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Effect of oral γ-aminobutyric acid (GABA) administration on sleep and its absorption in humans

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Abstract

The effects of γ-aminobutyric acid (GABA) on sleep and its levels in blood after oral administration were investigated in humans. A randomized, single-blind, placebo-controlled crossover-designed study was conducted to evaluate the effect of GABA on sleep. Sleep was evaluated by electroencephalography (EEG) after oral GABA administration. GABA significantly shortened sleep latency and increased the total non-rapid eye movement (non-REM) sleep time. Questionnaires showed that subjects receiving GABA realized its effects on sleep. In addition, the blood level of GABA after administration was investigated, and the absorption and metabolism rates of GABA were determined. GABA was quickly absorbed, and the blood level of GABA was the highest 30 min after oral administration, with a subsequent decrease in concentration. As GABA strongly affected the early stage of sleep, the effect of GABA on sleep may be connected to its levels in blood.

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... The connection between GABA and sleep has been reported by several studies [7,21,22]. A previous study showed that a mixture of GABA and theanine promotes sleep in rodent models. ...
... However, the observed actions were not GABA-dependent [21]. An inhuman study showed that GABA favorably affected sleep latency and non-rapid eye movement (NREM) sleep time, but there is no information of total sleep time with the deteriorated sleep parameters of placebo group [22]. Thus, more systematic studies are necessary to clarify and confirm the relationship between GABA and sleep behaviors as well as the underlying mechanistic actions in various experimental models. ...
... This result correlated with those of an investigation of a GABA/theanine mixture that showed an increase in NREM [21]. The effect of GABA on NREM was also partially verified in a previous human study, although the effect of GABA on total sleep time was not mentioned [22]. The effect of LB-GABA on the brain wave of NREM in the current study was different under normal and caffeine-induced conditions. ...
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The aim of this study was to investigate the effect of Lactobacillus breves-fermented γ-aminobutyric acid (LB-GABA) on sleep behaviors in invertebrate and vertebrate models. In Drosophila melanogaster, LB-GABA-treated group showed an 8–9%-longer sleep duration than normal group did. LB-GABA-treated group also showed a 46.7% lower level of nighttime activity with a longer (11%) sleep duration under caffeine-induced arousal conditions. The LB-GABA-mediated inhibition of activity was confirmed as a reduction of total movement of flies using a video tracking system. In the pentobarbital-induced sleep test in mice, LB-GABA (100 mg/kg) shortened the time of onset of sleep by 32.2% and extended sleeping time by 59%. In addition, mRNA and protein level of GABAergic/Serotonergic neurotransmitters were upregulated following treatment with LB-GABA (2.0%). In particular, intestine- and brain-derived GABAA protein levels were increased by sevenfold and fivefold, respectively. The electroencephalography (EEG) analysis in rats showed that LB-GABA significantly increased non-rapid eye movement (NREM) (53%) with the increase in theta (θ, 59%) and delta (δ, 63%) waves, leading to longer sleep time (35%), under caffeine-induced insomnia conditions. LB-GABA showed a dose-dependent agonist activity on human GABAA receptor with a half-maximal effective concentration (EC50) of 3.44 µg/mL in human embryonic kidney 293 (HEK293) cells.
... Although there is some evidence showing that biosynthetic GABA could reach the human brain as evidenced by various EEG responses (Abdou et al., 2006;Yoto et al., 2012), to date, there are no data showing GABA's BBB permeability in humans. Although it has been shown that the blood GABA levels were elevated 30 min after oral GABA intake (Yamatsu et al., 2016), it's not known if oral GABA intake would increase brain GABA concentrations or not. ...
... Three 1 to 3-week long intervention studies (albeit with very low sample sizes), investigated the effects of biosynthetic GABA consumption on sleep in individuals with poor sleep quality (one with PSQI > 5 scorers, and two with PSQI > 6 scorers; PSQI: Pittsburgh Sleep Quality Index). In their first 1 week long intervention study, Yamatsu et al. (2016) showed that the intake of 100 mg GABA capsule (vs. control) improved feelings upon awakening scores, objectively measured reduced sleep latency, and increased total Non-REM (N1, N2, and N3/SWS) sleep time after intervention. ...
... control) group at the 4th week of treatment, but not with GABA use beyond that. On the other hand, only some of the subjective sleep scores including sleep disturbance, feelings upon awakening, onset and maintenance of sleep, drowsiness in the morning, and recovery from fatigue scores improved only when there was a prolonged GABA use for at least 1 week (Okada et al., 2000;Yamatsu et al., 2013Yamatsu et al., , 2016. Remaining studies showed either trends toward improvements or insignificant subjective improvement of sleep. ...
