The results of this study suggest that intake of L-serine before going to bed improves subjective sleep quality among individuals who are dissatisfied with their sleep. The results of objective evaluation using actigraphy also support these findings.
In Study 1, parameters related to nighttime awakening and sleep initiation on the OSA were significantly improved, but Study 2 found no significant improvements in the corresponding items. This may have been influenced by the smaller number of subjects in Study 2 and differences in the questionnaire used. Objective evaluation using actigraphy showed that nighttime awakenings tended to be decreased. In terms of distinguishing sleep/wakefulness, the concordance between actigraphy and polysomnography (PSG) in healthy individuals is ≥90%, and a high concordance of 78-85% has also been reported in patients with sleep disorders (Kushida et al. 2001). However, results from the questionnaires used in our study and actigraphy did not show changes in sleep depth or rapid eye movement (REM) sleep/non-REM sleep. Studies using PSG are needed to identify changes in sleep structure.
With regard to L-serine and reversible conversion to glycine in vivo, oral administration is reported to improve sleep in humans (Inagawa et al. 2006; Yamadera et al. 2007). Glycine is an inhibitory neurotransmitter like gamma-aminobutyric acid (GABA). Shigemi et al. investigated the effects of simultaneous administration of the GABAA receptor antagonist picrotoxin, the glycine receptor antagonist strychnine, and L-serine (Shigemi et al. 2008). They found that the hypnotic effects of L-serine were inhibited by the GABAA receptor antagonist picrotoxin, but not by strychnine. On the other hand, the hypnotic effects of glycine were inhibited by the glycine receptor antagonist strychnine. That report showed that the mechanism of action differs from that for glycine. However, whether a similar mechanism of action exists in humans is unknown from our study.
In a social isolation stress model in neonatal chicks, Furuse et al. compared L-serine-related phosphoserine, acetyl serine, lysophosphatidylserine, L-alanine, lysine, methionine, and tryptophan; and reported that L-serine had both hypnotic and anxiolytic effects (Koutoku et al. 2005; Asechi et al. 2008). In addition, D-serine, an optical isomer of L-serine, is present in the vertebrate brain, and particularly in mammals, is an N-methyl-D-aspartate (NMDA) receptor agonist. However, in the neonatal chick model of isolation stress, decreased locomotor activity and vocalization, as well as prolonged sleep-like behavior, were confirmed only with L-serine, while administration of D-serine had no effect (Asechi et al. 2006). Furthermore, measurement of plasma and cerebral cortical levels of L- and D-serine after oral administration in rats showed that L-serine levels increased in both plasma and the cerebral cortex, whereas D-serine did not (Tomonaga et al. 2012). The improvement in human sleep with L-serine observed in our study was thus probably not mediated by D-serine synthesis.
Subjects in our study took L-serine 30 min before going to bed. With oral administration of L-serine to rats, plasma L-serine levels peaked 30 min after administration, then decreased, reaching baseline levels within 10 h (Tomonaga et al. 2012). We have confirmed increased plasma L-serine levels in humans 30 min after L-serine ingestion (data not shown). These results suggest that the timing of L-serine administration in our study was appropriate. In addition, subjects in both Studies 1 and 2 felt refreshed and had no problems the next morning after taking L-serine. No hangover effects of drowsiness were reported the next day.
When taking sleep-improving drugs, resistance after long-term administration or rebound insomnia after discontinuation are frequently problematic. We have shown that when subjects who are dissatisfied with their sleep drink a beverage containing 3 g of L-serine on consecutive days for 1 month, the improvement in sleep quality persists even 1 month after starting administration (data not shown). Moreover, follow-up for 1 month after discontinuing L-serine showed no worsening of sleep quality compared to before administration. Instead, although the effects were diminished compared to during L-serine intake, improved sleep status tended to be maintained. These results indicate no resistance to the effects of L-serine and no problems with rebound insomnia.
In a study of neonatal chicks, L-serine prolonged the time of sleep-like behavior that had been shortened by social isolation stress (Koutoku et al. 2005; Asechi et al. 2006; Asechi et al. 2008; Shigemi et al. 2010). In our Study 1, stratified analysis of 27 subjects who experienced stress in their daily lives also showed a significant improvement in “sleep initiation” (p = 0.017). These results demonstrate that L-serine can also improve sleep among individuals suffering from stress.
Our findings suggest that L-serine improves sleep initiation and nighttime awakenings, resulting in improved feelings of having slept well when waking in the morning. L-serine may represent a good option for individuals who suffer from difficulty sleeping.