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Home , Benzodiazepine, Hypnotic, Insomnia, Valerian (herb)

COMPLEMENTARY AND

Valerian SUSAN HADLEY, M.D., Middlesex Hospital, Middletown, Connecticut JUDITH J. PETRY, M.D., Vermont Healing Tools Project, Brattleboro, Vermont

Valerian is a traditional remedy that has been studied with a variety of methodologic designs using multiple dosages and preparations. Research has focused on subjective evaluations of sleep patterns, particularly sleep latency, and study populations have primarily consisted of self-described poor sleepers. Valerian improves subjective experiences of sleep when taken nightly over one- to two-week periods, and it appears to be a safe / choice in patients with mild to moderate . The evi- dence for single-dose effect is contradictory. Valerian is also used in patients with mild , but the data supporting this indication are limited. Although the profile and tolerability of this are excellent, long-term safety studies are lacking. (Am Fam Physician 2003;67:1755-8. Copyright©2003 American Academy of Family Physicians)

he root of valerian, a perennial triates, valeric acid) and interaction with neu- herb native to North America, rotransmitters such as GABA (valeric acid and Asia, and , is used most unknown fractions).2,3 commonly for its sedative and hypnotic properties in patients Uses and Efficacy Twith insomnia, and less commonly as an SEDATIVE/HYPNOTIC . Multiple preparations are available, Several clinical studies have shown that and the herb is commonly combined with valerian is effective in the treatment of insom- other herbal . This review nia, most often by reducing sleep latency. A addresses only studies that used valerian root double-blind, -controlled trial4 com- as an isolated herb. As with most herbal prod- pared a 400-mg aqueous extract of valerian and ucts available in the United States, valerian a commercial valerian/ preparation with root extracts are not regulated for quality or placebo of encapsulated brown . A total of consistency. Independent testing laboratories 128 volunteers completed a subjective study4 (such as www.consumerlab.com) generally use evaluating the effects of single doses of each test valeric acid content as a marker for pharmaco- compound taken in random order on sleep logic activity and represent one source for reli- latency, sleep quality, sleepiness on awakening, able information to support product choice. night awakenings, and recall. Valerian extract demonstrated statistically significant improvement over placebo in sleep latency and The chemical composition of valerian sleep quality. There was no difference between includes of the volatile oil valerian extract and placebo in the other two (including valeric acid), (valepotri- parameters. The commercial valerian/hops ates), , furanofuran , and free preparation resulted in no changes in sleep amino acids such as -aminobutyric acid latency, sleep quality, or night awakenings, and (GABA), tyrosine, , and . an increase in sleepiness on awakening. No Although the components of information on the preparation of the com- the volatile oil are believed to be responsible mercial product was available, so the reasons for most of valerian’s biologic effects, it is for the lack of effect are unknown. likely that all of the active constituents of Examination of the study subgroups valerian act in a synergistic manner to pro- showed that the positive effects of valerian 1 See page 1649 for duce a clinical response. Research into physi- extract on sleep were most significant in older definitions of strength- ologic activity of individual components has male patients who considered themselves to of-evidence levels. demonstrated direct sedative effects (valepo- be poor sleepers, female poor sleepers,

