J Sleep Res. 2016 Dec;25(6):746-753. doi: 10.1111/jsr.12434.

Oral administration of Japanese sake yeast (Saccharomyces cerevisiae sake) promotes non-rapid eye movement sleep in mice via adenosine A2A receptors.


Correspondence should be addressed to Yoshihiro Urade, International Institute for Integrative Sleep Medicine, Tsukuba University, Ibaraki 305-8575, Japan. E-mail. uradey@gmail.com.




Insomnia causes serious problems for our health and performance [1-4]. Benzodiazepine drugs (e.g. diazepam, triazolam) are widely used for clinical treatment of insomnia but also have many adverse effects, such as drug dependence, tolerance, rebound insomnia, amnesia, muscle relaxation and hangover feeling in the morning [5, 6].


Adenosine A2A receptors and Sleep

Recent studies revealed that adenosine is an endogenous sleep-promoting molecule and regulates sleep/wake behavior via adenosine A1 and A2A receptors (R) [7-9], which are involved in the sleep promoting effect distinctly in different brain areas [10-12]. Intracerebroventricular infusion of adenosine A2AR-selective agonist, CGS21680, promoted non-rapid eye movement (NREM) sleep, whereas A1R-selective agonist, cyclopentyladenosine, did not affect sleep/wake behavior [13]. Caffeine inhibits sleep by blocking A2AR but not A1R, functioning as an A2AR antagonist [14]. These findings suggest that A2AR is a promising target to modulate sleep/wake behavior and that A2AR agonist may act as sleep-promoting substance.


Sake yeast activates A2A receptor in vitro

We screened food-materials associated with the A2AR agonist activity, and found that the crude extracts of Japanese sake yeast (Saccharomyces cerevisiae sake) are enriched in adenosine analogues, such as S-adenosyl methionine and methyl thio-adenosine, and activate human and mouse A2AR overexpressed on HEK cells [15]. Japanese sake yeast has traditionally been used for brewing sake (Japanese rice wine) [16], the most popular alcohol beverage in Japan, and was also often used as a food additive and seasoning in the traditional Japanese cuisine Washoku, which was added to the UNESCO intangible cultural heritage list in 2013..


Sake yeast promotes physiological NREM sleep in mice via A2A receptor

In the present study, we investigated the effects of oral administration of Japanese sake yeast extracts on sleep/wake behavior by measuring electroencephalogram (EEG) and found that the oral administration of sake yeast (100 to 300 mg kg-1 ) increased NREM sleep from 25 ± 6 min in the vehicle-administered group to 37 ± 6 to 60 ± 4 min. The sake yeast-induced sleep was very similar to physiological NREM sleep, as judged by mean episode duration and EEG power density spectral analysis, and clearly different from benzodiazepine (e.g., diazepam, triazolam)-induced NREM sleep with a decreased delta activity and increased beta activity (13-28 Hz) [17, 18]. Therefore, sake yeast may be more suitable than those drugs to induce natural physiological NREM sleep for improving the quality of sleep.

We then confirmed that the NREM sleep-promoting effect of sake yeast was abolished by pretreatment with an A2AR antagonist, ZM241385 (15 mg kg-1), but not affected by an A1R antagonist, 8-cyclopentyltheophylline (10 mg kg-1), indicating that sake yeast promotes NREM sleep by activation of A2AR but not A1R.


Sake yeast improves sleep quality in human

Long traditional use of sake yeast in the food industry proves its own safety, After confirming the safety of sake yeast in healthy volunteers, we examined the effect of sake yeast on human sleep. Japanese sake yeast ingestion improved sleep quality in humans in terms of an increase in the EEG delta power during the first slow-wave cycle, reduction of morning sleepiness, and an increase of growth hormone secretion in morning urine [15].

In conclusion, Japanese sake yeast is a potential candidate for a supplement improving the quality of sleep.



Figure 1. Increase in NREM sleep in wild type mice by Japanese sake yeast in the absence or presence of antagonist for adenosine A2A R, ZM241385. means±SE, n=11, *P<0.05, Tukey-Kramer method.



