation into the active metabolite homobaldrinal and mediated by calcium metabolism.2,4 In animal models, both ethanolic and aqueous extracts decrease coronary and bronchial spasm, as well as decrease blood pressure.2

With respect to how valerian acts, some human trials have begun to illustrate what valerian does not do, at least in a single dose. Fourteen people older than age 65 were randomized to receive single oral doses of temazepam (15-30 mg), diphenhydramine (50-75 mg), or Jamieson brand valerian capsules (400-800 mg) in a double-blind study protocol.8 No significant differences with placebo were noted with either dose of valerian on subjective or objective sleep measures, mood, psychomotor performance, or side effects. The valerenic acid concentration in these capsules was 0.683%, slightly less than the industry standard of 0.8%.

Another small trial in 10 young healthy volunteers studied 3 different doses of a valerian extract (600, 1,200, 1,800 mg), diazepam, and placebo, and documented no effects in the valerian groups on subjective symptoms, as per five standardized questionnaires exploring mood and psychomotor/cognitive performance.9

Clinical trials

There have been numerous clinical trials examining the use of valerian, both alone and in combination with other herbs, to treat insomnia; some of these are summarized in two systematic reviews and one meta-analysis, comprising a total of 62 clinical trials. One showed a relative risk of 1.8 for improved sleep, though there were concerns over methodological flaws and publication bias for the 16 trials examined,10 and another revealed inconclusive and contradictory findings for its nine trials.11

The most recent review included 37 studies of valerian for insomnia and noted the type of valerian extraction (water-based or alcohol-based), other herbs added to the product, and the sleep measure utilized as an outcome.3 There were 29 clinical trials (20 using valerian alone, three with valerian and lemon balm, six with valerian and hops, and one with valerian, hops, and lemon balm — and eight open-label trials. A variety of doses, formulations, and subject populations using aqueous extracts were reported in this review. Overall, the clinical trials using ethanol-based extractions failed to show improvement in subjective (sleep efficiency, sleep latency, awakenings) or objective (polysomnographic) sleep outcomes compared to placebo, but valerian improved subjective sleep ratings similarly to benzodiazepines in several of the studies. In some cases, no significant differences were reported between valerian and placebo, while in others an improvement in sleep quality and latency was noted in both elderly individuals with sleep problems and people without sleep problems.

In another small, double-blind trial, 16 patients with insomnia were randomized to either placebo or a single 600 mg dose and 14 subsequent doses of a dry valerian extract in tablet form (Sedonium®).12 The single dose of valerian caused no change in objective or subjective sleep parameters. After 14 days, however, the valerian group had a significant increase in slow-wave sleep, with a shift to earlier in the sleep period, as well as a decrease in subjective sleep-onset latency. Other parameters were the same between placebo and valerian groups. Twenty-one adverse events were reported, 18 of which were in the placebo group; the three adverse events in the valerian group included a migraine headache, a gastrointestinal condition, and an accident with the polysomnogram machine.

Valerian has been studied in combination with other sedative plants, such as hops (Humulus lupulus), passionflower (Passiflora sp.), and lemon balm (Melissa officinalis). For example, 184 people with mild insomnia were randomized to two tablets of a valerian and hops extract (187 mg of valerian and 42 mg of hops per tablet), diphenhydramine (two tablets, 25 mg each), or two placebo tablets; sleep diaries, polysomnography, a seven-item insomnia index scale, and a self-rated general well-being index were used to analyze the different groups over four weeks.13 All groups had a decrease in sleep latency and improved insomnia indices, but only diphenhydramine had an improvement in sleep efficiency (P = 0.039), as well as a statistically significant improvement in the insomnia index (P = 0.003). There was no significant difference in adverse effects between the three groups, and no serious adverse events were reported.

Researchers conducting another trial randomized 30 patients with non-organic sleep disorders to receive either a valerian extract (Ze 911, 500 mg of valerian), a valerian-hops combination product (Ze 91019,), or placebo nightly for four weeks.14 The researchers used P = 0.10 as the cut-off for statistical significance; with this criteria, the valerian-hops combination was statistically better than placebo in reducing sleep latency, the length of slow-wave sleep, and clinical global impression. The rest of the parameters studied, such as sleep time, wake percentage, and other sleep stages, were not statistically significant. No adverse events were reported in any of the groups.

One researcher reviewing valerian studies noted some unique aspects of the use of valerian as a sedative: the lack of documented interactions with alcohol, an absence of "hangover" effects with the use of valerian, and the fact that in many cases it took about two weeks for the sedative effect of valerian to appear.4

An extract of V. wallichii root (Valmane®) was used in 19 patients who were withdrawing from chronic benzodiazepine use and having trouble sleeping.15 Compared to the placebo group, the valerian group had subjectively better sleep and less wake time after sleep onset, though valerian did not decrease sleep latency.

Dosages and Formulation

Valerian is available as a tea, tincture, or tablet, but most research has been done on capsules of a root extract. One commercial preparation used in clinical trials is LI 156 (Sedonium), a 70% ethanol extraction of V. officinalis usually dosed 300-600 mg before bedtime. One aqueous preparation of valerian used in clinical trials is Valdispert®, dosed 405 mg three times daily.