APRIL 15, 2003 / VOLUME 67, NUMBER 8 www.aafp.org/afp AMERICAN FAMILY PHYSICIAN 1755 younger poor sleepers, smokers, and those mg) of an aqueous extract of valerian root who habitually have lengthy sleep latencies. demonstrated that both groups experienced a Subjects who rated themselves as habitually greater than 50 percent improvement in sleep good sleepers were largely unaffected by the latency and wake time after . The valerian extract.4 efficacy results were based on questionnaires, In a double-blind study,5 eight subjects who self-rating scales, and nighttime motor activ- described themselves as having lengthy sleep ity. Electroencephalographic recordings in the latency wore a wrist activity meter and pro- laboratory section of the study showed no dif- vided subjective sleep ratings in a study of the ferences in efficacy between valerian and effects of valerian. Participants received either placebo, and data indicated a dose-dependent a 450- or 900-mg dose of an aqueous extract mild hypnotic effect of the valerian extract.7 of valerian root or placebo. Single-dose (450 A recent systematic review8 of randomized and 900 mg) valerian extract resulted in sig- trials of the effect of valerian on patients with nificant decreases in measured and subjective insomnia included reports in all languages.8 sleep latency and more stable sleep during the [Evidence level B, systematic review of studies first quarter of the night, with no effect on other than randomized controlled trials total sleep time. The 900-mg dose produced (RCTs)] The authors found nine randomized, increased sleepiness on awakening compared double-blind, placebo-controlled trials that with placebo. met the inclusion criteria. Two studies9,10 A randomized, placebo-controlled, double- showed improvement in sleep-related para- blind, cross-over study6 involving 16 patients meters in patients with insomnia who with insomnia confirmed by polysomnogra- received repeated administration over two to phy demonstrated no effects on sleep efficiency four weeks. Another study11 demonstrated after a single 600-mg dose of the valerian effects after days 1 and 8 in slow-wave sleep, extract Sedonium, while multiple doses over 14 but no effect on subjective measures of sleep. days resulted in significant improvement in Results were contradictory in six -dose parameters of slow-wave sleep measured by studies.4,5,7,12,13 The authors pointed out the . There was a nonsignificant wide variety of methodologies used in the trend toward reduced subjective sleep latency studies, and the lack of attention to factors after the long-term valerian treatment.6 such as randomization, blinding, compliance, Several studies have shown valerian’s effi- withdrawal, confounding variables, diagnostic cacy in patients who do not have sleep distur- criteria, and statistical analysis. They con- bances. A small study7 of 10 patients at home cluded that evidence for valerian in the treat- and eight patients at a sleep laboratory who ment of insomnia is inconclusive, and that received two different dosages (450 and 900 more rigorous trials are necessary. A recent multicenter14 (RCT) compared a 600-mg dose of the valerian extract Sedonium with 10 mg of over a six-week The Authors period in 202 patients who were diagnosed SUSAN HADLEY, M.D., is on staff in the family practice division at Middlesex Hospital with non-organic insomnia. The two agents in Middletown, Conn. She is also a member of the Board of Integrative Medicine at Middlesex Hospital. She received her medical degree from the University of Arizona were equally effective in increasing sleep qual- College of Medicine, Tucson, and completed a social medicine residency at Montefiore ity as measured by the Sleep Questionnaire B Medical Center, Bronx, N.Y. (SF-B), and these results were confirmed by JUDITH J. PETRY, M.D., is a consultant in integrative medicine in Westminster, Vt., and subscales of the SF-B, the Clinical Global medical director of Vermont Healing Tools Project in Brattleboro. She received her Impression Scale, and the Global Assessment medical degree from Albany Medical College, Albany, N.Y., and is board certified in general and plastic surgery. of Efficacy. Mild to moderate adverse events occurred in 28.4 percent of patients receiving Address correspondence to Susan Hadley, M.D., Middlesex Hospital, 90 S. Main St., Middletown, CT 06457 (e-mail: [email protected]). Reprints are not avail- the valerian extract and 36.0 percent of able from the authors. patients taking oxazepam.