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Article
Gamma-aminobutyric acid (GABA) is a non-proteinogenic amino acid and is the main inhibitory neurotransmitter in the mammalian brain. GABA's stress-reducing, and sleep enhancing effects have been established. However, although several human clinical trials have been conducted, results regarding the role of natural and/or biosynthetic oral GABA intake on stress and sleep are mixed. We performed a systematic review to examine whether natural and/or biosynthetic oral GABA intake has an effect on stress and sleep. We systematically searched on PubMed database for studies published up to February 2020 following PRISMA guidelines. Only placebo-controlled human trials that assessed stress, sleep, and related psychophysiological outcomes as a response to natural GABA (i.e., GABA that is present naturally in foods) or biosynthetic GABA (i.e., GABA that is produced via fermentation) intake were included. Fourteen studies met the criteria and were included in the systematic review. Although more studies are needed before any inferences can be made about the efficacy of oral GABA consumption on stress and sleep, results show that there is limited evidence for stress and very limited evidence for sleep benefits of oral GABA intake.
... Recently, it has been manufactured and widely used as a dietary supplement. Previous studies in human trials demonstrated that dietary GABA induces antihypertensive effects [6], alleviates anxiety [7], and improves sleep quality [8] and cognitive functions [9,10]. As a result, GABA is blended into many functional foods and is sold worldwide including in Europe, the United States, and Asia. ...
... Researchers reported that orally administered GABA is absorbed into the blood in humans [8]. Here, we examined and compared the abilities to increase plasma GABA concentration after the po vs. ip administration of GABA. ...
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Gamma-aminobutyric acid (GABA) is present in the mammalian brain as the main inhibitory neurotransmitter and in foods. It is widely used as a supplement that regulates brain function through stress-reducing and sleep-enhancing effects. However, its underlying mechanisms remain poorly understood, as it is reportedly unable to cross the blood–brain barrier. Here, we explored whether a single peroral administration of GABA affects feeding behavior as an evaluation of brain function and the involvement of vagal afferent nerves. Peroral GABA at 20 and 200 mg/kg immediately before refeeding suppressed short-term food intake without aversive behaviors in mice. However, GABA administration 30 min before refeeding demonstrated no effects. A rise in circulating GABA concentrations by the peroral administration of 200 mg/kg GABA was similar to that by the intraperitoneal injection of 20 mg/kg GABA, which did not alter feeding. The feeding suppression by peroral GABA was blunted by the denervation of vagal afferents. Unexpectedly, peroral GABA alone did not alter vagal afferent activities histologically. The coadministration of a liquid diet and GABA potentiated the postprandial activation of vagal afferents, thereby enhancing postprandial satiation. In conclusion, dietary GABA activates vagal afferents in collaboration with meals or meal-evoked factors and regulates brain function including feeding behavior.
... Some scientific publications have confirmed the bioavailability and effectiveness of oral GABA supplementation in humans [25,26]. In studies on mycelium and fruiting bodies of C. militaris, the concentration of GABA was determined, respectively, at 68.6-180.1 mg/kg and 756.30 ...
... Other complications related to GABA include difficulty in penetrating the blood-brain barrier and short biological half-life [24]. Some scientific publications have confirmed the bioavailability and effectiveness of oral GABA supplementation in humans [25,26]. ...
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Cordyceps spp. mushrooms have a long tradition of use as a natural raw material in Asian ethnomedicine because of their adaptogenic, tonic effects and their ability to reduce fatigue and stimulate the immune system in humans. This review aims to present the chemical composition and medicinal properties of Cordyceps militaris fruiting bodies and mycelium, as well as mycelium from in vitro cultures. The analytical results of the composition of C. militaris grown in culture media show the bioactive components such as cordycepin, polysaccharides, -aminobutyric acid (GABA), ergothioneine and others described in the review. To summarize, based on the presence of several bioactive compounds that contribute to biological activity, C. militaris mushrooms definitely deserve to be considered as functional foods and also have great potential for medicinal use. Recent scientific reports indicate the potential of cordycepin in antiviral activity, particularly against COVID-19.
... GABA is found naturally in external food sources such as fruits, vegetables, and fermented foods [17]. Previous studies confirmed that intake of GABA leads to reduced physiological stress [18] and improved relaxation and sleep quality [19,20] by increasing the parasympathetic nerve activities. Additionally, serum GABA levels increase 30 min after exogenous GABA intake [19], and the elevated levels of GABA may be responsible for the physiological adjustment of the pituitary gland to secrete GH [21]. ...
... Previous studies confirmed that intake of GABA leads to reduced physiological stress [18] and improved relaxation and sleep quality [19,20] by increasing the parasympathetic nerve activities. Additionally, serum GABA levels increase 30 min after exogenous GABA intake [19], and the elevated levels of GABA may be responsible for the physiological adjustment of the pituitary gland to secrete GH [21]. Clinical studies have also demonstrated that oral administration of GABA reportedly elevated resting serum GH and IGF-1 levels compared to the placebo control [22]. ...
