Sleep is universally perceived to be an essential health factor. Inadequate sleep is associated with multiple health issues including obesity, type II diabetes, metabolic syndrome, depression, cardiovascular issues, and impaired cognitive function (1–3). Conditions such as stress, depression, and anxiety activate hypothalamic–pituitary–adrenal (HPA) axis and produces cortisol, which is considered as an important factor in the sleep deprivation (4–6). Sleep deprivation can lead to weight gain or obesity through elevated ghrelin and decreased leptin secretions (7). Various studies have demonstrated that progressively longer (≥ 9 h/night) or shorter (≤ 5 h/night) sleep spans are associated with age-specific mortalities (8, 9). In the pre-COVID period, nearly 70 million adults in the US and 45 million in Europe were estimated to suffer from sleeplessness (10, 11). The outbreak of the COVID-19 pandemic has severely affected sleep quality (12). Sleep disturbances pose serious risks to public safety in terms of, lack of concentration, absenteeism, loss of productivity and accidents. Extensive internet usage, late bedtimes, daytime sleep, sedentary lifestyle, and stress have been identified as the major factors affecting sleep (13). Nonrestorative sleep (NRS) is a common sleep disorder which refers to the subjective feeling that sleep has not been adequately rejuvenating or restful. It is typically considered as a secondary manifestation of insomnia according to international classification of sleep disorders (14, 15). Nonrestorative sleep has consistently been recognized as a distinct component of insomnia in the Diagnostic and Statistical Manual of Mental Disorders (DSM-4) (16, 17). Nonrestorative sleep arises from disrupted sleep and is indicative of the human body’s inability to recover from both physical and mental fatigue. Individuals experiencing nonrestorative sleep are more susceptible to impairments in daily activities, decline in cognitive functions, daytime sleepiness, mood swings, and fatigue (15). Consequently, nonrestorative sleep is considered to have a detrimental impact on overall quality of life. Modern treatment approach aims at improving/restoring the sleep.

Currently approved over-the-counter sleep therapy drugs include benzodiazepine receptor agonists and non-benzodiazepines (18). However, these drugs have been reported to be associated with various side effects, including drowsiness, nausea, dizziness, nightmares, agitation, headache, somnolence, fatigue, and dependency (19–21). Long-term exposure to these drugs is associated with dependency, nocturnal confusion, daytime dysfunction, and rebound insomnia (RIS) (22–24). Herbal remedies have garnered considerable interest in this context. Nigella sativa (black cumin/black seed/kalonji) is a widely distributed medicinal and culinary spice found in North Africa, Middle East, Europe, and Asia. Black cumin seeds, powder, paste and oils have been traditionally used since ancient times for the treatment of various diseases such as cardiovascular, respiratory, rheumatism, headache, back pain, anorexia, amenorrhea, mental illness, eczema and hypertension. A number of phytochemicals including thymoquinone, thymohydroquinone, thymol, carvacrol, p-cymene, nigellidine, saponins, and flavonoids have also been identified in black cumin (25, 26). Black cumin oil and its major bioactive component, thymoquinone, have been found to possess anti-inflammatory, anti-arthritic, anti-allergic, anti-microbial, anti-diabetic, hypolipidemic, hepatoprotective, neuroprotective, and anticancer properties (27–29). Recently, we showed that a unique black cumin extract composition (BCO-5, registered as BlaQmax®/ThymoDream™) acts as a calming agent and helps manage sleep disorders in human volunteers when consumed at a dose of 200 mg/day (30). It was also shown to be safe when a randomized placebo-controlled study was performed for three months at a dose of 200 mg/day (31). Acute and sub chronic toxicity studies have indicated its safety for human consumption at 900 mg/day per adult (32). Thus, the present randomized, double-blind, placebo-controlled trial was conducted on healthy volunteers with a non-restorative sleep pattern to investigate the influence of BCO-5 on sleep parameters, sleep quality, and sleep efficiency. The study used 200 mg/day dosage for just seven days and employed actigraphy, a non-invasive screening tool worn like a wristwatch, to monitor the effect.

The present randomized, double-blind, placebo-controlled clinical trial was conducted to investigate the short-term effects of BCO-5 on participants reported with non-restorative sleep problems when supplemented at 200 mg/day after dinner for seven days. It has been reported that, sleep disorders and distinct sleep patterns in conditions such as nonrestorative sleep can be identified and quantified using subjective (questionnaires) and objective measures (instruments) (35). Considering this, our present study employed actigraphy as objective measure along with the restorative sleep questionnaire (RSQ-W) as a subjective measure.

All participants were characterized by typical nonrestorative sleep issues, as evident from the weekly version of the restorative sleep questionnaire (RSQ-W). RSQ was developed to validate nonrestorative sleep, which helps assessment on how restored an individual would feel after waking up (37, 38). It has good psychometric properties and can distinguish healthy controls from people with primary insomnia, and people with isolated non-restorative sleep complaints. The RSQ-W score observed in the present study shows significant restoration of sleep and improved quality of life indicating the primary efficacy of treatment with a single dose (200 mg × 1/day) of BCO-5 approximately half an hour before bedtime for 7 days. These findings were further supported by actigraphy data, which revealed remarkable enhancement in sleep quality as evident from various sleep parameters, including sleep onset latency, WASO and total sleep time.

