Ohashi et al.
Journal of Physiological Anthropology(2022) 41:31
https://doi.org/10.1186/s40101-022-00306-z

ORIGINAL ARTICLE

Open Access

Intake of l‑serine before bedtime prevents
the delay of the circadian phase in real life
Michihiro Ohashi1,2 , Sang‑il Lee3 , Taisuke Eto2,4 , Nobuo Uotsu5, Chie Tarumizu5, Sayuri Matsuoka5,
Shinobu Yasuo6 and Shigekazu Higuchi4*   

Abstract
Background: It has been shown in laboratory experiments using human subjects that ingestion of the non-essential
amino acid l-serine before bedtime enhances the advance of circadian phase induced by light exposure the nextmorning. In the present study, we tested the effect of ingestion of l-serine before bedtime on circadian phase in reallife and whether its effect depends on the initial circadian phase.
Methods: The subjects were 33 healthy male and female university students and they were divided into an l-serinegroup (n = 16) and a placebo group (n = 17). This study was conducted in a double-blind manner in autumn andwinter. After a baseline period for 1 week, the subjects took 3.0 g of l-serine or a placebo 30 min before bedtime for
2 weeks. Saliva was collected twice a week at home every hour under a dim light condition from 20:00 to 1 h after
habitual bedtime. Dim light melatonin onset (DLMO) was used as an index of phase of the circadian rhythm.
Results: DLMO after intervention was significantly delayed compared to the baseline DLMO in the placebo group (p= 0.02) but not in the l-serine group. There was a significant difference in the amount of changes in DLMO between
the two groups (p = 0.04). There were no significant changes in sleeping habits after intervention in the two groups.
There were significant positive correlations between advance of DLMO and DLMO before intervention in the l-serinegroup (r = 0.53, p < 0.05) and the placebo group (r = 0.69, p < 0.01). There was no significant difference in the slopesof regression lines between the two groups (p = 0.71), but the intercept in the l-serine group was significantly higher
than that in the placebo group (p < 0.01). The levels of light exposure were not significantly different between the twogroups.
Conclusions: Our findings suggest that intake of l-serine before bedtime for multiple days might attenuate the circa‑
dian phase delay in the real world and that this effect does not depend on the initial circadian phase.
Trial registration: This study is registered with University Hospital Medical Information Network in Japan(UMIN000024435. Registered on October 17, 2016).
Keywords: Circadian rhythm, Sleep, l-Serine, Amino acids, University students, Field study*Correspondence: higu-s@design.kyushu-u.ac.jp
4
Department of Human Science, Faculty of Design, Kyushu University, 4‑9‑1
Shiobaru, Minami‑ku, Fukuoka 815‑8540, Japan
Full list of author information is available at the end of the article

Background
The intrinsic period of the human circadian rhythm islonger than 24 h, and morning light plays an important role in resetting the circadian rhythm to 24 h [1, 2].
On the other hand, light at night from artificial lighting causes delays in sleep timing and circadian rhythm
phases through non-visual effects of light [3–5]. In modern society, circadian phase delays can also be caused© The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which
permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to theoriginal author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images orother third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line
to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory
regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of thislicence, visit http://​creat​iveco​mmons.​org/​licen​ses/​by/4.​0/. The Creative Commons Public Domain Dedication waiver (http://​creat​iveco​
mmons.​org/​publi​cdoma​in/​zero/1.​0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Ohashi et al. Journal of Physiological Anthropology(2022) 41:31

by nighttime digital media use [6, 7] and night work [8].
Since disruption of circadian rhythms due to these factors results in various negative health outcomes including
insomnia, mood disorders, obesity, and type 2 diabetes,
some countermeasures are needed [8, 9].
l-Serine is a non-essential amino acid synthesized in
the body. It is also a precursor for the synthesis of otheramino acids including the optical isomers D-serine andglycine as well as lipids and nucleotides [10] and it plays
a role in mediating the nutritional supply for neuroglial
cells [11, 12]. Furthermore, recent studies have shownthat l-serine is involved in improvement of depression[13], Alzheimer’s disease [14], and amyotrophic lateralsclerosis (ALS) [15]. Those studies indicate that bothl-serine biosynthesis and external ingestion are important for biological functions. Moreover, a previous study
in which sleep quality was evaluated by using wrist actigraphy and self-reporting questionnaires showed thatl-serine administration improved the subjective feelingof sleep and tended to decrease the number of nighttime
awakenings in humans [16].
The results showing improved sleep quality in that previous study might be due to a contribution of l-serine
to circadian entrainment. Our previous study [17] using
mice and healthy human subjects showed that light exposure after administration of l-serine affected the phaseshift of circadian rhythms. In the experiments using
mice, we found that light-induced wheel-running phaseshifts in mice that were administrated l-serine weregreater than those in mice administrated water.
In a double-blind crossover test using twenty-one
human subjects, subjects with a single intake of l-serine(3.0 g) before bedtime showed a significant circadianphase advance by bright light exposure in the morning(2000 lx, 90 min) compared with that in subjects in theplacebo condition. The findings in our laboratory study
indicate that l-serine may have the potential to promote
light-induced circadian phase advance in humans. However, it was not clear whether the same results could beobtained in real life.
Therefore, in this study, we investigated whether l-serine intake before bedtime promotes circadian phaseadvance in real life. Since there are large individual differences in the circadian phase in humans in real life
[18, 19], we also examined whether the effect of l-serine
depends on the individual initial phase of the subject.