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Insulin-like growth factor-1 (IGF-1) primarily increases the release of gamma-aminobutyric acid (GABA) in neurons; moreover, it is responsible for the promotion of longitudinal growth in children and adolescents. Therefore, in this study, we investigated whether exogenous GABA supplementation activates IGF-mediated growth performance. Zebrafish larvae treated with GABA at three days post fertilization (dpf) showed a significant increase in the total body length from 6 to 12 dpf through upregulation of growth-stimulating genes, including IGF-1, growth hormone-1 (GH-1), growth hormone receptor-1 (GHR-1), and cholecystokinin A (CCKA). In particular, at 9 dpf, GABA increased total body length from 3.60 ± 0.02 to 3.79 ± 0.03, 3.89 ± 0.02, and 3.92 ± 0.04 mm at concentrations of 6.25, 12.5, and 25 mM, and the effect of GABA at 25 mM was comparable to 4 mM β-glycerophosphate (GP)-treated larvae (3.98 ± 0.02 mm). Additionally, the highest concentration of GABA (50 mM)-induced death in 50% zebrafish larvae at 12 dpf. GABA also enhanced IGF-1 expression and secretion in preosteoblast MC3T3-E1 cells, concomitant with high levels of the IGF-1 receptor gene (IGF-1R). In zebrafish larvae, the GABA-induced growth rate was remarkably decreased in the presence of an IGF-1R inhibitor, picropodophyllin (PPP), which indicates that GABA-induced IGF-1 enhances growth rate via IGF-1R. Furthermore, we investigated the effect of GABA receptors on growth performance along with IGF-1 activation. Inhibitors of GABAA and GABAB receptors, namely bicuculline and CGP 46381, respectively, considerably inhibited GABA-induced growth rate in zebrafish larvae accompanied by a marked decrease in the expression of growth-stimulating genes, including IGF-1, GH-1, GHR-1, and CCKA, but not with an inhibitor of GABAC receptor, TPMPA. Additionally, IGF-1 and IGF-1R expression was impaired in bicuculline and CGP 46381-treated MC3T3-E1 cells, but not in the cells treated with TPMPA. Furthermore, treatment with bicuculline and CGP 46381 significantly downregulated GABA-induced IGF-1 release in MC3T3-E1 cells. These data indicate that GABA stimulates IGF-1 release via GABAA and GABAB receptors and leads to growth promotion performance via IGF-1R.
... The combination of γ-aminobutyric acid (GABA; an amino acid produced by natural fermentation) and Apocynum venetum leaf extract treatment yielded a modest decrease in SOL of 4.3 min and shortening of deep non-REM sleep latency by 5.3 min [33]. Similar magnitude reductions in SOL were reported for 100 mg of GABA supplementation only [39], while supplementation with 300 mg of GABA induced reductions in SOL and WASO in concert with an increase in SE [34]. In comparison, the consumption of two kiwifruits 1 h before bedtime yielded a substantial increase in TST of 55 min, as well as a 2% increase in SE and decreased SOL (14 min) and WASO (6.1 min) [32]. ...
... Akin to kiwifruit consumption, ingestion of GABA in different quantities has yielded improvements in the sleep quality of poor sleepers or those dissatisfied with sleep [33,39]. GABA is an inhibitory neurotransmitter that is often present in food, and its receptors in the central nervous system are often targeted by pharmacological agents such as benzodiazepines for treatment of several conditions including insomnia [63]. ...
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Article
Athletes often experience sleep disturbances and poor sleep as a consequence of extended travel, the timing of training and competition (i.e., early morning or evening), and muscle soreness. Nutrition plays a vital role in sports performance and recovery, and a variety of foods, beverages, and supplements purportedly have the capacity to improve sleep quality and quantity. Here, we review and discuss relevant studies regarding nutrition, foods, supplements, and beverages that may improve sleep quality and quantity. Our narrative review was supported by a semi-systematic approach to article searching, and specific inclusion and exclusion criteria, such that articles reviewed were relevant to athletes and sporting environments. Six databases—PubMed, Scopus, CINAHL, EMBASE, SPORTDiscus, and Google Scholar—were searched for initial studies of interest from inception to November 2020. Given the paucity of sleep nutrition research in the athlete population, we expanded our inclusion criteria to include studies that reported the outcomes of nutritional interventions to improve sleep in otherwise healthy adults. Carbohydrate ingestion to improve sleep parameters is inconclusive, although high glycemic index foods appear to have small benefits. Tart cherry juice can promote sleep quantity, herbal supplements can enhance sleep quality, while kiwifruit and protein interventions have been shown to improve both sleep quality and quantity. Nutritional interventions are an effective way to improve sleep quality and quantity, although further research is needed to determine the appropriate dose, source, and timing in relation to training, travel, and competition requirements.
