1. A cohort review of the safety and efficacy of Valerian for insomniaClass of 2013, School of Pharmacy, Virginia Commonwealth University Authors: James Behler, Courtney Cropper, Tyler Halstead, Tom Heath, Theresa Nguyen, Mike Seabright, Derrick West INTRODUCTION ABSTRACT Herbal medications have been used for centuries; Valerian, a very popular herbal medication has been used ubiquitously throughout history. Valerian is derived from the root of the leafy plant Valerianaofficinalis, and is found to grow indigenously in Europe, Asia and North America. This resistant perennial flowering plant has been claimed effective for many medical, cosmetic, and fragrant purposes; however the scope of this systematic review it to evaluate the effectiveness on insomnia through meta-analysis of published literature. 1 Efficacy of herbal medicine is constantly put to the test through multiple forms of clinical trials testing multiple demographics and populations. A misconception can result by claiming that an herb such as Valerian has proven efficacy based on the results on a single research experiment on a targeted population. The benefits of creating a cohort review of published research presents a more generalized conclusion of the overall claimed efficacy of a particular herbal medication for a particular use. In addition, assessing the overall efficacy Valerian can be an imperative task when the proposed benefits have the potential to improve the quality of life in an individual who experiences insomnia. A plausible treatment for the most common sleep disorder which affects approximately one-third of the U.S adult population (over 60 million people) can be an area of heightened discussion among medical professionals and those who report common symptoms associated with insomnia.2 It has been reported throughout numerous published research that Valerian is among the top-selling herbals in the U.S. and is marketed as a “promoter of restful sleep.”2 Currently there are over hundreds of published research article on the use of Valerian for common symptoms of insomnia. It is important to note that in a multitude of these articles reference sources that claim Valerian to be successful. A specific systematic review states that the clinical evidence of the value of Valerian for improving sleep was almost entirely based on observational studies and anecdotal reports.8 The scope of this review is to target specific clinical trials based on the safety and efficacy of Valerian and its use for insomnia. In summary the hypothesis of this report is that based on published clinical trials the efficacy and safety can be concretely stated by reviewing actual experimental methods on living breathing individual’s scientific data. There are a plethora of published articles looking at efficacy and adverse effects, that give results regarding the use of Valerian for insomnia. Results range from having slight to no improvements in sleep quality (graph 2). However, there were more articles disproving the claims for valerian than for it. Many herbal supplements are used to help patients self treat a variety of medical conditions. These products are not subjected to government regulation and are poorly monitored. Valerian is an herbal product used in the self treatment of insomnia, irritability, anxiety and several other conditions. Clinical studies are growing to verify the efficacy of Valerian and many other herbal products. One large focus of these studies involves the use of Valerian for insomnia. Many clinical studies are being performed to evaluate the usefulness of Valerian as an alternative sleep aid. These studies include several population groups, including patients of varying age groups and ranges, and an evaluation of sleep improvement in older women. The results of these trials are inconsistent, with certain trials showing an improvement in sleep (with regards to duration, onset, and waking state) while other trials showed that no improvement was observed when compared to placebo. More studies are essential to determine the efficacy of Valerian as a sleep aid. Many variables are present that interfere with the consistency of the product and further studies in additional populations with larger sample sizes are needed. Figure 1. Graph 2 DISCUSSION Valerian is an herbal supplement that is commonly used as a sleep aid. It has been recommended as helpful for older adults and is made from the root of Valeriana officinalis.6 Valerian contains various compounds including valerenic acid, hydroxyvalerenic acid, acetoxcyvalerenic acid, and valerenal that all may act together to exert the sedative effects.7 Similar to usual sedative-hypnotic medications, the chemical compounds of valerian are believed to activate gamma-aminobutyric acid (GABA) receptors that are involved in sleep promotion and regulation. The effectiveness of valerian as an aid for sleep is unclear due to the variation among clinical trials. The quality of the research evidence in these trials was questionable and inappropriate. Complications such as source of plant material, preparations, and adequately masking the placebo cause the