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the experimental period. We confirmed that melatoninsecretion in all subjects started before the usual bedtime.
The subjects were divided into two groups: a placebogroup (13 men and 4 women, 22.1 ± 2.5 years old) andan l-serine group (10 men and 6 women, 21.3 ± 1.9 yearsold). Table 1 shows the characteristics of subjects in eachgroup. All of subjects were Asian living in Fukuoka City,
Japan. Chronotype was determined by the Japanese version of Morningness-Eveningness Questionnaire (MEQ)[20, 21]. There was no significant difference in sex ratio,age, or chronotype between the two groups. In addition,subjects answered their sleep habits on the Japanese version of the Munich ChronoType Questionnaire (MCTQ)[22] on their school days and free days. No significant
differences were found between the two groups about
all parameters of sleep habits. This study was carried out
with the approval of the Ethics Committee of Kyushu
University. The subjects were given oral and written
explanations, and written consent for participation in the
study was obtained.
The experiment was conducted in a double-blind
manner. The experiment consisted of a 1-week baseline
period and a 2-week intervention period. After the startof the intervention, the subjects in each group ingested
l-serine (3.0 g) or a placebo (Trehalose, 3.0 g) dissolvedin 100 ml of water 30 min before bedtime every day. The
intake dose was the same as that used in a previous study[16, 17]. The subjects were asked to keep their habitual
Table 1 Characteristics of subjects in each group

Mean age [years]

Participants and protocol

This study was conducted in Japan (Fukuoka City) in
October and December. Thirty-three healthy university students participated in this study. None of the subjects were engaged in shift work or night shifts duringl-serine(n = 16)22.1 ± 2.5

21.3 ± 1.9

Sex

13M 4F

10M 6F

MEQ score

48.1 ± 7.3

47.4 ± 8.5

Sleep habits (school days)
BedtimeSleep latency [min]Sleep onset time
Wake time
Midpoint of sleep
Sleep period time [h]Sleep habits (free days)
BedtimeSleep latency [min]Methods

Placebo(n = 17)

Sleep onset time
Wake time
Midpoint of sleep
Sleep period time [h]Social jetlag [h]Values are means and S.D

0:56 ± 0:53

16.9 ± 11.6

1:13 ± 0:58

8:12 ± 0:54

4:42 ± 0:51

7.00 ± 0.77
1:18 ± 1:12

17.2 ± 12.2

1:35 ± 1:18

9:11 ± 1:24

5:23 ± 1:17

7.59 ± 0.83

0.68 ± 0.68

0:36 ± 0:51

15.3 ± 8.5

0:51 ± 0:51

8:01 ± 1:04

4:26 ± 0:50

7.16 ± 0.98
1:23 ± 0:47

15.3 ± 8.5

1:38 ± 0:50

9:03 ± 0:55

5:20 ± 0:47

7.41 ± 0.82

0.90 ± 0.75

p valuep = 0.30

p = 0.42

p = 0.82
p = 0.29

p = 0.65

p = 0.27

p = 0.59

p = 0.36

p = 0.60
p = 0.83

p = 0.60

p = 0.91

p = 0.74

p = 0.90

p = 0.54

p = 0.37

Ohashi et al. Journal of Physiological Anthropology(2022) 41:31

sleep-wake schedule during the experiment. Excessive
alcohol drinking and ingestion of sleeping pills were prohibited. The subjects were asked to record their sleep
diary and wear a wrist actigraph device (MotionWatch
8, CamNtech, Cambridge, UK) for 24 h to determine
their daily sleep-wake schedule and daily light exposure.
The average illuminance of light exposure was log-transformed and calculated 5 h after the average wake timeand 5 h before the average bedtime before and during theintervention period.
Saliva samples for melatonin assays were collected byeach subject at home twice a week (on Thursday and Sunday). The subjects were forbidden from ingesting caffeine
and performing strenuous exercise on the day of saliva
collection. Saliva samples were collected every hour from
20:00 to each subject’s bedtime using a cotton swab (Salivatte® Sarstedt, Germany) under dim light in their home.
The subjects were instructed to use an incandescent lightbulb as indirect lighting from 19:30 in the room to makedim light (< 15 lx as measured by MotionWatch8). The
subjects were also instructed to send a text message tothe experimenter immediately after saliva collection.
Melatonin concentration in saliva was quantified by aradioimmunoassay (Buhlmann, RK-DSM2, Switzerland).
Dim light melatonin onset (DLMO), a reliable marker ofcircadian phase [23, 24], was determined by linear interpolation between the time points before and after themelatonin concentration increased and stayed above the3.0 pg/mL threshold [25].
Statistical analysis

One subject who showed an irregular sleep/wake schedule was excluded from the analysis. Even after exclusion,
there was still no significant difference in sex ratio, age,chronotype or sleep habits between the two groups.
Another subject whose wearing time of the actigraphdevice during the day was too short for accurate determination of light exposure was also excluded from theanalysis.