Figure 2. Increases in delta power of 1st NREM episode (left) and urinary growth hormone level after administration of placebo or sake yeast in healthy human volunteers. [15]



1. Groeger, J.A., F.R. Zijlstra, and D.J. Dijk, Sleep quantity, sleep difficulties and their perceived consequences in a representative sample of some 2000 British adults. J. Sleep. Res., 2004. 13(4): p. 359-71.
2. Hossain, J.L. and C.M. Shapiro, The prevalence, cost implications, and management of sleep disorders: an overview. Sleep Breath, 2002. 6(2): p. 85-102.
3. Stranges, S., et al., Sleep problems: an emerging global epidemic? findings from the INDEPTH WHO-SAGE study among more than 40,000 older adults from 8 countries across Africa and Asia. Sleep, 2012. 35(8): p. 1173-81.
4. Sutton, D.A., H. Moldofsky, and E.M. Badley, Insomnia and health problems in Canadians. Sleep, 2001. 24(6): p. 665-70.
5. Vgontzas, A.N., A. Kales, and E.O. Bixler, Benzodiazepine side effects: role of pharmacokinetics and pharmacodynamics. Pharmacology, 1995. 51(4): p. 205-23.
6. Aragona, M., Abuse, dependence, and epileptic seizures after zolpidem withdrawal: review and case report. Clin. Neuropharmacol., 2000. 23(5): p. 281-3.
7. Satoh, S., et al., Promotion of sleep mediated by the A2a-adenosine receptor and possible involvement of this receptor in the sleep induced by prostaglandin D2 in rats. Proc. Natl. Acad. Sci. U.S.A., 1996. 93(12): p. 5980-4.
8. Porkka-Heiskanen, T., et al., Adenosine: a mediator of the sleep-inducing effects of prolonged wakefulness. Science, 1997. 276(5316): p. 1265-8.
9. Huang, Z.L., Y. Urade, and O. Hayaishi, The role of adenosine in the regulation of sleep. Curr. Top. Med. Chem., 2011. 11(8): p. 1047-57.
10. Satoh, S., et al., Region-dependent difference in the sleep-promoting potency of an adenosine A2A receptor agonist. Eur. J. Neurosci., 1999. 11(5): p. 1587-97.
11. Methippara, M.M., et al., Effects on sleep of microdialysis of adenosine A1 and A2A receptor analogs into the lateral preoptic area of rats. Am. J. Physiol. Regul. Integr. Comp. Physiol., 2005. 289(6): p. R1715-23.
12. Oishi, Y., et al., Adenosine in the tuberomammillary nucleus inhibits the histaminergic system via A1 receptors and promotes non-rapid eye movement sleep. Proc Natl Acad Sci U S A, 2008. 105(50): p. 19992-7.
13. Urade, Y., et al., Sleep regulation in adenosine A2A receptor-deficient mice. Neurology, 2003. 61(11 Suppl 6): p. S94-6.
14. Huang, Z.L., et al., Adenosine A2A, but not A1, receptors mediate the arousal effect of caffeine. Nat. Neurosci., 2005. 8(7): p. 858-9.
15. Monoi, N., et al., Japanese sake yeast supplementation improves the quality of sleep: a double-blind randomised controlled clinical trial. J. Sleep. Res., 2016. 25(1): p. 116-123.
16. Kotaka, A., et al., Efficient generation of recessive traits in diploid sake yeast by targeted gene disruption and loss of heterozygosity. Appl. Microbiol. Biotechnol., 2009. 82(2): p. 387-95.
17. Tobler, I., et al., Diazepam-induced changes in sleep: role of the alpha 1 GABAA receptor subtype. Proc. Natl. Acad. Sci. U.S.A., 2001. 98(11): p. 6464-9.
18. van Lier, H., et al., Effects of diazepam and zolpidem on EEG beta frequencies are behavior-specific in rats. Neuropharmacology, 2004. 47(2): p. 163-74.