articleA dietary supplement to improve the quality of sleep : a randomized placebo controlled trial

Background: To evaluate the effect of a dietary supplement containing polyunsaturated fatty acids, in association with Humulus lupulus extract, on the quality of sleep using the Leeds sleep evaluation questionnaire (LSEQ) in subjects with moderate to severe sleep disorders. Methods: Randomized placebo-controlled trial, in a Population-based setting. Participants were adult patients 25 to 65 years old with a chronic primary insomnia who volunteered for the study. The tested intervention consisted of two soft gelatine capsules per day, containing either the dietary supplement (active group) or olive oil (placebo group) for a month. Subjects could also volunteer for two ancillary studies on melatonin and actigraphy. Evaluation criteria included i) perception of the quality of sleep at the end of treatment using the LSEQ questionnaire, ii) sleep efficiency measured by one-week actigraphic movement measurement performed before and during the treatment in a subsample of subjects, iii) night melatonin and 6 sulfatoxymelatonin (aMT6S) urine rates in a subsample of subjects. Results: The average of Leeds score was similar in both groups (p = 0.95). A marked improvement in the quality of sleep was observed in both placebo (62%) and active (65%) group (p = 0.52). The evolution of urinary melatonin, aMT6S, and of the Mel/aMT6S ratio showed no differences between the two groups. Sleep efficiency, as measured by actigraphy, improved similarly in both groups during the treatment period, from 72% to 76% and 75% in the active and placebo group respectively (p = 0.91). Conclusions: The dietary supplement had neither effect on the perceived quality of sleep, nor on the melatonin metabolism and sleep-wake cycle. Trial registration: clinical trials.gov:NCT00484497 Background The estimated incidence of primary insomnia in the general population is 10 to 20% [1-3]. The consequences of this disorder are an impaired quality of life, an increase in medical consultations and in hypnotic drug consumption [4]. Increase in drug consumption reinforces the risk of work accident and absenteeism, resulting in a decrease in productivity [1,2]. It can also leads to adverse cognitive and psychomotor effects, daytime sleepiness [5], loss of memory, increased risk of falling in old subjects [6], and impaired driving abilities [7]. Alternative therapeutics would therefore be welcome. Melatonin, a hormone produced mostly during the night by the pineal gland, displays the role of an endogenous synchronizer, especially on the sleep-wake cycle [8]. Melatonin receptors are present at the level of the endogenous circadian clock located in the suprachiasmatic nuclei. The study product is a dietary supplement composed of natural components. It contained a specific ratio of polyunsaturated fatty acids (PUFA, linolenic and linoleic acids), in association with Humulus lupulus extract. PUFA were claimed to favor melatonin synthesis [9]. The short half-life of melatonin requires the administration of high doses to balance its quick metabolism. Recently, a controlled release melatonin preparation has been shown effective in insomnia in aged patients [10-13]. Humulus lupulus extract has been shown to decrease the hepatic * Correspondence: catherine.cornu@chu-lyon.fr 1 INSERM, CIC201, Lyon, F-69000 France; CHU Lyon, Service de Pharmacologie Clinique, Lyon, F-69000 France; Univ Lyon, UMR 5558, Lyon, F-69000 France Full list of author information is available at the end of the article © 2010 Cornu et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Cornu et al. BMC Complementary and Alternative Medicine 2010, 10:29 http://www.biomedcentral. com/1472-6882/10/29 Page 2 of 9 metabolism of drugs which are metabolised by the CYP1A2, a cytochrome that also allows melatonin transformation into its main metabolite: 6 sulfatoxymelatonin (aMT6s) [10]. This combined action could increase melatonin bioavailability and is likely to reset the endogenous biological clock. Besides, Humulus lupulus extract could directly act on sleep by enhancing the melatonin-mediated effects on the sleep-wake cycle [10]. Our objective was to evaluate the effect of the dietary supplement on the quality of sleep using the Leeds sleep evaluation questionnaire (LSEQ) in adult subjects with moderate to severe primary insomnia in a prospective double blind, randomized, placebo-controlled clinical trial. Methods Study population Overall, 101 patients were enrolled between September 2006 and June 2007. The study was carried out at the Clinical Investigation Centre (CIC) located at the Lyon university hospital (France). Subjects were invited to volunteer for the study through press announcements and a website for healthy volunteers' recruitment http://www.volterys. fr/. On the day of enrolment, subjects had a medical visit and a written consent was obtained after further information has been given. The study was conducted in accordance with the Declaration of Helsinki. The protocol was approved by Lyon Ethics Committee (Comité de Protection des Personnes Lyon B) on July 18th 2006. The study design is shown in Figure 1. In addition to the main study, subjects could volunteer for two ancillary studies before randomization. The first ancillary study was based on overnight urinary melatonin and aMT6s measurements (melatonin sub-study) and the second, a one-week actigraphic movement measurement (Actigraphic sub-study). Men and women aged 25 to 65 years, with a chronic primary insomnia were eligible to participate to the main study. Subjects had to be affiliated to the French Social Security System. Primary insomnia was defined according to the Diagnostic and Statistical Manual of Mental Disorders [14] (DSM-IV) and the International Classification of Sleep Disorders [15]. The severity of insomnia was classified by using the Insomnia Severity Index (ISI) [16]. The baseline minimum inclusion ISI score was 12, but was changed to strictly superior to 10 on February 6th, 2007, due to recruitment difficulties. Exclusion criteria Sleep disorders secondary to another health problem; pharmacological resistance to common hypnotic drugs; any ongoing long term treatment (except contraceptive and postmenopausal hormone replacement); acute disease during the previous three months; medical history that could interfere with sleep; history of psychiatric disorder in the five years preceding the inclusion (detected using the MINI questionnaire) [17], depressive disorder measured by a score above 30 (or identification of a risk of suicide) on the Beck self-questionnaire [18], pregnant or lactating women; subjects for whom a poor adherence to the study protocol can be anticipated (i.e. likely to leave the study area); individuals protected by law; lifestyle habits which would modify the wake-sleep rhythm (e.g. night work), or which would be likely to be modified during the study period; known allergy to one of the dietary supplement components; subjects with excessive daytime sleepiness as measured by an Epworth score equal to or superior to ten [19]. Randomization/intervention A permuted-block algorithm was used for randomization. Concealed allocation was performed by the coordination centre after eligibility check and baseline data collection. Patients were asked to take two soft gelatine capsules per day two hours before sleep for a month. Capsules contained the dietary supplement (active group) or olive oil (placebo group). The dietary supplement is currently on the market under the brand name Cyclamax® and contains 260 mg Soya oil (Glycine max), 173 mg. Cade oil (Cannabis sativa), 50 mg Houblon (Humulus lupulus) and 6 mg Soya lecithin. Its envelope is composed of modified starch, glycerine, Iota carrageenan, glyceryl monostearate, titanium dioxide, lecithin certified nonGMO, and disodium phosphate. Evaluation criteria and follow-up The primary criterion was to evaluate the perception of the quality of sleep at the end of the treatment (D30) using the LSEQ questionnaire [20]. This is a standardized self-reporting instrument comprising ten 100-mm visual analogue quetions that pertain to four items: i) the ease of getting to sleep (GTS, items 1-3), ii) the quality of sleep (QOS, items 4, 5), iii) awakening from sleep (AFS, items Figure 1 Study design. Day 30 Day 0 Actigraphy 7 Day 45 Visites 2 à 4 Randomization