Page 3 of 8

In the statistical analysis, a two-sided, Welch’s t test
was used for comparison of sleep habits, DLMO, amountof DLMO advance, and light exposure between the twogroups. A two-sided paired t test was used for investigating changes in sleep habits and DLMO within thegroups. Greenhouse–Geisser correction was performed
whenever Mauchly’s test of sphericity was significant.
Pearson’s correlation test was used to assess the relation between DLMO before intervention and DLMO
advance in each group. Afterwards, the general linear
model (GLM) was used for comparison of the slopes andintercepts of regression lines between the two groups. A
p value less than 0.05 was considered statistically significant. Statistical analyses were performed using SPSS software ver. 25 (IBM, NY, USA).

Results
There were no significant differences in bedtime (p = 0.47),
wake time (p = 0.55), time in bed (p = 0.98), and DLMO(p = 0.26) between the two groups before intervention(Table 2 and Fig. 1). A significant difference before and after
intervention was found for DLMO in the placebo groupbut not in the l-serine group (Table 2). DLMO in the placebo group was significantly delayed after intervention (t =− 2.59, p < 0.05). No significant changes in sleep measurements after intervention were found in the two groups.
The magnitudes of changes after intervention werecompared in the placebo group and l-serine group(Table 3). A significant difference in changes in DLMO
was found between the two groups (placebo < l-serine,t = − 2.14, p = 0.04) (Table 3 and Fig. 2).
Figure 3 shows the results for mean light exposure.
No significant differences were found after wake time
before intervention (p = 0.89), after wake time during
intervention (p = 0.84), before bedtime before intervention (p = 0.90), and before bedtime during intervention(p = 0.58).
Figure 4 shows the relationship between DLMO before
intervention and DLMO advance. There were significant

Table 2 DLMO and sleep/wake time before and after intervention in each group
Placebo(n = 17)
Beforeintervention
DLMO
Bedtime
Wake time

22:56 ± 1:11

1:29 ± 0:50

8:45 ± 1:06

Time in bed [h] 7.27 ± 0.86
Values are means and S.D*p < 0.05

l-serine(n = 15)

Afterintervention
23:22 ± 0:52

1:37 ± 0:39

8:59 ± 0:55

7.36 ± 0.71

p value(before vs.
after)
p = 0.02*

p = 0.21

p = 0.16

p = 0.53

BeforeAfterp valueintervention intervention (before vs. after)
22:29 ± 1:06

1:16 ± 0:54

8:32 ± 0:54

7.28 ± 0.61

22:23 ± 0:56

1:43 ± 0:39

8:48 ± 0:32

7.09 ± 0.73

p = 0.62

p = 0.13

p = 0.30

p = 0.24

p value(Beforeintervention,
betweengroups)p = 0.26

p = 0.47

p = 0.55

p = 0.98

Ohashi et al. Journal of Physiological Anthropology(2022) 41:31

Page 4 of 8

Fig. 1 DLMO and sleep/wake time before and after intervention in each group (mean ± S.D., *: p < 0.05) (The triangles represent DLMO and thethick horizontal bars represent bedtime to wake time)

Table 3 Amount of advance in DLMO and sleep/wake time ineach group
Placebo(n = 17)
DLMO
Bedtime
Wake time
Time in bed [h]− 0:25 ± 0:41

− 0:08 ± 0:26

− 0:13 ± 0:37

0.09 ± 0.54

l-serine(n = 15)

0:05 ± 0:41

− 0:28 ± 1:06

− 0:16 ± 0:57

− 0.19 ± 0.61

p valuep = 0.04*

p = 0.30

p = 0.88

p = 0.18

Values are means and S.D. *p < 0.05
Amount of increase only in time in bed

Fig. 2 Individual data for amount of DLMO advance (mean ± S.D., *:p < 0.05)

positive correlations between the advance of DLMO andDLMO before intervention in the l-serine group (r = 0.53,
p < 0.05) and the placebo group (r = 0.69, p < 0.01).
The GLM with groups as a dependent variable and
DLMO before intervention as a between-subject factor
was used to test independence of DLMO before intervention. The main effect of groups was not statistically significant (p = 0.26), and independence of DLMO before
intervention was thus confirmed. The GLM with DLMO
advance as a dependent variable, groups as a betweensubject factor and DLMO before intervention as a covariate was used to compare the slopes of regression lines. Theinteraction between groups and DLMO before intervention was not statistically significant (p = 0.71). Therefore,
it was confirmed that there was no significant differencein slopes of regression lines. The GLM without interaction
between groups and DLMO before intervention was used
to test the significance of regression and to compare theintercepts of regression lines. The effect of DLMO before
intervention was statistically significant (p < 0.001), andthe significance of regression was therefore confirmed.
Moreover, the main effect of groups was statistically significant (ηp2 = 0.30, p < 0.01). This means that the interceptof the regression line in the l-serine group was significantly greater than that in the placebo group.

