Received: 21 September 2017 Revised: 9 December 2018 Accepted: 14 December 2018 DOI: 10.1002/ptr.6286 RESEARCH ARTICLE Valerian extract alters functional brain connectivity: A randomized double‐blind placebo‐controlled trial Daeyoung Roh1,2 | Jae Hoon Jung1,2 | Kyung Hee Yoon1 | Chang Hyun Lee1,2 | Lee Young Kang1,2 | Sang‐Kyu Lee1,2 | Kitack Shin1 | Do Hoon Kim1,2 1 Department of Psychiatry, Hallym University College of Medicine, Chuncheon, Korea Valerian root is the most commonly used herbal supplement for sedation and 2 Mind‐neuromodulation Laboratory, Hallym anxiolysis, but it is unknown whether it may affect functional brain connectivity. University College of Medicine, Chuncheon, Korea Our goal was to use electroencephalography (EEG) to investigate whether valerian Correspondence root extract (VRE) affects resting‐state connectivity changes and whether such Do Hoon Kim, MD, PhD, Department of changes are associated with clinical symptoms. This 4‐week, double‐blinded, random- Psychiatry, Hallym University College of Medicine, Chuncheon Sacred Heart Hospital, ized, placebo‐controlled clinical trial was conducted with 64 nonclinical volunteers ‐ ‐ 77 Sakju ro, Chuncheon, Gangwon Do 24253, suffering psychological stress. The participants received VRE (100 mg) or a placebo Korea. Email: [email protected] thrice daily. We examined VRE's therapeutic effects on anxiety and stress‐related Funding information psychological constructs. Functional brain connectivity changes were measured as High Value‐added Food Technology Develop- EEG coherence in the alpha and theta frequency bands. The VRE and placebo groups ment Program, Ministry for Agriculture, Food and Rural Affairs, Republic of Korea, Grant/ both exhibited significant postintervention improvements on all clinical scales, but no Award Number: 111118‐032‐HD110; significant between‐group differences in these changes were noted. Compared with National Research Foundation of Korea (NRF) Grant Funded by the Korea Government the placebo group, the VRE group exhibited significantly greater increases in frontal (MSIP), Grant/Award Number: brain region alpha coherence across four electrode pairs, and these changes were 2017R1A2B4008920; Hallym University Research Fund significantly correlated with anxiolysis. The VRE group also exhibited significantly greater decreases in theta coherence across another four electrodes pairs. Our findings indicate that VRE alters functional brain connectivity in relation to anxiety. Further EEG studies are needed to confirm VRE's neurophysiological effects. KEYWORDS alpha band, brain connectivity, coherence, electroencephalography, herbal supplement, valerian 1 | INTRODUCTION profile (Wachtel‐Galor & Benzie, 2011) regardless of potential risks (Niggemann & Grüber, 2003). Therefore, in recent years, the use of Anxiety is among the most common mental problems, currently affect- over‐the‐counter psychotropic herbal medicines as self‐treatment for ing 7.3% of people worldwide (Baxter, Scott, Vos, & Whiteford, 2013). various afflictions has been rapidly growing (Cavaliere, Rea, Lynch, & Conventional anxiolytic medications are considered efficacious and Blumenthal, 2009). safe, but their use is still limited. Conventional drugs such as antide- Valeriana officinalis, commonly known as valerian, has been used pressants and benzodiazepines do not alleviate all affective symptoms, as a sedative–hypnotic herb for over 1,000 years. Valerian is the most and intolerable adverse effects may cause nonadherence (Kinrys, commonly used herbal supplement (Blumenthal, Ferrier, & Cavaliere, Coleman, & Rothstein, 2009). There is little evidence that conven- 2006; Morris & Avorn, 2003). Valerian is listed by the US Food and tional antidepressant drugs are effective, particularly for people with Drug Administration as a food supplement and is approved as an mild to moderate depression (Fournier et al., 2010). Herbal remedies over‐the‐counter medicine in Western Europe (Ross, 2014). There could be an attractive option for patients as they are perceived as are no contraindications to its use (Blumenthal, 1998). It is most complementary and commonly have a more favorable side effects commonly utilized for its sedative–hypnotic effects, but it has been Phytotherapy Research. 