Valerian: Root of All Zzz’s or Just Another Bedtime Story?

Amidst the boom of supplement use in America, finding accurate and evidence-based information on these products can be a challenge for both patients and practitioners. Although most vitamins and herbal products are not approved by the FDA to treat or prevent disease, many patients elect to use these options due to ease of access and the appeal of remedies that are believed to be more natural than prescription products. While health care professionals may have different opinions on the value of supplements and herbal products, providing evidence-based recommendations on using these supplements can help build trust within the patient-provider relationship.

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One popular supplement and one of the most recognizable members of the Valerianacaea family is valerian (Valeriana officinalis).¹ The perennial plant is native to Europe and Asia, known for its small pinkish-white flowers, and strong distinct odor.^1,2 Valerian has become naturalized in North America, first established from transplants in 1998 at the Western Agricultural Research Center.^1,3

Historically, use of valerian dates back to as early as the second century.¹ Today, valerian is commercially available as a dietary supplement (essential oils, teas, powdered root, root extract and tinctures).¹ It is advertised as an agent that improves insomnia and other sleep disorders, as well as restlessness, anxiety and mood disorders.^1,2 A survey investigating the popularity of herbal products revealed valerian was one of the most popular herbs sold in US retail stores.⁴

Despite its popularity, however, many questions remain about the plant and its efficacy and safety. It was once believed the proposed mechanism for valerian was agnostic activity on receptors involved in sleep (specifically GABA, adenosine, barbiturate, and benzodiazepine receptors).⁵ However, additional research has begun to disprove these theories, thus the mechanism remains unknown.

Valerian Efficacy Profile

Several studies on valerian have been conducted in the past 50 years for indications varying from insomnia, anxiety, restless leg syndrome, headaches, and more. Despite this, there is no clear agreement on what benefits valerian offers. The most studied indication, insomnia, has a wide degree of variability on trial type, extract types, doses used, and duration. To analyze the data as best we can, 3 meta-analyses with over 60 unique studies evaluating valerian were examined and a few of the most relevant cases are described here.^6-8

The largest study within the 3 meta-analyses evaluating efficacy in sleep or sleep-related effects that utilized a placebo-controlled group was by Oxman et al. in 2007.⁹ This was a double-blind randomized controlled trial for 2 weeks that involved 405 adults with self-described insomnia. Participants were required to fill out a daily sleep diary for 14 days before randomization and for 14 days after initiation with valerian 600 mg or placebo. None of their individual measurements for improvements in sleep, including latency, night awakenings, duration of sleep, or energy level the next day, had any statistically significant improvements between valerian and placebo groups. This study is limited by its short duration and use of strictly subjective outcomes but is strengthened by sample size. Several outcomes were close to meeting significance, leading the authors to conclude that valerian is safe but has only a very small potential for improving sleep quality.⁹

One of the longest sleep-centered studied within the 3 meta-analyses that utilized a placebo-controlled group was by Barton et al. in 2011.¹⁰ This was a double-blind randomized placebo-controlled trial in 227 patients who received daily valeriana officinalis whole root extract 450 mg for 8 weeks. Outcomes measured include the Pittsburgh Sleep Quality Index score (PSQI) and questionnaires around sleep, fatigue, and mood. PSQI and questionnaires were collected at baseline, week 4, and week 8. The authors found no statistically significant difference between valerian and placebo for PSQI or the sleep questionnaire. They did find a statistically significant improvement from baseline in the valerian group in the amount of sleep at night and overall mood, though these were not significantly different from the placebo group. The fatigue questionnaire was the only endpoint to have significant differences of valerian compared to placebo with the treatment arm reporting improvements in usual and current fatigue.¹⁰ This study is limited by its lower than typical dosing of valerian, its evaluation of strictly subjective outcomes, and its failure to meet power. The study is strengthened by its longer duration. The authors conclude that to be insufficient evidence to support valerian’s usefulness in improving sleep, though they did observe multiple non-significant improvements for the treatment group compared to placebo.¹⁰

Unfortunately, as is the case for most herbal products, there is insufficient evidence to determine valerian’s potential benefits. All 3 meta-analyses reiterate the need for controlled studies of multiple doses and extract types for extended durations. One meta-analysis concluded that they believe there is a subjective improvement in sleep that does not result in quantitative differences in sleep quality. The other 2 propose that valerian may have the potential to improve sleep quality, but the lack of evidence prevents their ability to form conclusions.