Discussion
In this study, a significant delay in DLMO was confirmedin the placebo group but not in the l-serine group. Moreover, the amount of DLMO changes was significantly different between the two groups. However, given that there
were no significant differences between the groups in sex,age, MEQ score, and results for DLMO and sleep habits
before the intervention, it is difficult to interpret that thecharacteristics of the group caused the result of phaseOhashi et al. Journal of Physiological Anthropology(2022) 41:31

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Fig. 3 Five-hour mean light exposure after wake time and before bedtime (mean ± S.D.)

Fig. 4 Relationship between DLMO before intervention and DLMO
advance (*: p < 0.05)

delay in the placebo group. Furthermore, the amounts of
exposure to daily light just before bedtime and after waketime, which are thought to affect the results of DLMO
shift, were not significantly different between the twogroups.
In the present study, we showed that l-serine has a preventative effect on the delay of circadian rhythms. However, unlike in the laboratory experiments conducted in
our previous study [17], no significant phase advance ofthe circadian rhythm was observed by l-serine intake
before bedtime. One possible reason for this may be thedifference in the light environment between the laboratory and field experiments. In the laboratory experiment,
evening light (from 6 pm to bedtime) was dim light (< 15lx), whereas in the field experiment, the subjects were
exposed to night light by artificial lighting except on days
when saliva samples for melatonin measurement weretaken. It is known that artificial lighting at night in reallife delays the phase of circadian rhythms [26, 27]. In
other words, the lack of phase advance in this study may
have been canceled out by phase delay due to exposure tolight at night.
Thus, if the effects of night light cannot be avoided indaily life, increasing l-serine intake might be a possible way to induce the phase advance that was observedin the laboratory experiments [17]. However, while adose-response relationship was observed for the effects
of l-serine in a previous animal study [17], no comparison of the effects of increased intake in humans has been
conducted. For example, patients with ALS were tested
with l-serine at doses of up to 15 g twice daily for 6
months and no serious adverse effects were observed andthe drug is generally considered safe [15]. Since l-serine
is “generally recognized as safe” by the Food and Drug
Administration (FDA), field studies should be conductedin the future to examine the effects of increased doses ofl-serine on circadian rhythm phase advance.
In addition to eating behavior, exercise habits have apotential to impact on light-induced circadian phase shift[28]. In many studies, physical activity level was measured by using a wrist accelerometer [29, 30]. However, inthe present study, wrist accelerometer data were measured to mainly determine the daily sleep-wake timing
and daily light exposure of the subjects and we instructed
the subjects to remove the wrist accelerometer during
intense exercise to avoid damage to the device. Determination of the interactions between light exposure andphysical activity including their timing and intensity interms of circadian phase shift in daily life would be challenging but is expected to be done in a future study.
We did not expect the delay in DLMO observed in
the placebo group. This result means that the phase of
the circadian rhythm was delayed in the placebo group,and there could be several reasons for this. First, in theOhashi et al. Journal of Physiological Anthropology(2022) 41:31

