Risk Factor: B
Fetal Risk Summary
Valeriana officinalis, the plant most often used for medicinal purposes, is one species of approximately 200 of the genus Valeriana, a herbaceous perennial that grows widely in the temperate regions of North America, Europe, and Asia (1). A large number of preparations containing valerian are commercially available (2). The herb is used as a sedative and hypnotic for anxiety, restlessness, and sleep disturbances (1,2,3,4 and 5). Other pharmacologic claims that have been made for valerian include antispasmodic, anticonvulsive, antidepressant, and antihypertensive properties (1,3,4). The extracts and root oil have also been used as flavorings for foods and beverages (1).
Although the specific agents responsible for the effects of valerian are unknown, as is the mechanism of action, three classes of compounds have been identified: a volatile oil that contains sesquiterpenes; nonglycosidic iridoid esters (known as valepotriates); and alkaloids (1,3). Of these, the valepotriates, found primarily in the roots, are most likely responsible for the sedative action, but components from the other two classes probably contribute as well (1,3). Because these compounds produce central nervous system depression, they should not be used with other depressants, such as alcohol, benzodiazepines, barbiturates, or opiates (3,4 and 5). Moreover, nonpregnant adult human hepatotoxicity has been associated with short-term use (i.e., a few days to several months) of herbal preparations containing valerian (6). Long-term use in a male has also been associated with benzodiazepine-like withdrawal symptoms resulting in cardiac complications and delirium (7).
Reproductive studies in animals with valerian have not shown antiovulation, antifertilization, or embryotoxic effects (8). Further, the valepotriates exhibit low toxicity in mice, producing no deaths in doses of up to 1600 mg/kg intraperitoneally or 4600 mg/kg orally (1). Toxicity in mice was characterized by ataxia, hypothermia, and increased muscle relaxation (1).
The cytotoxic activities of three valepotriate compounds, valtrate, didrovaltrate, and baldrinal (a degradation product of valtrate), in cultured rat hepatoma cells were described in a 1981 Reference (9). Both valtrate and didrovaltrate demonstrated much greater cytotoxic activity than did baldrinal, with rapid and irreversible toxicity. In addition, the antitumor activity of didrovaltrate was demonstrated in vivo on female mice KREBS II ascitic tumors (9). Five surviving mice were then bred with normal male mice 50 days after treatment with didrovaltrate. Each had a normal pregnancy and produced normal offspring.
In a 1988 report, two cases of attempted suicide with valerian dry extract plus other drugs were described (10). In one case, a woman at 10 weeks’ gestation ingested 2.5 g of valerian dry extract and 0.5 g of phenobarbital. An apparently normal, 4350-g female infant was delivered at 42 weeks’ gestation. Examination of the child (age not specified) indicated an IQ in the range of 111 to 120. In the second case, the mother ingested a combination of valerian dry extract (3.0 g), phenobarbital (0.6 g), glutethimide (5.0 g), amobarbital (5.0 g), and promethazine (0.3 g) at 20 weeks’ gestation. A mentally retarded, 2650-g male infant was born at 36 weeks’ gestation. About 2 years later in her next pregnancy, this woman again attempted suicide at 20 weeks’ gestation, by ingesting glutethimide (3.75 g), amobarbital (3.75 g), and promethazine (0.23 g). She delivered another mentally retarded, 2650-g male infant at 43 weeks’. The infant also had a unilateral undescended testicle. Of interest, none of the woman’s other 10 children is mentally retarded.
Two additional cases of self-poisoning with valerian were described in 1987 by the same group responsible for the above report (11). In both cases exposure occurred early in gestation, with ingestion of 5 g and 2 g of valerian at 3 and 4 weeks of fetal development, respectively. No congenital abnormalities were observed in the offspring.
In summary, the very limited animal and human data do not allow a conclusion as to the safety of valerian during pregnancy. Moreover, as a natural, unregulated product, the concentration, contents, and presence of contaminants in valerian preparations cannot be easily determined. Because of this uncertainty and the potential for cytotoxicity in the fetus and hepatotoxicity in the mother, the product should be avoided during pregnancy. Other authors have arrived at the same conclusion (3,4). The risk to a fetus from short-term or inadvertent use during any part of gestation, however, is probably low, if it exists at all.
Breast Feeding Summary
No reports describing the use of valerian during lactation have been located. For the reasons cited above, the use of this herbal product should be avoided during breast-feeding.
- Valerian. The Lawrence Review of Natural Products. Facts and Comparisons. St. Louis, MO: J.B. Lippincott, October 1991.
- Reynolds JEF, editor. Martindale. The Extra Pharmacopoeia. 31st ed. London, England: Royal Pharmaceutical Society, 1996:17656.
- Klepser TB, Klepser ME. Unsafe and potentially safe herbal therapies. Am J Health-Syst Pharm 1999;56:12538.
- Wong AHC, Smith M, Boon HS. Herbal remedies in psychiatric practice. Arch Gen Psychiatry 1998;55:103344.
- Miller LG. Herbal medicines. Selected clinical considerations focusing on known or potential drug-herb interactions. Arch Intern Med 1998;158:220011.
- MacGregor FB, Abernethy VE, Dahabra S, Cobden I, Hayes PC. Hepatotoxicity of herbal remedies. Br Med J 1989;299:11567.
- Garges HP, Varia I, Doraiswamy PM. Cardiac complications and delirium associated with valerian root withdrawal. JAMA 1998;280:15667.
- Randor S, Einarson TR, Pastuszak A, Koren G. Maternal-fetal toxicology of medicinal plants: a clinician’s guide. In Koren G, editor. Maternal-Fetal Toxicology. A Clinician’s Guide. 2nd ed. New York, NY: Marcel Dekker, 1994:4956.
- Bounthanh C, Bergmann C, Beck JP, Haag-Berrurier M, Anton R. Valepotriates, a new class of cytotoxic and antitumor agents. Planta Med 1981;41:218.
- Czeizel A, Szentesi I, Szekeres H, Molnar G, Glauber A, Bucski P. A study of adverse effects on the progeny after intoxication during pregnancy. Arch Toxicol 1988;62:17.
- Czeizel AE, Tomcsik M, Timar L. Teratologic evaluation of 178 infants born to mothers who attempted suicide by drugs during pregnancy. Obstet Gynecol 1997;90:195201.