... As a result of the investigation about the effects of GABA intake on central nervous system activities in healthy people under mental task stress, it was found that GABA alleviated the stress (Yoto et al., 2012). According to another study, GABA reduced the sleep latency and increased the total non-rapid eye movement sleep time (Yamatsu, Yamashita, Pandharipande, Maru, & Kim, 2016). Moreover, human intervention trials have demonstrated that GABA enriched foods are effective for blood pressure regulation (Yoshimura et al., 2010). ...
... Reducing phycological and physical fatigue and improvement of task-solving ability in humans (Kanehira et al., 2011) Psychological stress-reducing effect (Nakamura et al., 2009) Alleviation stress (Yoto et al., 2012) Reducing of the sleep latency and increasing of the total non-rapid eye movement sleep time (Yamatsu et al., 2016) Blood pressure regulation (Yoshimura et al., 2010) ...
... Its antidepressant effect was suggested due to recovering the level of monoamines norepinephrine, dopamine, and 5-hydroxytryptamine in the hippocampus [20]. Meanwhile, Yamatsu et al. (2016) reported that Gaba administration significantly shortened sleep latency and increased the total non-rapid eye movement sleep time, indicating the essential role of Gaba in the prevention of a sleep disorder [21]. Moreover, the mixture of Gaba and l-theanine could decrease sleep latency, increase sleep duration, and up-regulate the expression of Gaba and glutamate GluN1 receptor subunit [22]. ...
... Its antidepressant effect was suggested due to recovering the level of monoamines norepinephrine, dopamine, and 5-hydroxytryptamine in the hippocampus [20]. Meanwhile, Yamatsu et al. (2016) reported that Gaba administration significantly shortened sleep latency and increased the total non-rapid eye movement sleep time, indicating the essential role of Gaba in the prevention of a sleep disorder [21]. Moreover, the mixture of Gaba and l-theanine could decrease sleep latency, increase sleep duration, and up-regulate the expression of Gaba and glutamate GluN1 receptor subunit [22]. ...
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Gamma-aminobutyric acid (Gaba) is a non-proteinogenic amino acid that is widely present in microorganisms, plants, and vertebrates. So far, Gaba is well known as a main inhibitory neurotransmitter in the central nervous system. Its physiological roles are related to the modulation of synaptic transmission, the promotion of neuronal development and relaxation, and the prevention of sleeplessness and depression. Besides, various pharmaceutical properties of Gaba on non-neuronal peripheral tissues and organs were also reported due to anti-hypertension, anti-diabetes, anti-cancer, antioxidant, anti-inflammation, anti-microbial, anti-allergy, hepato-protection, reno-protection, and intestinal protection. Therefore, Gaba may be considered as potential alternative therapeutics for prevention and treatment of various diseases. Accordingly, this updated review was mainly focused to describe the pharmaceutical properties of Gaba as well as emphasize its important role regarding human health.
... In vertebrates, GABA exists in the brain and acts as an inhibitory neurotransmitter in the central nervous system [14]. Oral GABA administration relieves anxiety [15], reduces psychological stress [16], induces relaxation [17], and improves sleep [18] by increasing total and parasympathetic nerve activities [19]. GABA also supports the physiologic adjustment of pituitary gland function and controls growth hormone (GH) secretion from the pituitary gland [20,21]. ...
... Sleep deprivation negatively influences exercise performance and post-exercise recovery [37,38]. GABA improves sleep quality by shortening sleep latency and increasing non-rapid eye movement (REM) sleeping time [18]. GABA also reduces acute psychological and physical fatigue by suppressing sympathetic response and increasing parasympathetic response under stressful tasks [19,39]. ...
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Background Oral gamma-aminobutyric acid (GABA) supplementation increases growth hormone (GH) serum levels and protein synthesis. Therefore, post-exercise supplementation using GABA and protein may help enhance training-induced muscle hypertrophy. We evaluated whether GABA with whey protein enhanced muscular hypertrophy in men after progressive resistance training. Methods Twenty-one healthy men (26 - 48 years) were randomized to receive whey protein (WP; 10 g) or whey protein + GABA (WP + GABA; 10 g + 100 mg) daily for 12 weeks. Both groups performed resistance training twice per week (three sets of 12 repetitions at 60% of maximal strength; leg press, leg extension, leg curl, chest press, and pull down). Body composition was assessed using dual-energy X-ray absorptiometry. Results In the WP + GABA group, resting plasma GH concentrations were significantly elevated at 4 and 8 weeks, compared to baseline. However, resting plasma GH concentrations in the WP group were only significantly elevated at 8 weeks. After 12 weeks, the WP + GABA group exhibited significantly greater increase in whole body fat-free mass than the WP group. Conclusions The GABA and whey protein combination was more effective for increasing whole body fat-free mass; daily GABA supplementation may help enhance exercise-induced muscle hypertrophy.
