Our results showed that L-ornithine supplementation had a favourable effect on the cortisol response as an objective stress marker and improved perceived mood and sleep quality related to fatigue as well as subjective feelings derived from stress.
Previous studies reported that i.c.v. injections of L-ornithine had sedative and hypnotic effects on neonatal chicks exposed to acute stressful conditions
[31, 32]. That action was mediated by GABAA receptors. It was also confirmed that orally administered L-ornithine can be transported into the brain of mice
, and as a result, reduced the plasma corticosterone concentration induced by restraint stress in mice. L-ornithine levels in the brain increased after oral administration of L-ornithine in mice
. Moreover, it was shown that i.c.v. injected L-arginine, the precursor of L-ornithine, increased both L-arginine and L-ornithine concentrations in the telencephalon and diencephalon in chicks 10 min post-injection
, however, the GABA content was not changed. This suggests that the sedative and hypnotic effects of L-ornithine were not due to changes in GABA synthesis
The role of GABA in HPA axis regulation has been well established, indicating that corticotropin-releasing hormone (CHR) neurons receive robust GABAergic inhibition
. In addition, micro infusion of GABA agonists, such as the stress-derived neurosteroid tetrahydrodeoxycorticosterone (THDOC), into the paraventricular nucleus (PVN) decreased circulating levels of stress hormones
. Our result showing that orally administered L-ornithine decreased the serum cortisol level in human subjects was in agreement with previous animal studies on the effectiveness of stress reduction through the alleviation of HPA axis hyperactivity
We observed that L-ornithine supplementation for 8 weeks reduced the serum cortisol level and cortisol/DHEA-S ratio, mainly due to reduction in the cortisol level. An imbalance between cortisol and DHEA-S may be a key factor in physical and psychiatric disease
[36, 37]. The molar DHEA-S/cortisol ratio was shown to be significantly lower in non-medicated depressed patients than in control subjects, and evening salivary DHEA/cortisol ratios were inversely correlated with the length of the current depressive episode
. Elevated cortisol/DHEA-S ratios in schizophrenia patients were positively associated with higher scores for anxiety and anger, depression and hostility, age, age at onset of illness, and duration of illness
These reports provide support for our results showing that the decrease in cortisol/DHEA-S ratios through the administration of L-ornithine corresponded to the improvement in mood related to “anger-hostility” as well as sleep quality.
The initial decreasing tendency of the cortisol/DHEA-S ratios in the placebo group may be due to a non-specific, natural change which occurs after formal ornithine and placebo intake treatments. It is widely accepted that on average, brief initial interventions yield outcomes similar to those with prolonged treatments, suggesting that changes could be triggered after a brief phase of treatment
“Anger-hostility”, an item on the POMS, is one of the phenotypes resulting from activation of sympathetic nerves. A physiological change accompanying stress was shown to be the increased excretion of cortisol and adrenaline
. Adrenalin promotes activation of the sympathetic nerve system suggesting L-ornithine supplementation might affect, not only the HPA axis, but also the autonomic nervous system. Unfortunately, we did not examine whether L-ornithine supplementation could affect either the autonomic nervous system or adrenaline levels.
Our results also suggested that sleep quality was improved by L-ornithine, as revealed by both AIS and OSA-MA questionnaires, along with alleviation of stress (cortisol/DHEA-S). The present finding is in accordance with a previous report that L-ornithine supplementation after alcohol consumption improved sleep quality as perceived upon awakening in flushers
 and that ornithine increased the amount of non-rapid eye movement (NREM) sleep without reducing the power spectrum density of NREM sleep in mice
. This result replicated findings of our previous study, that ornithine could improve sleep in an animal model and suggested the effectiveness of orally administered L-ornithine on stress reduction through improvement of sleep quality in human subjects.
Furthermore, it was shown that L-ornithine administration stimulated release of growth hormone
[45, 46], which is secreted as the largest pulse after the onset of sleep, and that there is a correlation between night-time growth hormone release and sleep satisfaction
A serotonin metabolite (5-hydroxyindole acetic acid, 5-HIAA) was induced in the striatum after L-ornithine supplementation
. Day-time serotonin levels stimulate production of melatonin during the night
[50–52], therefore, L-ornithine might be considered an important nutrient to maintain the circadian rhythm and to allow individuals to sleep well.
Job stress is one of the most important social problems for workers today. This study has provided further objective evidence of the usefulness and effectiveness of L-ornithine for managing stress and sleep quality related to fatigue. Future studies must address how L-ornithine affects regulation of blood glucose and the autonomic nervous system.
Limitations exist in this study: first, we did not evaluate plasma ornithine levels, so we were unable to assess any direct correlation between ornithine and suppressing stress markers or improved subjective feelings. Second, we used three tests to assess fatigue and mood states, however, many tests, using differing strategies, are required to properly evaluate psychological status. Third, we determined the sample size of this study on the basis of a previous report
, however, this sample size (n = 26) was not sufficient to lead to draw firm conclusions and more extensive studies are needed to confirm our findings.