period of October to December, when this experiment
was conducted, the time of sunrise is becoming later andthe amount of sunshine is less than that in summer in the
Northern Hemisphere. It is well known that the light anddark cycle of sunlight is the strongest zeitgeber for circadian rhythm and that morning light is important to reset
the human circadian period, which is intrinsically longer
than 24 h [1]. Some studies showed that circadian phasein winter was later than that in summer in countries in
the Northern Hemisphere [31–33]. Next, the subjects inthis study were healthy university students. University
students generally tend to be night owls biologically andsocially [34, 35] and experience relatively little light exposure in the morning and more light exposure later in the
day in terms of both intensity and duration [36, 37]. It is
possible that these factors affected the easiness for delayof circadian phase in daily life.
In this study, trehalose was used as a placebo. Although
animal studies suggested that trehalose has effects inneurodegenerative diseases such as Huntington’s disease[38], Alzheimer’s disease [39], and ALS [40], there has
been no study in which the relationship between trehalose ingestion and circadian rhythms was investigatedin animals and humans. On the other hand, it has beenreported that carbohydrate intake is related to sleep andcircadian rhythms in humans through blood glucose levels [41, 42]. In addition, animal studies have shown that
insulin directly affects the peripheral circadian clock[43, 44]. Although trehalose is converted to glucose andincreases insulin concentrations [45], the dose of trehalose used as a placebo in this study (3.0 g) was very small,and its effect on glucose and insulin concentrations islikely to be limited. Therefore, the possibility that theplacebo condition directly affected the delay in circadianrhythm is considered negligible. However, since we did
not examine or control for the subjects’ daily diet in thisexperiment, we cannot exclude the possibility that differences in eating behavior between the two groups may
have affected the results.
In this study, the regression coefficient by DLMO before
intervention was significant for the amount of DLMO
advance. A significant positive correlation between
advance of DLMO and DLMO before intervention was
found in both groups. This indicates that the later DLMO
was, the greater was the subsequent DLMO advance. One
probable cause of this is that the phase angle between thecircadian phase and sleep timing affected the amount ofcircadian phase shift. When sleep timing is primarily tied
to social factors, late circadian timing results in a shortphase angle. If the phase angle is short, the phase delayzone around DLMO of the phase response curve (PRC)
to light [46, 47] is masked by sleep. It is thought that thecircadian phase tends to advance thereafter.

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On the other hand, the effect of the group on DLMO
before intervention was not significant, and there was nodifference in DLMO before intervention between the twogroups and DLMO before intervention did not dependon the group. Uniformity of the slopes of regression lines
in the two groups was also shown. In addition, a significant difference in the intercepts of regression lines wasfound between the two groups. These results suggest thatthe DLMO advance in the l-serine group was greaterthan that in the placebo group in all ranges of confirmed
DLMO in this study. The fact that the effect of l-serine
was confirmed regardless of the subject’s circadian phasemeans that l-serine may be useful for various chronotypes of people.
In recent years, much attention has been focused on
research on the relationship between social jetlag andhealth [48]. In the present study, the effects of social
jetlag did not be assessed because the average social jetlag of the subjects was less than 1 h (Table 1). This smallsocial jetlag may be related to the less social constraints
of weekday life for university students. However, it is
known that social jet lag is greater in nocturnal chronotypes [49] and that loss of morning light exposure due
to weekend recovery sleep leads to a delay of the circadian phase [50]. The effects of l-serine in populations
with greater social jetlag should be examined in futurestudies.
The effect of l-serine was confirmed in an autumn/
winter experiment, but it is necessary to consider seasonal differences in the effect of l-serine in considerationof the day length and amount of daytime sunshine in various seasons. However, considering that seasonal affective disorder [51], which is presumed to be associatedwith circadian rhythm disorder, is likely to develop in the
period in which this study was conducted and considering the results of a study showing that l-serine enhanced
the antidepressant effect of light in a mouse model ofseasonal affective disorder [52], the effect of l-serine on
light-induced circadian phase advance in humans thatwas confirmed in this study is a notable finding. This
study was conducted in healthy subjects, and the effectiveness of l-serine in patients with circadian rhythm disorders as well as patients with seasonal affective disordershould also be examined.
Finally, although the mechanism by which l-serine
affects the light-induced phase shift of circadian rhythms
is not yet well understood, our previous study in mice
(CBA/N) showed that light exposure after l-serine
ingestion altered the long-term expression pattern ofclock genes in the suprachiasmatic nucleus (SCN) [17].
As a possible mechanism for this, we focused on the
MNDA receptor, which is believed to have a major rolein light signaling in the SCN [53]. However, since theOhashi et al. Journal of Physiological Anthropology(2022) 41:31

effectiveness of l-serine was not blocked by MK801, anantagonist of the NMDA receptor, we considered that
this receptor was not involved [17]. On the other hand,
we found that antagonists of the ­GABAA receptor completely blocked the effectiveness of l-serine. In otherwords, l-serine was thought to affect circadian rhythm
phases via activation of G
­ ABAA receptors. This is consistent with the results of a previous study showing thatthe sedative and hypnotic effects of l-serine are mediated by ­GABAA receptors [54]. ­GABAA is also known toplay an important role in circadian clock function in the
SCN [55]. Therefore, the light-induced phase advance ofl-serine in mice may be involved in the phase shift of circadian rhythms via the GABAergic system. Furthermore,
l-serine did not affect the light-induced expression ofc-fos, Per1, and Per2 in the SCN, but it altered the longterm expression of Per2 and Bmal1 [17]. These results
suggest that the action of l-serine occurs in extra-SCN
regions that convey information to the SCN via a posttranscriptional process. However, given that the mechanism of effects of light may differ among species [17], it
is unclear whether the same mechanism of action is also
true in humans. In addition, there are limitations in referring to the mechanism based on the results obtained in
the present field study.