Valerian Safety Profile

Within the 3 meta-analyses, there were zero reports of any serious adverse events. The most common non-serious adverse events associated with valerian were headache, gastrointestinal upset, and drowsiness.¹ These effects were reflected in the meta-analyses with special attention to diarrhea, which 2 of the meta-analyses reported was statistically significantly more likely in valerian groups compared to placebo. Outside of the meta-analyses, 1 case report of a patient that consumed 20-times the recommended dose of valerian resulted in non-serious side effects that resolved within 24 hours.¹¹ However, this case report is missing information that precludes meaningful analysis.

Studies evaluating valerian’s interactions with other drugs are severely limited with the full picture largely unknown. It is widely recommended to take extra precautions when using valerian with known nervous system depressants (CNS) due to the potential risk of additive effects.¹ One study in rats found that valerian had the potential to prolong thiopental and pentobarbital induced sleep, strengthening this recommendation for patients.¹² It is uncertain if and how this interaction could present in a human.

There are some oncological patient resources that recommend against using herbal extracts, including valerian, due to risk of cytochrome P450 (CYP) interactions. A handful of in vitro and in vivo studies have been conducted to evaluate these interactions. The CYP enzyme with the most evidence of potential to be influenced by valerian is CYP3A4. Two in vitro studies (Hellum 2007, Lefebvre 2004) found valerian to mildly induce CYP3A4 in human hepatocytes, and 1 in vivo study (Donovan 2004) also found a statistically significant inducing effect of valerian when given as 1000 mg once daily after 14 days.^13-15 However, a second in vivo study (Gurley 2005) gave its subjects 125 mg of valerian 3 times a day for 28 days and did not find a significant effect on CYP3A4.¹⁶ There is insufficient evidence to claim a dose-effect correlation, but caution is warranted when combining valerian with a CYP3A4 dependent drug.

Two CYP enzymes have evidence of not being affected by valerian, including CYP1A2 and CYP2E1. CYP1A2 has an in vitro study (Yokotani, 2013) in human liver microsomes and the same in vivo study used for testing CYP3A4 (Gurley 2005), which both found valerian to not affect CYP1A2.16-17 CYP2E1 also has evidence suggesting lack of effect from an in vitro study (Hellum, 2009) in cultured human hepatocytes and the aforementioned in vivo study (Gurley, 2005).^16,18 Several other enzymes including CYP2D6, CYP2C19, and CYP3A1 have been evaluated, although their evidence is either insufficient or conflicting, preventing us from forming conclusions.

Conclusion

Ultimately, there exist many challenges surrounding herbal supplements due to lack of evidence-based information and regulation. Valerian is advertised as a supplement that can help with multiple disorders, especially including sleep and sleep-related issues, but current evidence is insufficient to support these claims. Although all herbal products have the potential risk of contamination due to lack of regulation by the FDA, valerian by itself is generally an overall safe supplement for most patients. Additional caution in patients with concurrent CNS depressants and CYP3A4 dependent medications is warranted with the current evidence available. It is not well-established if valerian has any benefit at all for sleep or other advertised indications, however for most patients, if they desire to try it, we can conclude that it is generally safe.

References

1. National Institutes of Health, Office of Dietary Supplements. Valerian. [Internet]. Available from: https://ods.od.nih.gov/factsheets/Valerian-HealthProfessional/

2. National Toxicology Program, National Institute of Environmental Health Sciences. NTP Technical Report on the Toxicology and Carcinogenesis Studies of Valerian Root Extract. [Internet]. Available from: https://ntp.niehs.nih.gov/sites/default/files/ntp/noms/support_docs/valerian_nov2009_508.pdf

3. Montana State University, Agricultural Experiment Station. Valerian: A New Crop for Montana. [Internet]. Available from: https://agresearch.montana.edu/warc/research_current/research_past/herbsandoils/valerian.html