2019;33:939–948. wileyonlinelibrary.com/journal/ptr © 2019 John Wiley & Sons, Ltd. 939 940 ROH ET AL. suggested for several other uses, including alleviating anxiety, depres- activities are linked to decreased anxiety (Boutcher, 1993) and emo- sion, and psychological stress (Kinrys et al., 2009). Although its tional arousal (Knyazev, 2007), respectively. Based on prior studies, effectiveness remains unconfirmed, valerian is considered a highly we hypothesized that VRE would alter functional brain connectivity promising herbal agent (Baek, Nierenberg, & Kinrys, 2014). and that these changes would correlate with anxiolysis. Valerian's exact pharmacological mechanism remains undeter- mined, but some mechanisms have been identified. The valepotriates 2 | METHODS and valerenic acid in valerian root cause sedation and anxiolysis by enhancing γ‐aminobutyric acid (GABA) transmission (Benke et al., 2009; Savage, Firth, Stough, & Sarris, 2018). Valerian compounds also 2.1 | Participants act on the GABAA receptor, similarly to benzodiazepines (Hadley & Petry, 2003). Another core mechanism involves serotonergic effects This study was conducted in the psychiatry units at Chuncheon Sacred via partial agonism of the 5‐hydroxytryptamine‐2A receptor (Dietz, Heart Hospital, a teaching hospital affiliated with the Hallym Mahady, Pauli, & Farnsworth, 2005). University College of Medicine. It was retrospectively registered with During the last 20 years, several clinical trials have investigated the Clinical Trials Registry Korea (registration: KCT0002406). We used valerian's efficacy for psychological stress and anxiety, but few have advertisements at the local university and in the community to recruit been properly controlled. Valerian's stress‐reducing effects have been participants with stress that was not serious enough for a psychiatric shown in healthy volunteers in short‐term care settings (Kennedy, diagnosis. The study protocols were approved by the hospital's Ethics Little, Haskell, & Scholey, 2006; Kohnen & Oswald, 1988), but not in and Medical Research Committee and conducted according to the long‐term care settings. Moreover, systematic reviews of its anxiolytic principles of the Declaration of Helsinki. All subjects gave written effects have found inconsistent results due to a lack of standardization informed consent. ‐ and quality controls (Kinrys et al., 2009; Nunes & Sousa, 2011). Recent The inclusion criteria were (a) a self reported score above 4 on at ‐ ‐ animal studies have shown that valerian extracts have potent anxio- least 1 of the 0 to 10 visual analogue scales separately administered lytic effects (Murphy, Kubin, Shepherd, & Ettinger, 2010) and reduce for anxiety, depression, and insomnia; (b) being between 18 and physical and psychological stress (Jung et al., 2015). However, rigorous 65 years old; and (c) being able to understand and follow the instruc- studies involving objective measures are needed to confirm valerian's tions and procedures. The exclusion criteria were (a) experiencing a long‐term efficacy in human subjects. current depressive episode or anxiety disorder, a current or past One particularly unfortunate lacuna in the literature on valerian is psychotic disorder or bipolar disorder, or a current alcohol or sub- the lack of any studies examining valerian's effects on electroenceph- stance use disorder according to the Diagnostic and statistical manual ‐ ‐ alography (EEG) rhythms or functional brain connectivity. Cerebral of mental disorders fifth edition (DSM 5) criteria (American Psychiat- EEG rhythms reflect brain network activity (Steriade, 2006), and ric Association, 2013); (b) having any history of serious liver or kidney ‐ resting‐state EEG can be used for serial examinations of psychological disease; and (c) using relaxation techniques or herbal therapies. Face ‐ symptom changes (Kim et al., 2017; Roh et al., 2011). EEG measure- to face diagnostic interviews were performed to determine whether ments of brain wave coherence in particular reflect brain dynamics each participant had any functional impairment or major symptoms in terms of the coupling and functional association of paired regions such as suicidal ideation related to anxiety disorders and affective ‐ (Shaw, 1984; Sklar, Hanley, & Simmons, 1972). EEG coherence mea- disorders according to DSM 5 criteria. surements have been used to evaluate cortical functional connectivity The results of prior study (Ahmadi et al., 2017) indicated that the ‐ (French & Beaumont, 1984) and are very sensitive to mental states mean difference of HAM A scores before and after treatment with (Chen & Rappelsberger, 1994). Pharmaco‐EEG studies have proposed valerian was 2.92 and the standard deviation of the difference that administering psychotropic medications can affect EEG measure- between subjects was 4.70. Based on a standard sample size formula ments in clinical populations (Aiyer, Novakovic, & Barkin, 2016). EEG (Noordzij et al., 2010), we aimed for a sample size of 32 for each group, ‐ studies of valerian are limited to a few sleep studies using crude for a total sample size of 64, to cover an anticipated 10% loss to follow ‐ EEG‐based polysomnography measurements (Diaper & Hindmarch, up, for a two sided type I error of 5% and