To better understand the significance of our protocol and results, we reviewed previous actigraphy studies on certain herbal extracts currently using for the treatment of sleep disorders. Supplementation of passion flower extract at 60 mg/day for 14 days was reported to improve sleep efficiency and WASO (39). Tart cherry juice consumption for 7 days has shown to significantly increase total sleep time and sleep efficiency (40). In another study, significant improvement in sleep efficiency was reported when a rice bran extract was supplemented for 14 days at 1000 mg/day (41). These studies justify our protocol involving 7 days’ supplementation to investigate the influence of BCO-5 on sleep.

Valerian is one of the herbal extracts widely using as herbal supplement for sleep issues, though its clinical studies at various dosage ranging from 150 to 600 mg/day have provided mixed results. While the subjective measurements reported positive effect, the objective measures such as actigraphy and polysomnography failed to show efficacy (42). Another commercially available extract to treat insomnia is saffron. Most of its studies are based on the subjective measurements with mixed results. Kell et al. reported no effect on sleep quality when 128 subjects were treated with a standardized saffron extract (affron®) for four weeks at 22 and 28 mg/day though there was a decrease in negative mood and symptoms related to stress/anxiety (43). Another standardized saffron extract (Saffr’active®), resulted in significant increase in ‘time in bed’ when treated with 15.5 mg/day for six weeks; none of the other parameters showed improvement (44). Ashwagandha is yet another widely using herbal extract for better sleep. Deshpande et al. reported significant improvement in various actigraphy parameters when treated with a standardized ashwagandha leaf extract (Shoden®) for 6 weeks (45). In another study, standardized ashwagandha root extract (KSM66®) supplementation at 600 mg per day for 70 days reported to improve sleep (46). Thus, our results on BCO-5 were found to be superior to many other herbal extracts presented in the last decade, especially in the last 3 years, when considering the low dose of 200 mg/day, short-term duration of the study protocol (7 days), sample size (n = 70), randomized controlled design with both subjective and objective measurements of sleep and finally the statistically significant correlation observed between both the measurements.

Actigraphy results of the present study were also in agreement with a previous single-arm, open-label pilot study where BCO-5 improved both Non-Rapid Eye Movement (NREM) and REM sleep by 82.5 and 29.4%, respectively. A significant reduction (p < 0.05) in anxiety, stress and cortisol was also reported in the study (30). Increased cortisol level was generally correlated with reduced NREM and REM stages. In another recent randomized controlled study employing Pittsburgh sleep quality questionnaire (PSQI), more than 70% of participants treated with BCO-5 at 200 mg/day were satisfied with their sleep improvement in 7 days (47).

The sleep effect of BCO-5 may be attributed to its essential oil content. Certain essential oils such as lavender, chamomile and orange peel have already been reported to possess sleep promoting effect, when administered orally (48–50), though their major practice is in aromatherapy for sleep. Terpenes and terpenoids are the bioactive principles in essential oils. GC–MS/MS analysis showed that BCO-5 contains carvacrol, α-thujene and p-cymene as the major terpenes and terpenoids in addition to thymoquinone, in a unique ratio of 10:1:1:2 (v/v).

Recently we had reported the influence of BCO-5 on the hypothalamus-pituitary–adrenal (HPA)-axis to act as a dual orexin receptor antagonist (DORA) and hence to modulate cortisol/melatonin levels and thereby to balance stress/sleep and sleep/wake cycle (47). Inhibition of orexin activation can reduce cortisol and promote sleep signals by enhancing melatonin. Orexin agonism on the other hand promote wakefulness (51). Serotonergic and GABAergic effect of black cumin and BCO-5 have been reported previously which also play an important role in stress and sleep modulation (52–56).

The fact that BCO-5 did not cause any significant side effects or adverse events further supports its safety. In an animal study (acute and sub chronic toxicity), as per the Organization for Economic Cooperation and Development (OECD) guidelines, it was reported that BCO-5 is safe at 94 mg/kg body weight, indicating suitability for human consumption (32). Recently, a randomized, double-blind, placebo-controlled trial also evaluated the safety of BCO-5 at 200 mg/adult/day for 90 days in healthy volunteers and showed no adverse events or deviations in biochemical and hematological parameters (31). However, it was effective in significantly reducing (p < 0.05) total cholesterol, low-density lipoproteins, very-low-density lipoproteins, and triglycerides (p < 0.05).

The measurement of sleep within a short time of one week using both subjective and objective measures following a randomized, double-blind, placebo-controlled design exist as the major strength of the present study. However, lack of measurements of cortisol and melatonin, lack of measurement of the systemic absorption, distribution and elimination of the suspected bioactive molecules in BCO-5 and the absence of inclusion of a washout period in the study protocol may be considered as limitations of the present study.

Sleep disorders have become a common global problem, owing to increased stress and hormonal imbalance. One of the most widely observed sleep disorder is non-restorative or non-refreshed insomnia. The present randomized, double-blind, placebo-controlled study illustrated the beneficial effects of BCO-5, a unique composition of black cumin oil extract, in alleviating nonrestorative sleep in just a week time when supplemented at 200 mg/day. Actigraphy study could establish the improvement in sleep efficiency, sleep onset latency, total sleep time, and WASO without adverse side effects. However, future studies on various population types are warranted to determine their full therapeutic potential for the management of sleep issues and related disorders.

The original contributions presented in the study are included in the article/Supplementary material, further inquiries can be directed to the corresponding author.

The studies involving humans were approved by Balagangadharanatha Swami Global Institute of Medical Sciences, dated 10th May, 2021. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.

IK and PB: conceptualization. MM: project administration, investigation, and data curation. PP: writing—original draft preparation. SS, MCM, and IK: writing—review and editing. All authors have read and agreed to the published version of the manuscript.