Determination of the sleep improving effects of phenolics from an orange peel extract

Against the background of numerous detrimental effects of reduced sleep and
sleep quality in the developed world, substances that are capable of improving
sleep have been of growing interest. Especially natural products, e.g. for
functional foods and nutritional supplements, such as valerian extracts have
been of interest. Valerian roots contain several polyphenolic compounds, some
of which are identical to polyphenols found in citrus fruits, specifically
hesperidin, linarin and apigenin. Published studies have indicated that
hesperidin, when administered intraperitoneally acutely prolonged sleep in
rodents, while it exhibited anxiolytic effects when administered chronically
over a four week time period orally. The positive effects of hesperidin on
sleep are exerted by the intact molecule, while the main metabolite, hesperitin
does not seem to exhibit potent effects. Recent in-vivo studies have shown that
orally administered Hesperidin does not impart sleep-promoting activity. Hence,
the need to develop and test a dosage form that make Hesperidin bioavailable by
avoiding premature metabolization in the gut and liver, and to subsequently
asses their efficacy in sleep improvement.

The present study aims to determine whether hesperidin or a hesperidin/apigenin
combined preparation can improve objective sleep duration and/or sleep quality,
and/or improve perceived sleep quality and feelings of rest.

The study is designed as a randomized cross over study in 76 healthy subjects.
During test nights, subjects will consume in randomized order a single dose of
(1) the orange peel extract standardized for 90-95% hesperidin, (2) the orange
peel extract standardized for 90-95% hesperidin with apigenin, or (3) a
placebo, after which a portable sleep monitor is worn throughout the night.
Test nights are separated by at least one day in between. Questionnaires are
completed on the morning and evening before and after the test night.

The study will take approximately 3-6 weeks per subject, during which the
selected dosage forms and a placebo is tested in triplicate, which adds up to 9
test nights. Test nights are separated by at least one day in between.

During the screening, one venepuncture is performed to obtain 10 mL blood for
clinical testing. Furthermore, subjects are interviewed during the screening,
to assess their suitability regarding potential sleep disorders and other
inclusion/exclusion criteria. Before the actual study nights, subjects are
asked to wear the sleep monitor for five nights of their own choosing to get
acquainted with the device and the feeling of wearing it. During this part of
the study, subjects have to fill in four questionnaires, i.e. in the morning
and evening of the day before and in the morning and evening of the day after
each test night. Furthermore, one serving of a finished dosage form has to be
consumed according to instructions and a sleep monitor has to be worn during
the night. The sleep monitor is an unobtrusive system, consisting of a
wireless headband that contains three small sensors on the forehead. The
discomfort associated with wearing this system was experienced as significantly
less than the discomfort associated with wearing an eye cover in a multi night
try out by one of the researchers. 76 subjects are asked to come to the
university once for screening. At home, subjects are asked to fill in 36
questionnaires, wear the sleep monitor for 5 unmonitored nights and 9 monitored
nights. The overall burden is relatively small. The risks associated with the
intake of hesperidin are negligible.