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

Takafumi Fukuda*, Atsushi Haraguchi, Masaki Takahashi, Takashi Nakaoka, Mayuko Fukazawa, Jin Okubo, Mamiho Ozaki, Ayana Kanatome, Rena Ohya, Yutaka Miura, Kuniaki Obara, Shigenobu Shibata

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

8 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)1445-1455
Number of pages11
JournalChronobiology International
Issue number10
Publication statusPublished - 2018 Oct 3
Externally publishedYes


  • DLMO
  • Ornithine
  • circadian rhythm
  • health care
  • melatonin
  • nutrition

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)


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