A randomized, double-blind and placebo-controlled crossover trial on the effect of l-ornithine ingestion on the human circadian clock

Abstract

In mammals, daily physiological events are regulated by the circadian rhythm, which comprises two types of internal clocks: the central clock and peripheral clocks. Circadian rhythm plays an important role in maintaining physiological functions including the sleep-wake cycle, body temperature, metabolism and organ functions. Circadian rhythm disorder, which is caused, for example, by an irregular lifestyle or long-haul travel, increases the risk of developing disease; therefore, it is important to properly maintain the rhythm of the circadian clock. Food and the circadian clock system are known to be closely linked. Studies on rodents suggest that ingesting specific food ingredients, such as the flavonoid nobiletin, fish oil, the polyphenol resveratrol and the amino acid L-ornithine affects the circadian clock. However, there are few reports on the foods that affect these circadian clocks in humans. In this study, therefore, we examined whether L-ornithine affects the human central clock in a crossover design placebo-controlled human trial. In total, 28 healthy adults (i.e. ≥20 years) were randomly divided into two groups and completed the study protocol. In the 1st intake period, participants were asked to take either L-ornithine (400 mg) capsules or placebo capsules for 7 days. After 7 days' interval, they then took the alternative test capsules for 7 days in the 2nd intake period. On the final day of each intake period, saliva was sampled at various time points in the dim light condition, and the concentration of melatonin was quantified to evaluate the phase of the central clock. The results revealed that dim light melatonin onset, a recognized marker of central circadian phase, was delayed by 15 min after ingestion of L-ornithine. Not only is this finding an indication that L-ornithine affects the human central clock, but it also demonstrates that the human central clock can be regulated by food ingredients.

Circadian Rhythm Dysregulation and Restoration: The Role of Melatonin

“…Additionally, in the cases of sleep studies, patients need not be awakened for a saliva collection, as Ogłodek et al utilize passive collection while subjects slept. In 2018, Cipolla-Neto et al stated that the gold standard for measurement is either melatonin in the serum or saliva, or urine 6-sulfatoxymelatonin during a morning collection [65]. Historically, Nowak et al stated that both salivary and urinary melatonin measurement methods were strongly correlated with serum concentrations, and would be useful as non-invasive tests for melatonin concentration [66].…”

“…Melatonin supplementation is not known to cause a classical feedback phenomenon [65], meaning that administration of the supplement should not result in tolerance or pineal atrophy. Theoretically, this should mean that melatonin can be taken indefinitely; however, practicality dictates that this must be confirmed via clinical study.…”

“…A brief literature search of animal and in vitro studies researching melatonin and circadian rhythms in the last 5 years yielded: research into melatonin associated with abnormal metabolism in rodents and humans [62], melatonin treating cognitive and endocrine deficits in zebrafish [63], genetic defects that lead to impaired circadian rhythms in rats with Smith-Magenis syndrome [64], sleep-assisting drug candidates in Drosophila model [65], and use of melatonin to inhibit chemotherapy resistance in rats with breast cancer [66]. Studies in rodents have shown light-at-night (LAN) is linked to metabolic derangements, possibly due to changes in circadian rhythms and circulating melatonin.…”

The Future of Shift Work: Circadian Biology Meets Personalised Medicine and Behavioural Science

“…This effect seems to translate to humans, as adults who consumed L-serine before bedtime experienced a greater advance in circadian phase in response to bright light exposure ( 109 ). Another study reported that 1 week of L-ornithine supplementation delayed the plasma melatonin rhythm by 15 min ( 110 ). However, LD cycles and meal timing were not fully controlled in these studies.…”

The use of melatonin preparations in sleep disorders

“…Анализ тем публикаций за последние 5 лет показывает интерес к изучению влияния этого гормона на метаболизм [24], для коррекции когнитивного и эндокринного дефицита [25], при нарушениях циркадных ритмов на фоне генетических дефектов [26], к использованию в качестве снотворного [27] и адъюнктивного средства при химиотерапии опухолей [28]. Оценивается эффективность мелатонина для контроля поведения, связанного с зависимостью от наркотических средств, синдрома отмены / рецидивов опиатов, поведенческой сенсибилизации, регуляции сна и/или нарушений циркадного ритма, нейропластичности в глубинных областях мозга, связанных с регуляцией вознаграждения и эмоций [29].…”