1756 AMERICAN FAMILY PHYSICIAN www.aafp.org/afp VOLUME 67, NUMBER 8 / APRIL 15, 2003 Valerian

therefore, not subject to regulatory control Anxiolytic beyond labeling requirements. According to Traditional herbalists have used valerian as an Commission E monographs,18 there are no anxiolytic, frequently in combination with contraindications to valerian. Reported other herbal preparations such as passion flower adverse effects of valerian are rare. In a and St. John’s wort. There is a minimal amount 14-day, multiple-dose study6 of 16 patients, of scientific data confirming this indication for there were only two adverse events (migraine valerian. One randomized, double-blind, and gastrointestinal effects) in patients receiv- placebo-controlled trial15 compared valerian ing valerian compared with 18 events in (100 mg) with (20 mg), a valerian- patients receiving placebo. A randomized, propranolol combination, and placebo in an controlled, double-blind study19 of 102 sub- experimental situation in 48 healthy sub- jects evaluated reaction time, alertness, and jects. Unlike propranolol, valerian had no effect concentration the morning after using valer- on physiologic arousal but significantly ian root extract (600 mg, LI 156) and found decreased subjective feelings of somatic arousal. no negative effect in single- or repeated-dose In a recent preliminary, randomized, double- administrations of valerian. Only one adverse blind, placebo-controlled trial,16 36 patients effect (dizziness) was attributed to the valer- with a diagnosis of generalized anxiety disor- ian extract. der were treated with placebo, in a No evidence of potentiation of valerian dosage of 2.5 mg three times daily, or valerian effects by concomitant ingestion of extract in a dosage of 50 mg three times daily has been found in animal and studies, (80 percent dihydrovaltrate, 15 percent val- but the combination should still be trate, and 5 percent acevaltrate; BYK-Gulden, avoided.1,20 Valerian may potentiate the seda- Lomberg, Germany) for four weeks. Dosage tive effects of , , and was regulated at one week if an interviewing other central .21 psychiatrist deemed an increase or decrease One case report22 suggests that sudden cessa- necessary. Although the study was limited by a tion of long-term high dose valerian small number of patients in each group, rela- (530 mg to 2 g, five times daily) may result in tively low dosages of the active agents, and a withdrawal symptoms similar to those occur- short duration of treatment, the authors ring with use. Perhaps found a significant reduction in the psychic because of the poorly defined effects of valer- factor of the Hamilton Anxiety Scale (HAM- ian on GABA neurotransmission, valerian A) with diazepam and valerian. appears to attenuate benzodiazepine with- Another RCT17 compared 120 mg of (LI drawal symptoms in animals and .23,24 150), 600 mg of valerian (LI 156), and placebo taken daily for seven days in relieving physio- Dosage logic measures of stress induced under labora- Based on the reviewed studies, the effective tory conditions in 54 healthy volunteers. Valer- dosage of valerian root extract for treatment of ian and kava, but not placebo, significantly insomnia ranges from 300 to 600 mg. An equiv- decreased systolic pressure responsivity, alent dose of dried herbal valerian root is 2 to heart rate reaction, and self-reported stress. 3 g, soaked in one cup of hot water for 10 to (NOTE: “LI 156” is an identification number 15 minutes.25 The product should be ingested referring to the specific herb and the manufac- 30 minutes to two hours before . turer; in this case, Lichtwer Pharma UK, Ltd.) Final Comment Contraindications, Adverse Effects, Valerian is a safe herbal choice for the treat- Interactions ment of mild insomnia and has good tolera- Valerian is listed by the U.S. Food and bility. Most studies suggest that it is more Administration as a food supplement and is, effective when used continuously rather than

APRIL 15, 2003 / VOLUME 67, NUMBER 8 www.aafp.org/afp AMERICAN FAMILY PHYSICIAN 1757 TABLE 1 Key Points About Valerian