... Prevention of sarcopenia is therefore important for extending a person's healthy lifespan. γ-Aminobutyric acid (GABA) is an amino acid found in plants and vertebrates, and various physiological functions of GABA have been reported, including improvement of sleep quality [7] , anti-stress effects [8] , and suppression of blood pressure elevation [9] . In addition, the expression of elastic fibers such as collagen and elastin is increased in human dermal fibroblasts following exposure to GABA [10][11] . ...
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Multiple physiological effects of γ-aminobutyric acid (GABA) as a functional food ingredient have been reported. However, the effects of GABA on cell proliferation and the expression of myogenic determination gene number 1 (MyoD), peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α), and myostatin in C2C12 myoblasts have not been reported. In this study, we examined the effects of GABA in myoblasts. In cell counting assays, 100 μg/mL and 1000 μg/mL of GABA significantly increased cell proliferation. In real-time polymerase chain reaction and western blotting studies, GABA increased mRNA and protein expression of MyoD and PGC-1α in a concentration-dependent manner. Similar experiments also showed that GABA significantly decreased the expression of myostatin mRNA and protein in a concentration-dependent manner, confirming that GABA promotes myoblast proliferation and increases the expression of MyoD and PGC-1α, and decreases the expression of myostatin. These results suggest that GABA may increase or inhibit the decrease in muscle mass.
... There are also reports of the effect of Dracocephalum on adenosine and 5HT-5α receptors, which are important receptors in sleep regulation and sleep disorders(33,34). In addition to Dracocephalum, other medicinal herbs have also been investigated to improve sleep problems in pre-or in post-menopausal women. ...
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Objective: Sleep disturbance is one of the most prevalent problems in post-menopausal females. The current research intended to evaluate the effects of Dracocephalum on sleep disorder in post-menopausal females. Method: The current study is a randomized, double-blind controlled trial, in which 110 post-menopausal women were randomly allocated to Dracocephalum or placebo groups. The intervention group took Dracocephalum capsules containing 250 mg Dracocephalum extract twice daily for one month. While, the placebo group took the same capsule containing 250 mg of starch twice daily for one month. Pittsburgh Sleep Quality Index was completed by the participants of both groups before and after the treatment and the data obtained were analyzed with Chi-square, paired and independent t-test in SPSS (version 20). Results: The mean score of sleep quality before and after the treatment was 12.69 ± 3.98 and 8.58 ± 1.97 in the treatment group, respectively. Also, the score of sleep quality in the placebo group was 13.48 ± 2.60 and 11.21 ± 2.74 at the beginning and end of the research, respectively. The symptoms of sleep disorder in the intervention group significantly improved after the treatment (P < 0.001), while this was not the case with the placebo group (P = 0.155). Besides, there was a significant difference between the two groups in the mean score of sleep quality after the treatment (P = 0.012). Conclusion: Dracocephalum extracts are effective in reducing symptoms of sleep disorders in post-menopausal women.
... (non-REM) sleep time [30]. In another placebocontrolled clinical trial, sleep latency decreased while sleep quality increased in insomnia patients who were given 300 mg GABA for 4 weeks [31]. ...
Article
Aim: Somatopause is the progressive and age-related decline of growth hormone (GH) production due to changes in hypothalamic-pituitary axis signaling and results in typical physiological changes associated with the aging process. The purpose of our study was to investigate the anti-aging potential of several botanical ingredients, including noni fruit juice, as well as a dietary supplement formulation. Methodology: Dipeptidyl peptidase-4 (DPP-4) influences hypothalamic-pituitary axis signaling and reduces GH production and secretion. Since DPP-4 concentrations increase with age, we evaluated the ability of several botanical ingredients to inhibit DPP-4 activity in vitro. We subsequently formulated an anti-aging dietary supplement with this blend of botanical ingredients by adding amino acids (L-arginine, L-Lysine, citrulline and beta-alanine), gamma-aminobutyric acid (GABA), flax seed oil and several nutrients. The supplement was evaluated for anti-arginase activity in vitro, as the expression of this enzyme also increases with age. The dietary supplement was also consumed by three men and one woman, ages 56 to 62, with relevant but disparate medical histories. Following short-term ingestion of the supplement, these volunteers were interviewed to ascertain any changes in health status. Results: We discovered that a blend of the botanical ingredients synergistically inhibited DPP-4 in vitro by up to approximately 99%. A concentration-dependent reduction in arginase activity was also observed for the anti-aging dietary supplement. Further, all volunteers reported positive improvements in at least one quality of life factor, which included more restful sleep, reduced musculoskeletal discomfort, increased energy, improved physical stamina and better skin quality. Conclusion: These initial findings suggest that the anti-aging dietary supplement can mitigate declines in quality of life associated with aging by reducing DPP-4 and arginase activities, thereby supporting healthy GH production and endothelial nitric oxide production.