Conclusions
The results of this study showed that external intake ofl-serine before bedtime for multiple days might enhance
circadian phase advance by light in the morning andsuppress the circadian phase delay. The results also suggested that the effect of l-serine does not depend on theinitial circadian phase. l-serine intake before bedtime isexpected to help prevent the delay of circadian rhythm inreal word conditions in various chronotypes of people.
Acknowledgements
We would like to thank Mr. Kota Takeoka for supporting our experiment.
Authors’ contributions
SL, NU, CT, SM, and SH contributed to the design of the experiment. MO andSL performed the experiment. MO and SL analyzed the data. MO wrote themanuscript with advice from SL, TE, NU, CT, SM, SY, and SH. All authors partici‑
pated in the discussion and preparation of the manuscript and approved thefinal manuscript.
Funding
This work was supported by JSPS KAKENHI Grant Number 16K21225.
Availability of data and materials
The datasets analyzed in this study are not publicly available due to a privacy
policy but are available from the corresponding author on reasonable request.

Declarations
Ethics approval and consent to participate
The study was approved by the Ethics Committee of Kyushu University(Approval No. 228). Written informed consent was obtained from allparticipants.

Page 7 of 8Consent for publication
Not applicableCompeting interests
The authors declare that they have no competing interests.
Author details
Department of Kansei Science, Graduate School of Integrated Frontier
Sciences, Kyushu University, 4‑9‑1 Shiobaru, Minami‑ku, Fukuoka 815‑8540,
Japan. 2 Research Fellow of the Japan Society for the Promotion of Science,
4‑9‑1 Shiobaru, Minami‑ku, Fukuoka 815‑8540, Japan. 3 Laboratory of Envi‑ronmental Ergonomics, Faculty of Engineering, Hokkaido University, Kita 13,
Nishi 8, Kita‑ku, Sapporo, Hokkaido 060‑8628, Japan. 4 Department of Human
Science, Faculty of Design, Kyushu University, 4‑9‑1 Shiobaru, Minami‑ku,
Fukuoka 815‑8540, Japan. 5 Research Institute, FANCL Co., 12‑13, Kamishinano,Totsuka‑ku, Yokohama, Kanagawa 244‑0806, Japan. 6 Laboratory of Regulationin Metabolism and Behavior, Faculty of Agriculture, Kyushu University, 744
Motooka, Nishi‑ku, Fukuoka 819‑0395, Japan.

1

Received: 14 March 2022 Accepted: 16 August 2022

References
1. Czeisler CA, Duffy JF, Shanahan TL, Brown EN, Mitchell JF, Rimmer DW,
et al. Stability, precision, and near-24-hour period of the human circadianpacemaker. Science. 1999;284:2177–81.
2. Minors DS, Waterhouse JM, Wirz-Justice A. A human phase-response
curve to light. Neurosci Lett. 1991;133:36–40.
3. Lockley SW, Gooley JJ. Circadian photoreception: spotlight on the brain.
Curr Biol. 2006;16(18):R795-7.
4. Lucas RJ, Peirson SN, Berson DM, Brown TM, Cooper HM, Czeisler CA,
et al. Measuring and using light in the melanopsin age. Trends Neurosci.
2014;37:1.
5. Katsuura T, Lee S. A review of the studies on nonvisual lighting effects inthe field of physiological anthropology. J Physiol Anthropol. 2019;38:1–18.
6. Higuchi S, Motohashi Y, Liu Y, Maeda A. Effects of playing a computer
game using a bright display on presleep physiological variables, sleep
latency, slow wave sleep and REM sleep. J Sleep Res. 2005;14:267–73.
7. LeBourgeois MK, Hale L, Chang AM, Akacem LD, Montgomery-Downs
HE, Buxton OM. Digital media and sleep in childhood and adolescence.
Pediatrics. 2017;140(Supplement_2):S92–6.
8. Lunn RM, Blask DE, Coogan AN, Figueiro MG, Gorman MR, Hall JE, et al.
Health consequences of electric lighting practices in the modern world:a report on the National Toxicology Program’s workshop on shift work atnight, artificial light at night, and circadian disruption. Sci Total Environ.
2017;607–608:1073–84.
9. Potter GDM, Skene DJ, Arendt J, Cade JE, Grant PJ, Hardie LJ. Circadianrhythm and sleep disruption: causes, metabolic consequences, andcountermeasures. Endocr Rev. 2016;37:584–608.
10. De Koning TJ, Snell K, Duran M, Berger R, Poll-The BT, Surtees R. L-serine indisease and development. Biochem J. 2003;371(Pt 3):653.
11. Mitoma J, Furuya S, Hirabayashi Y. A novel metabolic communication
between neurons and astrocytes: non-essential amino acid L-serine
released from astrocytes is essential for developing hippocampal neu‑rons. Neurosci Res. 1998;30:195–9.
12. Furuya S, Tabata T, Mitoma J, Yamada K, Yamasaki M, Makino A, et al.
l-Serine and glycine serve as major astroglia-derived trophic factors for
cerebellar Purkinje neurons. Proc Natl Acad Sci U S A. 2000;97:11528.
13. Nagasawa M, Otsuka T, Togo Y, Yamanaga M, Yoshida J, Uotsu N, et al.
Single and chronic l-serine treatments exert antidepressant-like effects inrats possibly by different means. Amino Acids. 2017;49:1561–70.
14. Cox PA, Davis DA, Mash DC, Metcalf JS, Banack SA. Dietary exposure to an
environmental toxin triggers neurofibrillary tangles and amyloid deposits
in the brain. Proc Biol Sci.. 2016;283(1823):20152397.
15. Levine TD, Miller RG, Bradley WG, Moore DH, Saperstein DS, Flynn LE,
et al. Phase I clinical trial of safety of L-serine for ALS patients. Amyotroph
Lateral Scler Front Degener. 2017;18:107–11.
16. Ito Y, Takahashi S, Shen M, Yamaguchi K, Satoh M. Effects of L-serine inges‑
tion on human sleep. Springerplus. 2014;3:456.

