Adverse Effects and Toxicity 71 Reproductive System

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There has been a theoretical concern with regard to pregnant women taking valerian because of possible effects on uterine contractions (1), but no problems were noted in three cases of intentional overdose with 2-5 g of valerian during weeks 3-10 of pregnancy (33). A mentally retarded child was born to a woman who overdosed on valerian 3 g, phenobarbital, glutethamide, amobarbital, and promethazine at 20 weeks of gestation, but this same woman delivered a mentally retarded child 2 years later after an overdose attempt with glutethamide, amobarbital, and promethazine (34).

V. officinalis (L.) was tested on rats and their offspring. A mixture, containing three valepotriates (80% dihydrovaltrate, 15% valtrate, and 5% acevaltrate), was orally administered to female rats for 30 days at 6-, 12-, and 24-mg/kg doses. Each dose was given to 10 rats, and placebo was given to another 10. No changes were noted in the average length of the estrus cycle, or the number of estrus phases during the 30-day observation period. The valepotriate mixture or placebo were also administered to 40 pregnant rats in the manner described previously from the day 1 through day 19 of pregnancy. Valerian did not increase the risk of fetotoxicity or external malformation. However, internal examination revealed a significant increase in the number of fetuses with retarded ossification with the 12- and 24-mg/kg doses. No developmental changes were detected in the offspring after treatment during pregnancy (35).

7.2. Cardiovascular System

Pharmacological investigations using a particular valepotriate fraction called Vpt2 extracted from the roots of V. officinalis (L.) have shown antiar-rhythmic activity and ability to dilate coronary arteries in experimental animals. Moderate positive inotropic and a negative chronotropic effect were also observed. Vpt2 contains valtratum (50%), valeridine (25%), and valechlorin (3%), with trace amounts of acevaltrate, dihydrovaltratum, and epi-7-desacetyl-isovaltrate (36).

Alcoholic extracts of V. officinalis (L.) root (labeled V103 and V115) demonstrated hypotensive effects in rats, cats, and dogs. The V115 fraction showed greater potency and was extracted by a countercurrent distribution to yield three fractions. The first two fractions demonstrated hypotensive effects in rats, with the first fraction showing a hypotensive effect at 30 mg/kg. The third fraction produced hypertensive effects at a dose of 200 mg/kg. The authors noted that, apparently, with each succeeding extraction, less of the hypotensive principle was extracted. The hypotensive effect of the V103 fraction in rats was demonstrated at a dose of 500 mg/kg, and was hypothesized to act via a parasympathomimetic effect, blockade of the carotid sinus reflex, and CNS depression (37).

7.3. Cytotoxicity

The valepotriates valtrate/isovaltrate and dihydrovaltrate were isolated from V. mexicana and V. wallichii, respectively. The valepotriates tested were cytotoxic to granulocyte/macrophage colony-forming units (GM-CFCUs), lymphocytes, and erythrocyte colony-forming units (E-CFCUs). Valtrate was found to be a more potent inhibitor of GM-CFCUs (ID50 ~3.7 x 10-6 M vs ~1.7 x 10-5 M) and T-lymphocytes (ID50 ~2.8 x 10-6 M vs ~3 x 10-5 M) than dihydrovaltrate. Valtrate and dihydrovaltrate were similar in their activity against E-CFCUs (ID50 ~2.3 x 10-8 M vs ~4.2 x 10-8 M). Because pharmaceutical products containing valepotriates are orally administered, their cyto-toxicity to gastrointestinal mucosal cells is of concern (38).

The effects of valtrate, dihydrovaltrate, and deoxido-dihydrovaltrate, valepotriates extracted from V. wallichii (DC.), on cultured rat hepatoma cells have been studied. Valtrate killed 50% of the cell population at a concentration of 5 ^M, Deoxido-dihydrovaltrate and dihydrovaltae demonstrated this same toxicity at double the dose. Valtrate was also the most potent inhibitor of DNA and protein synthesis (39). These results suggest a mechanism by which valerian may cause hepatotoxicity.

7.4. Case Reports of Toxicity

Four cases of women who sustained liver damage after taking valerian-containing herbal medicines to relieve stress have been described (40). In addition, valerian was used by a patient who exhibited hepatotoxicity attributed to Chaparral.