... According to the study of Byun et al. (2018), 4 weeks use of GABA reduced sleep latency in the participants. Similarly, with dosing 30 min before sleep, 1 week GABA intervention reduced sleep latency and increased total NREM sleep time in humans (Yamatsu et al. 2016). These studies revealed that GABA intake has no significant impact on sleep efficiency, REM sleep time and other sleep markers. ...
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Sleep disorders have received widespread attention nowadays, which have been promoted by the accelerated pace of life, unhealthy diets and lack of exercise in modern society. The chemical medications to improve sleep has shown serious side effects and risks with high costs. Therefore, it is urgent to develop efficient nutraceuticals from natural sources to ensure sleep quality as a sustainable strategy. As the second most consumed beverage worldwide, the health-promoting effects of tea have long been widely recognized. However, the modulatory effect of teas on sleep disorders has received much less attention. Tea contains various natural sleep-modulating active ingredients such as L-theanine (LTA), caffeine, tea polyphenols (TPP), tea pigments, tea polysaccharides (TPS) and γ-aminobutyric acid (GABA). This review focuses on the potential influence and main regulating mechanisms of different tea active ingredients on sleep, including being absorbed by the small intestine and then cross the blood-brain barrier to act on neurons in the brain as neurotransmitters, manipulating the immune system and further affect sleep-wake cycle by regulating the levels of cytokines, and controlling the gut microbes to maintain the homeostasis of circadian rhythm. Current research progress and limitations are summarized and several future development directions are also proposed. This review hopes to provide new insights into the future elucidation of the sleep-regulating mechanisms of different teas and their natural active ingredients and the development of tea-based functional foods for alleviating sleep disorders. • Highlights • • Natural sleep-modulating active ingredients in tea have been summarized. • • Influences of drinking tea or tea active ingredients on sleep are reviewed. • • Three main regulating mechanisms of tea active ingredients on sleep are explained. • • The associations among nervous system, immune system and intestinal microbiota are investigated. • • The potential of developing delivery carriers for tea active ingredients is proposed.
... In humans, it acts as the major inhibitory neurotransmitter in the central nervous system. The latter has played a decisive role in the ongoing trend of enriching food with this molecule; however, Hepsomali et al. [46] mentioned that although GABA oral intake resulted in various responses [47][48][49], it is still unknown whether brain GABA concentration is increased. On the other hand, it seems to have a different role in microorganisms; it has been associated with resistance to acidic conditions [50] as well as spore germination, at least in Neurospora crassa [51] and Bacillus megaterium [52]. ...
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Consumption of lactic acid fermented fruits and vegetables has been correlated with a series of health benefits. Some of them have been attributed to the probiotic potential of lactic acid microbiota, while others to its metabolic potential and the production of bioactive compounds. The factors that affect the latter have been in the epicenter of intensive research over the last decade. The production of bioactive peptides, vitamins (especially of the B-complex), gamma-aminobutyric acid, as well as phenolic and organosulfur compounds during lactic acid fermentation of fruits and vegetables has attracted specific attention. On the other hand, the production of biogenic amines has also been intensively studied due to the adverse health effects caused by their consumption. The data that are currently available indicate that the production of these compounds is a strain-dependent characteristic that may also be affected by the raw materials used as well as the fermentation conditions. The aim of the present review paper is to collect all data referring to the production of the aforementioned compounds and to present and discuss them in a concise and comprehensive way.
... [10] and acts as a major inhibitory neurotransmitter in the central nervous system [11]. Moreover, GABA shows potential as a supplement for treating many conditions, including depression, poor sleep quality [12,13], poor immunity [14], and diabetes, as it strongly promotes insulin secretion [15,16]. Thus, various approaches for producing GABA have gained attention in recent years [8]. ...
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Background Bifidobacteria are gram-positive, probiotic, and generally regarded as safe bacteria. Techniques such as transformation, gene knockout, and heterologous gene expression have been established for Bifidobacterium , indicating that this bacterium can be used as a cell factory platform. However, there are limited previous reports in this field, likely because of factors such as the highly anaerobic nature of this bacterium. Bifidobacterium adolescentis is among the most oxygen-sensitive Bifidobacterium species. It shows strain-specific gamma-aminobutyric acid (GABA) production. GABA is a potent bioactive compound with numerous physiological and psychological functions. In this study, we investigated whether B. adolesentis could be used for mass production of GABA. Results The B. adolescentis 4–2 strain isolated from a healthy adult human produced approximately 14 mM GABA. It carried gadB and gadC , which encode glutamate decarboxylase and glutamate GABA antiporter, respectively. We constructed pKKT427::P ori -gadBC and pKKT427::P gap -gadBC plasmids carrying gadBC driven by the original gadB ( ori ) and gap promoters, respectively. Recombinants of Bifidobacterium were then constructed. Two recombinants with high production abilities, monitored by two different promoters, were investigated. GABA production was improved by adjusting the fermentation parameters, including the substrate concentration, initial culture pH, and co-factor supplementation, using response surface methodology. The optimum initial cultivation pH varied when the promoter region was changed. The ori promoter was induced under acidic conditions (pH 5.2:4.4), whereas the constitutive gap promoter showed enhanced GABA production at pH 6.0. Fed-batch fermentation was used to validate the optimum fermentation parameters, in which approximately 415 mM GABA was produced. The conversion ratio of glutamate to GABA was 92–100%. Conclusion We report high GABA production in recombinant B. adolescentis . This study provides a foundation for using Bifidobacterium as a cell factory platform for industrial production of GABA.
