Single Dose Administration of Valeriana officinalis Extract Improves Actual Sleep Time: A Randomized, Double-Blind, Placebo- Controlled Study

Sleep deprivation and poor-quality sleep is a major evolving health concern world-wide [1,2]. Sleep negatively impacts quality of life and well-being particularly affecting metabolic and cognitive health [3-13]. It is believed that changing lifestyle associated with diet, and workload are contributing to poor quality sleep [14,15]. Melatonin is widely used supplement to improve sleep but [16] known to cause headache, sleepiness, light-headedness and vomiting sensations. In addition to regulation of body’s sleep-wake cycles, melatonin also affects number of biological system, including cardiovascular, reproductive, endocrine and metabolic systems and hence not recommended for long-term use [17]. Prescription drugs for sleep disorders that include benzodiazepines, anti-histamines etc., although used in clinics to address severe sleep disorders are not advisable for long term use due to multiple undesired adverse-effects [18-27]. Herbal supplements used extensively in traditional medicine are considered as an effective alternate for managing sleep due to their relative safety and lesser adverse effects [28,29]. Valeriana officinalis has been traditionally used to manage sleep across the globe [30-33].

Root extract of V. officinalis is known to have sedative, and anxiolytic effects, and improve overall sleep quality after oral intake [34]. Valerianic acid, which is the most common marker used for qualitative and quantitative analysis of valerian extract has been demonstrated to have sleep inducing properties [30,33,35]. Valerenic acid is known to bind A1 adenosine receptors [36], benzodiazepine receptors [37], as well as increase GABA levels in synaptic space [38]. In experimental sleep models in mice, VE enhanced sleep quality by increasing serum levels of serotonin, melatonin, and dopamine as well as increased expression of GABA receptors [39]. Further human clinical studies have demonstrated that valerian extract reduced sleep latency and improved sleep quality in healthy subjects as well as those suffering from sleep disorders [40-45]. We previously reported beneficial effects of the standardised V. officinalis Extract (VE) on overall sleep quality, sleep latency, sleep efficiency and actual sleep time, in subjects with mild insomnia with a significant decrease in sleep latency as early as three days of oral intake through an 8-weeks long randomized, double-blind, placebo-controlled, clinical study [46]. This study focuses on the acute effects of VE on sleep, utilizing wrist actigraphy data following a single dose of VE on the first day postsupplementation.

Study material

Valerian extract (Sleeproot®) was extracted from valerian roots using water: ethanol mixture followed by spray drying (OmniActive Health Technologies, Mumbai, India). The final formulation prepared as a powder contained 26.23% of extract and 73.27% of cellulose polymer (novo excipients, Navi Mumbai, India) and 0.5%, of colloidal silicon dioxide (Daksh Medicare, Mumbai, India) with a final concentration of 2% total valerenic acid as established by high performance liquid chromatography [46].

Study design and procedures

This was a randomized, double-blind, placebo-controlled, parallel, supplementation study done over 56 days including individuals with mild insomnia problems. Study was approved by ethics committee at BGS Global Institute of Medical Sciences, Bengaluru, India and registered at Clinical Trials Registry of India (CTRI/2022/05/042818). We followed ethical and regulatory guidelines from Indian Council of Medical Research, International Council for Harmonization Guidance on Good Clinical Practice (E6R2), and the Declaration of Helsinki. Eligible candidates provided written informed consent prior to enrolment to the study (Inclusion and exclusion criteria used for subject selection is provided in Table 1). Subjects were randomly divided at 1:1 ratio (using R software version 4.2.1 through an independent non-study expert) and informed to consume one capsule that contained either VE (200mg) or placebo (microcrystalline cellulose) every night, one hour before sleep for 56 days.

Table 1:Key inclusion/exclusion criteria.

Efficacy parameters

Participants visited the study centre in the night for recording sleep latency, actual sleep time and sleep efficiency using wrist actigraphy device on day 1.

Wrist actigraphy: Actigraphy devices are worn on the wrist which record movements to calculate sleep characteristics using specialized algorithms derived from computer software applications. The participants underwent wrist actigraphy evaluation at the research location and were instructed to wear Wrist actigraphy device (motionwatch 8, CamNtech Ltd. Cambridgeshire, UK) after dinner on day 1.

Sample size calculation and statistical tests

In order to determine statistically significant clinical difference between VE and placebo groups with 90% power and a 5% significance, 80 subjects (40 per group) were recruited for the study including the consideration of drop-out rate of 10% during the study. R software version 4.2.1 was used for statistical analysis using mean, standard error, 95% confidence interval in case of normal distribution of data and median if data was not normally distributed. Efficacy was assessed using actual values and mean changes from baseline and within-group analysis was done using paired t-test. Intergroup analysis was conducted using independent t-test and p-value of less than 0.05 was considered statistically significant.

Efficacy endpoints evaluation: Sleep parameters such as actual sleep time, sleep latency, and sleep efficiency were measured using wrist actigraphy from baseline to end of day 1.