Efficacy In mild to moderate insomnia: appears effective In anxiety: limited evidence supports efficacy Adverse effects Rare: headache, gastrointestinal effects 8. Stevinson C, Ernst E. Valerian for insomnia: a sys- Interactions No significant herb/drug interactions with valerian have tematic review of randomized clinical trials. Sleep been reported. Med 2000;1:91-9. May potentiate sedative effects of barbiturates, anesthetics, 9. Kamm-Kohl AV, Janson W, Brockmann P. Moderne and CNS depressants. baldriantherapie gegen vervose storungen im Dosage Varies depending on brand; typically, 300 to 600 mg in senium. Med Welt 1984;35:1450-4. 10. Vorbach EU, Gortelmeyer R, Bruning J. Therapy of capsules taken 30 minutes to two hours before bedtime, insomnia. The efficacy and tolerability of valerian [in or 2 to 3 g of the dried root* German]. Psychopharmakotherapie 1996;3:109-15. Cost $0.08 to $0.30 per capsule, depending on brand 11. Schulz H, Stolz C, Muller J. The effect of valerian Bottom line Safe ; effective in treatment of mild to extract on sleep polygraphy in poor sleepers: a moderate insomnia pilot study. Pharmacopsychiatry 1994;27:147-51. 12. Leathwood PD, Chauffard F. Quantifying the effects of mild . J Psychiatr Res 1982- CNS = . 83;17:115-22. *—Add 2 to 3 g of dried root to one cup hot water and strain after 10 to 13. Gessner B, Klasser M. Studies on the effect of Har- monicum Much on sleep using polygraphic EEG 15 minutes. recordings [in German]. EEG EMG Z Elektroen- zephalogr Elektromyogr Verwandte Geb 1984;15: 45-51. 14. Ziegler G, Ploch M, Miettinen-Baumann A, Collet W. Efficacy and tolerability of valerian extract LI 156 as an acute sleep aid; more rigorous studies are compared with oxazepam in the treatment of non- needed to confirm these results. A potential organic insomnia: a randomized, double-blind, com- advantage of valerian over is parative clinical study. Eur J Med Res 2002;25:480-6. 15. Kohnen R, Oswald WD. The effects of valerian, the lack of sleepiness on awakening when used propranolol, and their combination on activation, at the recommended dosages. Valerian also performance, and mood of healthy volunteers may be helpful in weaning patients with under social stress conditions. Pharmacopsychiatry 1988;21:447-8. insomnia from benzodiazepines. The use of 16. Andreatini R, Sartori VA, Seabra ML, Leite JR. Effect valerian as an anxiolytic requires further of valepotriates (valerian extract) in generalized study. Long-term safety studies are lacking. : a randomized placebo-controlled pilot study. Phytother Res 2002;16:650-4. Table 1 discusses the efficacy, safety, tolerabil- 17. Cropley M, Cave Z, Ellis J, Middleton RW. Effect of ity, and cost of valerian. kava and valerian on human physiological and psy- chological responses to mental stress assessed under The authors indicate that they do not have any con- laboratory conditions. Phytother Res 2002;16:23-7. flicts of interest. Sources of funding: none reported. 18. Blumenthal M. German Federal Institute for and Medical Devices. Commission E. The Complete REFERENCES German Commission E monographs: therapeutic guide to herbal medicines. Austin, Tex: American 1. Houghton PJ. The scientific basis for the reputed activ- Botanical Council, 1998:227. ity of Valerian. J Pharm Pharmacol 1999;51:505-12. 19. Kuhlmann J, Berger W, Podzuweit H, Schmidt U. 2. Hendriks H, Bos R, Allersma DP, Malingre TM, The influence of valerian treatment on “reaction Koster AS. Pharmacological screening of valerenal time, alertness and concentration” in volunteers. and some other components of of Pharmacopsychiatry 1999;32:235-41. . Planta Med 1981;42:62-8. 20. Albrecht M. Psychopharmaceuticals and safety in 3. Ortiz JG, Nieves-Natal J, Chavez P. Effects of Valeriana traffic. Z Allg Med 1995;71:1215-21. officinalis extracts on [3H] binding, 21. Ang-Lee MK, Moss J, Yuan CS. Herbal medicines synaptosomal [3H] GABA uptake, and hippocampal and perioperative care. JAMA 2001;286:208-16. [3H] GABA release. Neurochem Res 1999;24:1373-8. 22. Garges HP, Varia I, Doraiswamy PM. Cardiac com- 4. Leathwood PD, Chauffard F, Heck E, Munoz-Box R. plications and associated with valerian Aqueous extract of valerian root (Valeriana offici- root withdrawal. JAMA 1998;280:1566-7. nalis L.) improves sleep quality in man. Pharmacol 23. Andreatini R, Leite JR. Effect of valepotriates on the Biochem Behav 1982;17:65-71. behavior of rats in the elevated plus-maze during 5. Leathwood PD, Chauffard F. Aqueous extract of diazepam withdrawal. Eur J Pharmacol 1994;260: valerian reduces latency to fall asleep in man. 233-5. Planta Med 1985;(2):144-8. 24. Poyares AR, Guilleminault C, Ohayon MM, Tufik S. 6. Donath F, Quispe S, Diefenbach K, Maurer A, Fietze Can valerian improve the sleep of insomniacs after I, Roots I. Critical evaluation of the effect of valer- benzodiazepine withdrawal? Prog Neuropsy- ian extract on sleep structure and sleep quality. chopharmacol Biol 2002;26:539-45. Pharmacopsychiatry 2000;33:47-53. 25. Schulz V, Hänsel R, Tyler VE. Rational phytotherapy: 7. Balderer G, Borbely AA. Effect of valerian on human a physician’s guide to herbal medicine. Berlin: sleep. [Berl] 1985;87:406-9. Springer, 1998:81.

1758 AMERICAN FAMILY PHYSICIAN www.aafp.org/afp VOLUME 67, NUMBER 8 / APRIL 15, 2003