... For instance, in a study, oral administration of GABA caused the increase of the GABA level in human blood after 30 min. 22 It was observed by Turska et al. that labeled kynurenic acid was detected in the blood of mice 1 h after its administration. 23 In another study, it was reported that the concentration of melatonin increased to 38 pg/mL in the blood of rats fed melatonin-containing walnuts (3.5 ng/g), while its value was 11.5 pg/mL in the control group of rats. ...
... Body builders also use it to increase muscle growth. Given the important role of GABA promoting human health, GABA is allowed to be added to a variety of foods except for special populations by many countries and organisations (Yamatsu et al. 2016). As one grows older, the GABA content in the body gradually decreases. ...
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γ-aminobutyric acid (GABA) is an important inhibitory neurotransmitter in the human body, but its content decreases with age. So it is suitable to supplement the body's GABA from diet. Hongqu wine is popular because of the addition of Monascus strains in the saccharification process, which makes the wine rich in functional ingredients such as GABA, and monacolin K. In this study, the fermentation parameters of Hongqu wine were optimised to maximise the GABA content through response surface methodology (RSM). The optimal conditions were as follows: 500 g of steamed rice was mixed with 115.4% of boiled water containing 10 g of sodium glutamate and adjusted to pH 3.8 with lactic acid, and then 32% of Hongqu seed inoculum was added. After 5 days of fermentation at 28 °C, 1.5 g of activated yeast was inoculated for ethanol fermentation at 30 °C for 5 days. Finally, the average content of GABA in Hongqu wine amounted to 710.24 mg L<sup>–1</sup>, which is close to the value predicted by RSM model (692.44 mg L<sup>–1</sup>), indicating the statistical fit is good. This provided technical support and theoretical guidance for the production of Hongqu wine rich in GABA by two-stage fermentation.
... Furthermore, it will be possible to develop diagnostic methods for brain function based on serum exosomes. To verify the effect of GABA administration on brain function, the effects of GABA on sleep, relaxation, and psychological and physical fatigue have been investigated in humans [15,18,37]. These results indicate that GABA strongly affects the early stages of sleep, reduces both psychological and physical fatigue, and acts as a natural relaxant inducer. ...
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γ-Aminobutyric acid (GABA) is a potent bioactive amino acid, and several studies have shown that oral administration of GABA induces relaxation, improves sleep, and reduces psychological stress and fatigue. In a recent study, we reported that exosomes derived from GABA-treated intestinal cells serve as signal transducers that mediate brain–gut interactions. Therefore, the purpose of this study was to verify the functionality of GABA-derived exosomes and to examine the possibility of improving memory function following GABA administration. The results showed that exosomes derived from GABA-treated intestinal cells (Caco-2) activated neuronal cells (SH-SY5Y) by regulating genes related to neuronal cell functions. Furthermore, we found that exosomes derived from the serum of GABA-treated mice also activated SH-SY5Y cells, indicating that exosomes, which are capable of activating neuronal cells, circulate in the blood of mice orally administered GABA. Finally, we performed a microarray analysis of mRNA isolated from the hippocampus of mice that were orally administered GABA. The results revealed changes in the expression of genes related to brain function. Gene Set Enrichment Analysis (GSEA) showed that oral administration of GABA affected the expression of genes related to memory function in the hippocampus.
... For the first time, this study showed that GABA was observed in the water extract and not detected in the ethanol extract of A. mellea, which may explain why the sedative-hypnotic effect was more effective with water extract than the ethanol extract under the same concentration. Although exogenous GABA administration has long thought to be unable to cross the blood-brain barrier (BBB), studies have reported that the oral GABA administration can act on the peripheral nervous system of the digestive organs and improves the sleep behaviors [38,39]. Moreover, there are studies which reported that GABA does cross BBB, even if it is a small amount [40,41]. ...