Out of 80 randomized subjects for the study, 35 in the placebo and 37 in the VE group completed the study and hence used for efficacy assessment (Figure 1). Five participants in the placebo group and three in the VE group were lost to follow-up and excluded from the study. The demographic details of the subjects who were included in the assessment are provided in the Table 2.

Table 2:Baseline demographics summary of study participants. N-Number of subjects in the specified treatment; n-number of subjects in the specified category; SE-Standard Error. Percentages are based on the number of subjects in the specified treatment.

Figure 1:Consort diagram.

Efficacy results

A summary of Wrist Actigraphy results are provided in Table 3 and Figure 2.

Figure 2:Summary of acute effects on day 1 from wrist actigraphy results.

Table 3:Summary of results assessed by wrist actigraphy by treatment and visit. VE -Valerian extract; N-No of subjects; SE-Standard error; Min-Minimum; Max- Maximum; Change=Timepoint vs. Baseline; ##-Paired t-test (Timepoint vs. Baseline); ‡-Independent t-test; *–p<0.05 Valerian over placebo; #- p<0.1 & p>0.05 VE over placebo.

Sleep latency (minutes) as assessed by wrist actigraphy: In the VE group, a non-significant (p>0.05) decrease in the sleep latency (in minutes) as assessed by Wrist Actigraphy was recorded from 89.39±8.20 minutes at baseline to 76.47±9.74 minutes on day 1 whereas a significant (p<0.05) increase in sleep latency was observed in case of placebo from 74.26±5.24 minutes at baseline to 126.60±10.97 minutes on day 1 (Table 3a). The between group analysis showed a significant (p<0.05) difference in sleep latency between VE and placebo groups on day 1 (-12.91±8.67 minutes for VE vs. 52.34±12.14 minutes for placebo). However, this significance was not attributed to VE as there was no statistical significance in VE group at day 1 compared to baseline (Table 3a & Figure 2a).

Actual sleep time: In the VE group, a significant (p<0.05) increase in the actual sleep time (in minutes) as assessed by wrist actigraphy was recorded from 306.09±7.61 minutes at baseline to 328.93±10.54 minutes at day 1. On the contrary, placebo group showed a significant (p<0.05) decrease in the actual sleep time (in minutes) as assessed by wrist actigraphy from 339.80±6.40 minutes at baseline to 300.53±9.27 minutes at day 1 (Table 3b). Based on the between group analysis, VE group showed a significant (p<0.05) increase in the actual sleep time as compared to placebo from baseline on day 1 (22.84 ±9.82 minutes for VE vs. -39.28 ±9.13 minutes for placebo) (Table 3b & Figure 2b).

Sleep efficiency (%) as assessed by wrist actigraphy: In the VE group, a non-significant (p>0.05) increase in the sleep efficiency (%) as assessed by wrist actigraphy was recorded from 66.40±1.67 % at baseline to 68.76±2.07 % at day 1. In contrast, the placebo group demonstrated a significant (p<0.05) decrease in the Sleep efficiency (%) as assessed by wrist actigraphy from 72.87±1.15 % at baseline to 61.98±1.88 % on day 1 (Table 3c). The between group analysis showed a significant (p<0.05) difference in sleep efficiency between VE and placebo groups on day 1 (+2.36±1.91 % for VE vs. -10.89±1.97 % for placebo). However, this significance was not attributed to VE as there was no statistical significance in VE group at day 1 compared to baseline (Table 3c and Figure 2c).

Sleep deficit impacts quality of life, cognitive performances, and increases risk of metabolic diseases [35,47-51]. Valerian extract has been widely used for improving sleep since antiquity [52]. Supplementation with VE has already been demonstrated to provide sleep benefits on various aspects of sleep by day 3 and several later time points during the course of 56 day study in subjects with mild insomnia [46]. Here we report acute effect of VE with significant improvement in the actual sleep time after a single oral dose of VE. We believe our observation in improvement of actual sleep time after single dose of standardized hydro-alcoholic extract of valerian is significant as it is an extract optimized to contain highest concentration of total valerenic acid (2%) reported to date with already reported sleep benefits after multiple doses of supplementation [46].

Further, the study material was found to be safe with no product related adverse events throughout the study period. Variety of valerian preparations and dosages that were evaluated in the past using various study designs, improved subjective experiences of sleep such as shortened sleep latency when ingested before sleep. In the past, clinical studies have used valerian extracts prepared as hydro-alcoholic extracts [53-60], aqueous extract [45,61,62], extracts prepared using unspecified solvents [63-65] or extracts defined as herbal substance (the whole root / rhizome) [66-70] to demonstrate sleep benefits. Interestingly, aqueous extracts of valerian found to provide sleep benefits after single dose such as improved subjective sleep quality in healthy volunteers [61,62]. Similarly, aqueous valerian extract provided dose-dependent increase in sleep latency as measured through wrist actigraphy at a dose of 450- or 900mg [62]. On the other hand, another study reported no sleep benefits as measured by polysomnography in subjects with insomnia after a single dose of valerian extract [53]. Further, other studies that used single dose of aqueous [45] or hydro-alcoholic [53,56] extract observed no sleep benefits although improved REM sleep was observed in insomnia patients [54]. Such inconsistent outcomes were observed also with repeated administration of hydro-alcoholic extracts [53,55,58-60,63]. There were 3 studies using extracts with unspecified procedures which showed inconsistent results with negative outcomes for 2 studies [64,65] and positive for an observational study [71].