Adverse Effects, Contraindications, and Drug Interactions

In clinical trials, valerian is generally well tolerated, with an incidence of side effects similar to placebo groups.3 There have been reports of headache, dizziness, morning "grogginess," and gastrointestinal side effects, such as nausea, diarrhea, stomach discomfort, and a bitter taste in the mouth;3,16 these were reported more in the trials using aqueous extracts. A randomized, three-armed trial of valerian (extract LI 156, 600 mg), flunitrazepam (1 mg), and placebo failed to find a "hangover" effect from valerian, or adverse effects on median reaction time, alertness, and two-handed coordination.16

In one case report, a 58-year-old man with a history of coronary artery disease, hypertension, and congestive heart failure (CHF) taking valerian five times daily experienced acute worsening of his CHF and development of delirium upon admission to the hospital, presumably secondary to valerian withdrawal.17

Other cautions mentioned are possible additive effects with other sedatives, such as benzodiazepines, barbiturates, anesthetic agents, and other central nervous system depressants.18

Four people taking herbal tablets for stress relief who suffered liver damage were described in a report; three of the four had jaundice, and hepatic injury began shortly after taking the tablets, suggesting a hypersensitivity reaction.19 The exact identity of the ingredients in the tablets were not definitively identified, but may have included skullcap (Scutellaria sp.) and valerian.

Valerian may have an effect on the cytochrome P450 system. An in vitro study of 14 commercially available valerian products demonstrated inhibition of CYP3A4, the same enzyme system that metabolizes such pharmaceuticals as lovastatin, triazolam, ketoconazole, and numerous chemotherapy agents.20

Conclusion

The most commonly used species of valerian, Valeriana officinalis, contains several physiologically active phytochemicals, including valepotriates, essential oils, and valerenic acid. In vitro and animal research point to an effect of valerian on the GABA system in the central nervous system.

Numerous clinical trials have been conducted on valerian for insomnia, but sample sizes are typically small and the results are mixed. It appears that no significant effects occur with single doses, but over several weeks of regular use there may be a decrease in sleep latency and an improvement in subjective sleep quality. Most trials have studied 300-600 mg before bed; standardized formulas are commercially available.

Mild side effects are occasionally reported, such as dizziness, gastrointestinal complaints, and headache. Liver damage has been raised as a concern, but it is difficult to distinguish between the reported serious hepatotoxicity in a combination preparation utilizing several other herbal medicines from the potential for hepatotoxicity with valerian alone, for which there currently appears little evidence. There may also be inhibition of the cytochrome P450 system.

Recommendation

Valerian has some convincing in vitro, animal, and human research for its sedative effects, but more research is clearly warranted. If a trial of valerian is to be employed, it should be used regularly for several weeks for the best effect, but it is not a long-term solution for insomnia in and of itself. An adequate dose seems to be 300-600 mg nightly. Caution is advised in people taking medicines metabolized through the CYP3A4 system, and perhaps for those with pre-existing hepatic pathology

References

1. Mills S, Bone K. Principles and practice of phytotherapy: Modern herbal medicine. Churchill Livingstone, Edinburgh, 2000.

2. Circosta C, et al. Biological and analytical characterization of two extracts from Valeriana officinalis. J Ethnopharmacol. 2007;112:361-367.

3. Taibi DM, et al. A systematic review of valerian as a sleep aid: Safe but not effective. Sleep Med Rev. 2007;11:209-230.

4. Houghton PJ. The scientific basis for the reputed activity of valerian. J Pharm Pharmacol. 1999;51:505-512.

5. Tokunaga S, et al. Effect of valerian extract preparation (BIM) on the sleep-wake cycle in rats. Biol Pharm Bull. 2007;30:363-366.

6. Yuan CS, et al. The gamma-aminobutyric acidergic effects of valerian and valerenic acid on rat brainstem neuronal activity. Anesth Analg. 2004;98:353-358.

7. Khom S, et al. Valerenic acid potentiates and inhibits GABA(A) receptors: Molecular mechanism and subunit specificity. Neuropharmacology. 2007;53:178-187.

8. Glass JR, et al. Acute pharmacological effects of temazepam, diphenhydramine, and valerian in healthy elderly subjects. J Clin Psychopharmacol. 2003;23:260-268.

9. Gutierrez S, et al. Assessing subjective and psychomotor effects of the herbal medication valerian in healthy volunteers. Pharmacol Biochem Behav. 2004;78:57-64.

10. Bent S, et al. Valerian for sleep: A systematic review and meta-analysis. Am J Med. 2006;119:1005-1012.

11. Stevinson C, Ernst E. Valerian for insomnia: A systematic review of randomized clinical trials. Sleep Med. 2000:1:91-99.

12. Donath F, et al. Critical evaluation of the effect of valerian extract on sleep structure and sleep quality. Pharmacopsychiatry. 2000;33:47-53.

13. Koetter U, et al. A randomized, double blind, placebo-controlled, prospective clinical study to demonstrate clinical efficacy of a fixed valerian hops extract combination (Ze 91019) in patients suffering from non-organic sleep disorder. Phytother Res. 2007;21:847-851.

14. Morin CM, et al. Valerian-hops combination and diphenhydramine for treating insomnia: A randomized placebo-controlled clinical trial. Sleep. 2005;28:1465-1471.

15. Poyares DR, et al. Can valerian improve the sleep of insomniacs after benzodiazepine withdrawal? Prog Neuropsychpharmacol Biol Psychiatry. 2002;26:539-545.

16. Kuhlman J, et al. The influence of valerian treatment of "reaction time, alertness and concentration" in volunteers. Pharmacopsychiatry 1999;32:235-241.

17. Garges HP, et al. Cardiac complications and delirium associated with valerian root withdrawal. JAMA. 1998;280:1566-1567.

18. Hadley S, Petry JJ. Valerian. Am Fam Physician. 2003;67:1755-1758.

19. MacGregor FB, et al. Hepatotoxicity of herbal remedies. BMJ. 1989;299:1156-1157.

20. Lefebvre T, et al. In vitro activity of commercial valerian root extracts against human cytochrome P450 3A4. J Pharm Pharm Sci. 2004;7:265-273.