Ohashi et al. Journal of Physiological Anthropology(2022) 41:31

17. Yasuo S, Iwamoto A, Il LS, Ochiai S, Hitachi R, Shibata S, et al. L-serine
enhances light-induced circadian phase resetting in mice and humans. J
Nutr. 2017;147:2347–55.
18. Burgess HJ, Fogg LF. Individual Differences in the Amount and Timing of
Salivary Melatonin Secretion. PLoS One. 2008;3:e3055.
19. Kantermann T, Sung H, Burgess HJ. Comparing the MorningnessEveningness Questionnaire and Munich ChronoType Questionnaire to
the Dim Light Melatonin Onset. J Biol Rhythms. 2015;30:449–53.
20. Horne JA, Ostberg O. A self-assessment questionnaire to determine
morningness-eveningness in human circadian rhythms. Int J Chronobiol.
1976;4:97–110.
21. Ishihara K, Miyashita A, Inugami M, Fukuda K, Yamazaki K, Miyata Y. The
results of investigation by the Japanese version of Morningess-Evening‑
ness questionnaire. Japanese J Psychol. 1986;57:87–91.
22. Kitamura S, Hida A, Aritake S, Higuchi S, Enomoto M, Kato M, et al. Valid‑
ity of the Japanese version of the Munich ChronoType Questionnaire.
Chronobiol Int. 2014;31:845–50.
23. Lewy AJ, Sack RL. The dim light melatonin onset as a marker for orcadianphase position. Chronobiol Int. 1989;6:93–102.
24. Pullman RE, Roepke SE, Duffy JF. Laboratory validation of an in-homemethod for assessing circadian phase using dim light melatonin onset(DLMO). Sleep Med. 2012;13:703–6.
25. Benloucif S, Burgess HJ, Klerman EB, Lewy AJ, Middleton B, Murphy PJ,
et al. Measuring melatonin in humans. J Clin Sleep Med. 2008;4:66.
26. Burgess HJ, Molina TA. Home Lighting Before Usual Bedtime Impacts
Circadian Timing: A Field Study. Photochem Photobiol. 2014;90:723.
27. Higuchi S, Il LS, Kozaki T, Harada T, Tanaka I. Late circadian phase in adults
and children is correlated with use of high color temperature light at
home at night. Chronobiol Int. 2016;33:448–52.
28. Miyazaki T, Hashimoto S, Masubuchi S, Honma S, Honma KI. Phaseadvance shifts of human circadian pacemaker are accelerated bydaytime physical exercise. Am J Physiol Regul Integr Comp Physiol.
2001;281(1):50–1.
29. Crouter SE, Flynn JI, Bassett DR. Estimating physical activity in youth usinga wrist accelerometer. Med Sci Sports Exerc. 2015;47:944–51.
30. Lin HP, Lynk N, Moore LL, Cabral HJ, Heffernan KS, Dumas AK, et al. A prag‑
matic approach to the comparison of wrist-based cutpoints of physicalactivity intensity for the MotionWatch8 accelerometer in children. PLoS
One. 2020;15(6):e0234725.
31. Skeldon AC, Dijk DJ. Weekly and seasonal variation in the circadian mela‑
tonin rhythm in humans: Entrained to local clock time, social time, light
exposure or sun time? J Pineal Res. 2021;71:e12746.
32. Zerbini G, Winnebeck EC, Merrow M. Weekly, seasonal, and chrono‑
type-dependent variation of dim-light melatonin onset. J Pineal
Res. 2021;70(3):e12723.
33. Honma KI, Honma S, Kohsaka M, Fukuda N. Seasonal variation in thehuman circadian rhythm: dissociation between sleep and temperaturerhythm. Am J Physiol. 1992;262(5 Pt):2.
34. Roenneberg T, Kuehnle T, Pramstaller PP, Ricken J, Havel M, Guth A, et al. A
marker for the end of adolescence. Curr Biol. 2004;14:R1038–9.
35. Fukuda K, Ishihara K. Age-related changes of sleeping pattern duringadolescence. Psychiatry Clin Neurosci. 2001;55:231–2.
36. Porcheret K, Wald L, Fritschi L, Gerkema M, Gordijn M, Merrrow M, et al.
Chronotype and environmental light exposure in a student population.
Chronobiol Int. 2018;35:1365–74.
37. Higuchi S, Lin Y, Qiu J, Zhang Y, Ohashi M, Lee SI, et al. Is the use of highcorrelated color temperature light at night related to delay of sleep tim‑
ing in university students? A cross-country study in Japan and China. J
Physiol Anthropol. 2021;40:1–8.
38. Tanaka M, Machida Y, Niu S, Ikeda T, Jana NR, Doi H, et al. Trehalose allevi‑
ates polyglutamine-mediated pathology in a mouse model of Hunting‑ton disease. Nat Med. 2004;10:148–54.
39. Tien NT, Karaca I, Tamboli IY, Walter J. Trehalose Alters Subcellular Traffick‑ing and the Metabolism of the Alzheimer-associated Amyloid Precursor
Protein. J Biol Chem. 2016;291:10528–40.
40. Castillo K, Nassif M, Valenzuela V, Rojas F, Matus S, Mercado G, et al. Treha‑lose delays the progression of amyotrophic lateral sclerosis by enhancing
autophagy in motoneurons. Autophagy. 2013;9:1308–20.
41. Vlahoyiannis A, Giannaki CD, Sakkas GK, Aphamis G, Andreou E. A
systematic review, meta-analysis and meta-regression on the effects ofcarbohydrates on sleep. Nutrients. 2021;13(4):1283.