Hospitals admitted 23 patients for treatment of intentional overdose with Sleep-Qik® (75 mg of valerian dry extract, 0.25 mg of hyoscine hydrobromide 2 mg of cyproheptadine hydrochloride) between 1988 and 1991. Of these 23, 9 were men and 14 were women, with a mean age of 23.8 years (range 15-37 years). They were previously healthy, except for two patients with histories of psychiatric illness. The mean number of Sleep-Qik tablets taken per patient history was 33 (range 6-166), for an average of 2.5 g (range 0.512 g) of valerian. Four patients were asymptomatic. The other 19 patients reported drowsiness (n = 11), dilated pupils (n = 11), tachycardia (n = 6), nausea (n = 4), confusion (n = 3), urinary retention (n = 3), visual hallucination (n = 2), flushing (n = 2), dry mouth (n = 1), and dizziness (n = 1). Coingestants were alcohol (n = 2), a pesticide (n = 1), and Pansedan® (n = 1) (Passiflora extract, Viscum album extract, Uncariarhyncophylla extract, and Humulus lupulus). One patient who was drowsy had also taken Panseden, and one who was confused had ingested alcohol.

Most patients received gastric lavage (n = 14), and one received syrup of ipecac. The patient who took 60 tablets of Sleep-Qik required ventilatory support. Liver function tests were performed on 12 patients approx 6-12 hours after ingestion with normal results. Drowsiness and confusion resolved within 24 hours. All patients recovered completely and were discharged after an average of 1.7 days (range 1-6 days). At an average of 43 months (range 27-65 months) after presentation, 10 patients were contacted by telephone. They had all remained well after discharge and none continued taking Sleep-Qik. Delayed onset of severe liver damage was ruled out via telephone interview, but subclinical disease could not be ruled out (41).

Subsequently, Chan reported on 24 cases of overdose of a product containing valerian dry extract 75 mg, hyoscine hydrobromide 0.25 mg, and cyproheptadine hydrochloride 2 mg. Six patients developed vomiting, and 15 underwent gastric lavage. Co-ingestants included alcohol (n = 10), cold products (n = 3), hypnotics (n = 2), unknown drugs (n = 2), and gasoline (n = 1). Symptoms were mainly CNS depression and anticholinergic symptoms. One patient required ventilatory support. Liver function tests were performed in 17 cases, and all were normal. Over the next 22-48 months postingestion, none of the patients returned to the hospital or clinic for any reason, suggest ing that serious hepatotoxicity did not occur. The author points out that gastric lavage and spontaneous vomiting may have limited the amount of valerian absorbed in these patients, thus decreasing the risk of any delayed adverse effects (42). Other adverse effects attributed to overdose or chronic use of valerian include headaches, excitability, restlessness, uneasiness, blurred vision, and cardiac disturbances (4).

In another reported suicide attempt, an 18-year-old female ingested between 40 and 50, 470-mg capsules (18.8-23.5 g valerian) of 100% powered valerian root (Nature's Way®, Springville, UT). The patient complained of fatigue, crampy abdominal pain, chest tightness, tremor of the hands and feet, and lightheadedness 30 minutes after ingestion. She presented to the emergency room 3 hours postingestion. Her vital signs were: blood pressure 111/64 mmHg, pulse 72 beats/minute, respiratory rate 14 breaths/minute, and temperature 37.6°C. Physical exam was unremarkable except for mydriasis (6 mm bilaterally). Electrocardiograph, complete blood count, and chemistry profile including liver function tests were normal. Toxicology screen was positive for marijuana, which she admitted using 2 weeks previously. She denied ingesting anything else. After two doses of activated charcoal, her symptoms resolved within 24 hours (43).

A withdrawal syndrome was described after abrupt discontinuation of valerian root extract in a 58-year-old man who had taken 530-2000 mg/dose five times daily as an anxiolytic and hypnotic for many years. Withdrawal symptoms included sinus tachycardia of up to 150 beats/minute, tremulous-ness, and delirium after recovery from general anesthesia (propofol, nitrous oxide, isoflurane, and thiopental) for open biopsy of a lung nodule. Medical history included coronary artery disease, hypertension, and congestive heart failure with an ejection fraction of 30-35%. Medications included isosorbide dinitrate, digoxin, furosemide, benazepril, aspirin, lovastatin, ibuprofen, potassium, zinc supplement, and vitamins. The biopsy was complicated by multiple episodes of oxygen desaturation, and after extubation, the patient experienced tacycardia, oliguria, and increasing oxygen requirement. Despite naloxone administration, symptoms worsened. Swan-Ganz catheterization revealed high-output heart failure. At this time, interview with family members revealed the patient's long-standing valerian use. Because valerian withdrawal was suspected, midazolam 1 mg/hour (total dose 11 mg in 17 hours) was administered. Signs and symptoms improved, and stabilized by the third postoperative day. He was switched to lorazepam 1 mg/hour as needed (total dose 5 mg in 24 hours), and then to a tapering dose of clonazepam. He was discharged on postoperative day 7, and was stable at 5-month follow-up. Other causes of high-output heart failure were ruled out, but because of the patient's multiple medical problems, postsurgical status, and medications administered, the cause of the patient's symptoms is unclear (44). The authors of this case report note that valerian has been reported to attenuate benzodiazepine withdrawal in rats (45).

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