results from these trials to be questionable. When analyzing the results from some of the clinical trials, they suggest that valerian may have both acute and cumulative effects on sleep3; however, not all studies have produced positive findings.5 The evaluation of the pharmacokinetics of valerian is also difficult as a very small number of studies have been done to measure these variables. Thus, there is lack of definitive data on this product. One of the few studies conducted evaluated 6 healthy individuals. It found that following a single oral dose, all subjects maximum concentrations occurred between 1 to 2 hours..9These concentrations ranged from 0.9 to 2.3 ng/mL..9 Of these 6 subjects, one showed double peaks occurring at 1 and 5 hours. The half life of these subjects was 1.1 +/- 0.6h.9 The outcomes of this study aided in determining appropriate dosing regimens for this supplement. While they did determine it was appropriate, findings from other studies indicate there is great variability in the effectiveness of this product. This may also indicate there is more variability in the pharmacokinetics of this product than this study shows. While the kinetics are not definitively stated, the pharmacodynamics are mostly understood. However, This understanding does not ensure Valerian's efficacy. As the active ingredient of valerian is unknown, it is possible its effects are due to more than one active constituent. The sedative effects it produces may be due to additive effects of multiple ingredients. Its activity is known to be similar to benzodiazepines.10 The mechanism by which valerian extract may cause sedation is by increasing the amount of GABA available in the synaptic cleft. It is thought to bind to GABA receptors as well as inhibits the enzyme which degrades GABA. This inhibition results in increased brain GABA, leading to sedation and decreased CNS activity. These cumulative events are those believed to contribute in the treatment of insomnia. Figure2. Figure 3. REFERENCES CONCLUSIONS Fernandez-San-Martin et. al. Effectiveness of Valerian on insomnia: A meta-analysis of randomized placebo-controlled trials. Sleep Medicine ( 2010) Taibi et. al. A systematic review of valerian as a sleep aid: Safe but not effective. Sleep Medicine. (2007) 11, 209-230. Stevinson et. al. Valerian for insomnia: a systematic review of randomized clinical trials. Sleep Medicine. 1 (2000) 91-99. Oxman, A. et. al. A Televised, Web-Based Randomised Trial of an Herbal Remedy (Valerian) for Insomnia. PlosOne. 10 (2007) e1040. Taibi et. al. A randomized clinical trial of valerian fails to improve self-reported, polysomnographic, and actigraphic sleep in older women with insomnia. Sleep Medicine. 10 (2009) 319-328. Cuellar NG, Rogers AE, Hisghman V. Evidenced based research of complementary and alternative medicine (CAM) for sleep in the community dwelling older adult. Geriatr Nurs 2007;28(1):46–52. 7. Houghton PJ. The scientific basis for the reputed activity of Valerian. J Pharm Pharmacol 1999;51(5):505–12. Adeyemi F. Valerian Monograph. University of Colorado. 8 May 2003. <http://www.uchsc.edu/sop/pharmd/6.Experiential_Programs/-downloads/valerian.pdf>. 7 April 2010. Anderson, G, et al. Pharmacokinetics of Valerenic Acid after administration of Valerian in healthy subjects. Phytotherapy Research, Volume 19, No. 9, p. 801-803, 2005, Copyright © 2005 John Wiley & Sons, Ltd. “Valerian.” Office of Dietary Supplements: National Institute of Health, Bethesda, MD. <http://ods.od.nih.gov/factsheets/valerian.asp> 5 April 2010. In conclusion, the evidence supporting the claims of Valerian, as with many herbal products, is clearly lacking and often is anecdotal. Ongoing efficacy studies continually find contradicting results, which is contributed to a lack of uniformity in the herbal product and to experimental design. Given these results, healthcare providers and researchers must push to improve experimental and clinical trials. Basic scientific experiments need to focus on determining the active ingredients and potentially active biological intermediates. The variability of each dosage form for Valerian should also be considered and a certain level of uniformity should be demanded for each product. Clinical experiments can be improved by exploring parameters of insomnia that are more quantitative than qualitative. For example, a quantitative measurement of neurotransmitters, such as GABA, acetylcholine, serotonin, etc., that have been associated with sleep should be used in future studies. In terms of safety, Valerian has been shown to have generally mild side effects, but further drug-drug interaction studies should continue., as there was not much data relating to these interactions. Overall, healthcare providers may find some use for this herbal product in the treatment of insomnia, but it should be done with great care given the lack of hard evidence. Perhaps with further study, this herbal remedy will join a long list of medications that have started from a small seed planted in the soil. RESULTS Score in Improvement in Sleep Quality Graph 1: Improvement in sleep quality from meta-analysis.1