MULTIPLE NIGHT-TIME DOSES OF VALERIAN (Valeriana officinalis) HAD MINIMAL EFFECTS ON CYP3A4 ACTIVITY AND NO EFFECT ON CYP2D6 ACTIVITY IN HEALTHY VOLUNTEERS

Abstract

ABSTRACT:Valerian (Valeriana officinalis) is a popular dietary supplement. The objective of this study was to assess the influence of a valerian extract on the activity of the drug-metabolizing enzymes cytochrome P450 2D6 (CYP2D6) and 3A4. Probe drugs dextromethorphan (30 mg; CYP2D6 activity) and alprazolam (2 mg; CYP3A4 activity) were administered orally to healthy volunteers (n ‫؍‬ 12) at baseline and again after exposure to two 500-mg valerian tablets (1000 mg) nightly for 14 days. The valerian supplement contained a total valerenic acid content of 5.51 mg/tablet. Dextromethorphan to dextorphan metabolic ratios (DMRs) and alprazolam pharmacokinetics were determined at baseline and after valerian treatment. Valerian (Valeriana officinalis) extracts are marketed as dietary supplements in the United States and were among the top 10 bestselling herbal supplements in the United States in 2002 (Blumenthal, 2003). Although they are currently promoted as a sedative/hypnotic, clinical trials are presently inconclusive with regard to the efficacy for insomnia (Houghton, 1999;Stevinson and Ernst, 2000;Krystal and Ressler, 2001).Valerian supplements contain a complex mixture of chemical constituents (Shohet et al., 2001). The main constituents are valerenic acid and its derivatives contained in the volatile oil (Houghton, 1999). These main constituents are widely thought to contribute to the putative sedative effects, although clinical effects may be a result of synergistic activity from numerous constituents. The valepotriates have also been investigated for pharmacologic activity but are relatively unstable and are often not present in most commercial supplements (Bos et al., 2002). Minor constituents include various alkaloids, furanofuran lignans, and free amino acids (Houghton, 1999). Valerian is well recognized by its unpleasant odor that is attributed to isovaleric acid formation during processing and storage.The widespread use of valerian supplements suggests that use with conventional medications is inevitable, and the potential for drug interactions is undefined (Fugh-Berman and Ernst, 2001;Markowitz et al., 2003b;Huang et al., 2004). The present study was undertaken in healthy volunteers to determine whether a valerian supplement containing known quantities of valerenic acid and its derivatives could alter the activity of two major drug-metabolizing enzymes, cytochrome P450 2D6 (CYP2D6) and CYP3A4 in healthy volunteers. These two enzymes were chosen since, together, they contribute to the metabolism of a substantial number of both prescription and nonprescription medications (Wrighton and Thummel, 2000;Zanger and Eichelbaum, 2000;Burk and Wojnowski, 2004). To our knowledge, this is the first clinical study assessing whether a standardized valerian supplement may participate in drug interactions mediated by any of the P450 enzymes. Materials and MethodsSubjects. The study was approved by the Medical University of South Carolina's Office of Research Integrity, and subjects provided written informed consent before...

Clinical applications of herbal medicines for anxiety and insomnia; targeting patients with bipolar disorder

“…Valerian was traditionally thought of as a cerebral stimulant and suggested to have a 'heating property' making people feel warm, but no associated side effects were reported in clinical trials. Minimal effects on cytochrome P450 enzymes were reported in healthy subjects (Donovan et al, 2004).…”

Pharmacokinetic interactions between drugs and botanical dietary supplements

“…Red clover (Trifolium pretense) CYP1B1 (Roberts et al, 2004); CYP2C8 (Liang et al, 2003;Piersen et al, 2004); CYP2C9 (Lin et al, 1998;Maliakal and Wanwimolruk, 2001) (Gurley et al, 2005); CYP3A4, CYP2D6 (Donovan et al, 2004) a Clinical interactions have been noted, as reported by Tsai et al (2014). b Clinical interactions have been reported, as noted by Hu et al (2005).…”

Valerian: No evidence for Clinically Relevant interactions

“…However, critical assessment of these studies suggests that the clinical relevance of the findings is questionable due to various methodological limitations (Table 1). This is underlined by the available clinical interaction studies on CYP isoenzymes, which do not indicate a relevant drug interaction potential of valerian in healthy volunteers [35,37].…”

“…One of these publications [34] contains, in addition, data on animal studies. Two publications [35,37] present clinical studies on pharmacokinetic interactions. 8 studies are available on the subject of pharmacodynamic interactions, thereof two in vitro and three animal studies, one clinical study, and in addition two case reports.…”

“…In twelve healthy volunteers (6 males and 6 females, age 30.9 ± 7.2 years, nonsmokers from South Carolina), the effect of a valerian root extract on the activity of the drug-metabolizing enzymes CYP 2D6 and CYP 3A4 was tested [37]. Daily before going to bed, participants took two tablets, with 500 mg valerian extract each (extraction solvent ethanol 70%, valerenic acid content 5.51 mg/tablet), for 14 subsequent days.…”