On the other hand, all the 5 studies that used dried root/ rhizome of valerian reported improved sleep after single dose of supplementation [62,66-69] suggesting maximum efficacy from the total extracts of root / rhizome. It is believed that variation in sleep outcome across different studies of valerian supplementation may be due to the nature of preparation and type of extraction solvent used which in turn determines the chemical content of the extract [33,72,73]. This is further complicated by lack of consistency across studies with regard to study methods including randomization, criteria used for subject selection and variation in statistical methods used for data analysis [42,44,61,62,74]. It was also observed that effect of valerian extract on sleep was most significant in older male patients who considered themselves to be poor sleepers with lengthy sleep latencies as compared to those habitually good sleepers [62]. The valerian that was used in the various past studies used poorly defined extracts or extract that contained an amount of valerenic acid comparable to the 0.8% standard and lack of sedative effect noted in these studies was probably due to a lack of sufficient quantities of pharmacologically active molecules in the extract [75].

In our study we used well defined valerian extract with 2% total valerenic acid formulated and spray dried using excipients that are known to improve bioavailability as well as demonstrated to improve organoleptic properties (data not shown). Thus, the improved actual sleep time observed after single dose supplementation in our study is more meaningful and additional future studies should focus on validation of these data with larger set of subject population using multiple data evaluation methods in future. Wrist actigraphy is a valuable tool for assessment of sleep over extended periods of time in the natural sleep environment. With advancement of device technology and scoring algorithms wrist actigraphy is increasingly being used under clinical settings to measure sleep which is also substantiated by American Academy of Sleep Medicine (AASM). Further multiple studies that conducted comparative evaluation of wrist actigraphy to other established methods of assessing sleep has concluded that wrist actigraphy is useful for estimation of total sleep time, sleep percentage, and wake after sleep onset [76].

Motion Watch device used in the current study is one of the leading actigraphy solutions for convenient long-term sleep monitoring with high patient compliance and extensively used in clinical and scientific research applications [77]. We observed a 9% improvement in actual sleep time over baseline in our study. This is an important finding as the actual sleep time is crucial to improve brain performance, mood and overall health. In addition, VE supplementation showed marginal non-significant improvements in sleep latency (8.49%) and sleep efficiency (4.69%) compared to baseline, whereas subjects in the placebo group showed significant worsening of these parameters. This could be due to the change in sleep environment of subjects as they were housed at the study facility, a different environment than their regular sleep environment at home. However, it is important to note that even in this situation, VE supplementation showed significant effects on actual sleep time and slightly improved sleep latency and sleep efficiency which could be a point of further research in future studies. It is generally recommended that valerian be taken approximately 30 minutes to 2 hours prior to bedtime [53] which is further supported by human pharmacokinetic (PK) data with maximum serum concentration for valerenic acid achieved between 1 and 2 hours after single oral administration of valerian extract.

The PK study while explains the possible early effect of valerian extract seen in our study due to the presence of plasma level of valerenic acid within an hour and also indicate absence of adverse effects of valerian such as residual sedation in the morning [78]. We believe that our study outcome was limited by type of subject recruited for the study. Our subjects possibly had mild to moderate insomnia as against our targeted subjects with mild insomnia which was apparent from higher sleep latency observed at baseline. Additionally, no elderly subjects were included in the study. A study involving elderly people may provide more insights on the early effects of VE on sleep time across all age groups. Further we measured limited evaluation parameters at the end of single dose administration using only wrist actigraphy as most of the other parameters were measured at later time points of supplementation as reported in our previous studies [46]. Future detailed studies using subjective and objective parameters should provide more conclusive outcome of sleep benefits for our optimized hydroalcoholic preparation of valerian extract that is standardized to 2% total valerenic acid content.

Valerian is one of the most promising sleep-aid solutions today not only for improving quality of sleep but also established safety as a widely used solution in clinic and traditional medicine. Valerian extract 200mg (Sleeproot®) containing 2% total valerenic acid showed a significant improvement in the actual sleep time after a single dose which is a significant health benefit for those looking for early sleep benefits as a safe alternative to melatonin.

We thank the participants of the study. Disclosures. The study was funded by OmniActive Health Technologies. Abhijeet Morde and Muralidhara Padigaru are employees of OmniActive Health Technologies. The remaining authors state that the research was done in the absence of any business or financial relationships that may be considered a possible conflict of interest.

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