Page 8 of 8

42. Pinkhasov BB, Selyatinskaya VG, Astrakhantseva EL, Anufrienko EV. Circa‑
dian rhythms of carbohydrate metabolism in women with different typesof obesity. Bull Exp Biol Med. 2016;161:323–6.
43. Sato M, Murakami M, Node K, Matsumura R, Akashi M. The role of theendocrine system in feeding-induced tissue-specific circadian entrain‑
ment. Cell Rep. 2014;8:393–401.
44. Crosby P, Hamnett R, Putker M, Hoyle NP, Reed M, Karam CJ, et al. Insulin/
IGF-1 Drives PERIOD Synthesis to Entrain Circadian Rhythms with Feeding
Time. Cell. 2019;177:896–909.e20.
45. Yoshizane C, Mizote A, Yamada M, Arai N, Arai S, Maruta K, et al. Glycemic,
insulinemic and incretin responses after oral trehalose ingestion in
healthy subjects. Nutr J. 2017;16:1–6.
46. St Hilaire MA, Gooley JJ, Khalsa SBS, Kronauer RE, Czeisler CA, Lockley
SW. Human phase response curve to a 1 h pulse of bright white light. J
Physiol. 2012;590:3035–45.
47. Khalsa SBS, Jewett ME, Cajochen C, Czeisler CA. A phase response curveto single bright light pulses in human subjects. J Physiol. 2003;549(Pt3):945–52.
48. Roenneberg T, Allebrandt KV, Merrow M, Vetter C. Social jetlag and obe‑
sity. Curr Biol. 2012;22:939–43.
49. Wittmann M, Dinich J, Merrow M, Roenneberg T. Social jetlag: misalign‑
ment of biological and social time. Chronobiol Int. 2006;23:497–509.
50. Crowley SJ, Carskadon MA. Modifications to weekend recovery
sleep delay circadian phase in older adolescents. Chronobiol Int.
2010;27:1469–92.
51. Johansson C, Willeit M, Smedh C, Ekholm J, Paunio T, Kieseppä T, et al.
Circadian clock-related polymorphisms in seasonal affective disorderand their relevance to diurnal preference. Neuropsychopharmacology.
2003;28:734–9.
52. Kawai M, Goda R, Otsuka T, Iwamoto A, Uotsu N, Furuse M, et al.
Antidepressant-like effect of bright light is potentiated by l-serine admin‑
istration in a mouse model of seasonal affective disorder. Brain Res Bull.
2015;118:25–33.
53. Golombek DA, Rosenstein RE. Physiology of circadian entrainment.
Physiol Rev. 2010;90:1063–102.
54. Shigemi K, Tsuneyoshi Y, Hamasu K, Han L, Hayamizu K, Denbow DM,
et al. l-Serine induces sedative and hypnotic effects acting at GABAA
receptors in neonatal chicks. Eur J Pharmacol. 2008;599:86–90.
55. Ono D, Honma K i, Yanagawa Y, Yamanaka A, Honma S. Role of GABA
in the regulation of the central circadian clock of the suprachiasmatic
nucleus. J Physiol Sci. 2018;68:333–43.

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