4. Taibi DM, Bourguignon C, Gill Taylor A. Valerian for sleep: a systematic review and meta-analysis. JAMA Internal Medicine. 2007;167(11): 1218-1225. doi:10.1001/archinte.167.11.1218

5. Ortiz JG, Nieves-Natal J, Chavez P. Effects of Valeriana Officinalis extracts on [3H]flunitrazepam binding, synaptosomal [3H]GABA uptake, and hippocampal [3H]GABA release. Phytomedicine. 1999;6(2): 115-120. doi:10.1016/S0944-7113(99)80010-0

6. Bent S, Padula A, Moore D, Patterson M, Mehling W. Valerian for sleep: a systematic review and meta-analysis. Am J Med. 2006;119(12):1005-1012. doi:10.1016/j.amjmed.2006.02.026

7. Fernández-San-Martín MI, Masa-Font R, Palacios-Soler L, Sancho-Gómez P, Calbó-Caldentey C, Flores-Mateo G. Effectiveness of Valerian on insomnia: a meta-analysis of randomized placebo-controlled trials. Sleep Med. 2010;11(6):505-511. doi:10.1016/j.sleep.2009.12.009

8. Shinjyo N, Waddell G, Green J. Valerian Root in Treating Sleep Problems and Associated Disorders-A Systematic Review and Meta-Analysis. J Evid Based Integr Med. 2020;25:2515690X20967323. doi:10.1177/2515690X20967323

9. Oxman AD, Flottorp S, Håvelsrud K, et al. A televised, web-based randomised trial of an herbal remedy (valerian) for insomnia. PLoS One. 2007;2(10):e1040. Published 2007 Oct 17. doi:10.1371/journal.pone.0001040

10. Barton DL, Atherton PJ, Bauer BA, et al. The use of Valeriana officinalis (Valerian) in improving sleep in patients who are undergoing treatment for cancer: a phase III randomized, placebo-controlled, double-blind study (NCCTG Trial, N01C5). J Support Oncol. 2011;9(1):24-31. doi:10.1016/j.suponc.2010.12.008

11. Willey LB, Mady SP, Cobaugh DJ, Wax PM. Valerian overdose: a case report. Vet Hum Toxicol. 1995;37(4):364-365.

12. Usami N, Okuda T, Yoshida H, et al. Synthesis and pharmacological evaluation in mice of halogenated cannabidiol derivatives. Chem Pharm Bull (Tokyo). 1999;47(11):1641-1645. doi:10.1248/cpb.47.1641

13. Hellum BH, Hu Z, Nilsen OG. The induction of CYP1A2, CYP2D6 and CYP3A4 by six trade herbal products in cultured primary human hepatocytes. Basic Clin Pharmacol Toxicol. 2007;100(1):23-30. doi:10.1111/j.1742-7843.2007.00011.x

14. Lefebvre T, Foster BC, Drouin CE, Krantis A, Livesey JF, Jordan SA. In vitro activity of commercial valerian root extracts against human cytochrome P450 3A4. J Pharm Pharm Sci. 2004;7(2):265-273. Published 2004 Aug 12.

15. Donovan JL, DeVane CL, Chavin KD, et al. Multiple night-time doses of valerian (Valeriana officinalis) had minimal effects on CYP3A4 activity and no effect on CYP2D6 activity in healthy volunteers. Drug Metab Dispos. 2004;32(12):1333-1336. doi:10.1124/dmd.104.001164

16. Gurley BJ, Gardner SF, Hubbard MA, et al. In vivo effects of goldenseal, kava kava, black cohosh, and valerian on human cytochrome P450 1A2, 2D6, 2E1, and 3A4/5 phenotypes. Clin Pharmacol Ther. 2005;77(5):415-426. doi:10.1016/j.clpt.2005.01.009

17. Yokotani K, Chiba T, Sato Y, Nakanishi T, Murata M, Umegaki K. Shokuhin Eiseigaku Zasshi. 2013;54(1):56-64. doi:10.3358/shokueishi.54.56

18. Hellum BH, Hu Z, Nilsen OG. Trade herbal products and induction of CYP2C19 and CYP2E1 in cultured human hepatocytes. Basic Clin Pharmacol Toxicol. 2009;105(1):58-63. doi:10.1111/j.1742-7843.2009.00412.x