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The present study aimed to explore whether water and ethanol extracts of Armillaria mellea mycelia produce sedative and hypnotic effects in rats. Male Sprague–Dawley rats were surgically implanted with two electroencephalogram electrodes on the skull and an electromyogram electrode on neck muscle to evaluate the alterations in rapid eye movement (REM) and non-REM (NREM) sleep after oral administration of the water and ethanol extracts. Following post-surgical recovery, thirty-six rats were randomly divided into four treatment groups and two control groups. They were treated orally with vehicle, 75 and 150 mg/kg doses of water and ethanolic extracts 15 min prior to the onset of dark (active) period. Electroencephalography results showed that the low dose of A. mellea mycelia water extract increased REM sleep time while the high dose enhanced both REM and NREM sleep times during the subsequent light (rest) period. On the other hand, although the low dose of A. mellea mycelia ethanolic extract did not alter both NREM sleep and REM sleep during the dark and light periods, the high dose increased both REM and NREM sleep during the light periods in naive rats. The HPLC-DAD analyses of both extracts allowed the identification of GABA and seven sesquiterpenoids. Based on these findings, the present study showed for the first time that water and ethanolic extracts of A. mellea mycelia, containing a source of biologically active compounds, could increase both NREM sleep and REM sleep during the rest period and may be useful for the treatment of insomnia.
... 249,250 However; Yamastu and colleagues displayed rapid gastrointestinal absorption and a peak in blood concentrations of GABA 30 minutes after consumption. 251 Moreover; GABA was revealed to successfully inhibit class I, II and III histone deacetylases, upregulate H3K9 acetylation and H4K12 acetylation in SH-SY5Y cells; therefore, we cannot rule out epigenetic modulation that may rapidly influence gene expression beyond the BBB. 247 In addition, neurosteroids are highly lipophilic and therefore, readily cross the BBB. ...
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Nutritional epigenetics is a rapidly expanding field of research, and the natural modulation of the genome is a non-invasive, sustainable, and personalized alternative to gene-editing for chronic disease management. Genetic differences and epigenetic inflexibility resulting in abnormal gene expression, differential or aberrant methylation patterns account for the vast majority of diseases. The expanding understanding of biological evolution and the environmental influence on epigenetics and natural selection requires relearning of once thought to be well-understood concepts. This research explores the potential for natural modulation by the less understood epigenetic modifications such as ubiquitination, nitrosylation, glycosylation, phosphorylation, and serotonylation concluding that the under-appreciated acetylation and mitochondrial dependant downstream epigenetic post-translational modifications may be the pinnacle of the epigenomic hierarchy, essential for optimal health, including sustainable cellular energy production. With an emphasis on lessons learned, this conceptional exploration provides a fresh perspective on methylation, demonstrating how increases in environmental methane drive an evolutionary down regulation of endogenous methyl groups synthesis and demonstrates how epigenetic mechanisms are cell-specific, making supplementation with methyl cofactors throughout differentiation unpredictable. Interference with the epigenomic hierarchy may result in epigenetic inflexibility, symptom relief and disease concomitantly and may be responsible for the increased incidence of neurological disease such as autism spectrum disorder.
... G-Aminobutyric acid (GABA) is widely recognized as a bioactive and functional compound thanks to a plethora of in vitro and in vivo studies reporting its beneficial effects in treating many metabolic disorders (Yoshimura et al., 2010;Yang et al., 2012). In humans, GABA functions as an inhibitory neurotransmitter (Owens and Kriegstein, 2002), and it has been reported that the intake of GABA is effective in lowering the blood pressure of hypertensive patients (Inoue et al., 2003), inducing relaxation (Abdou et al., 2006), reducing psychological stress (Nakamura et al., 2009), and shortening sleep latency (Yamatsu et al., 2016), among other health benefits. Consequently, in recent decades, the food industry has focused on releasing and developing new GABA-enriched products such as tea, yogurt, bread, cheese and fermented foods (Park and Oh, 2007;Poojary et al., 2017;Quıĺez and Diana, 2017). ...
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Over the last seven decades, γ-aminobutyric acid (GABA) has attracted great attention from scientists for its ubiquity in plants, animals and microorganisms and for its physiological implications as a signaling molecule involved in multiple pathways and processes. Recently, the food and pharmaceutical industries have also shown significantly increased interest in GABA, because of its great potential benefits for human health and the consumer demand for health-promoting functional compounds, resulting in the release of a plethora of GABA-enriched products. Nevertheless, many crop species accumulate appreciable GABA levels in their edible parts and could help to meet the daily recommended intake of GABA for promoting positive health effects. Therefore, plant breeders are devoting much effort into breeding elite varieties with improved GABA contents. In this regard, tomato (Solanum lycopersicum), the most produced and consumed vegetable worldwide and a fruit-bearing model crop, has received much consideration for its accumulation of remarkable GABA levels. Although many different strategies have been implemented, from classical crossbreeding to induced mutagenesis, new plant breeding techniques (NPBTs) have achieved the best GABA accumulation results in red ripe tomato fruits along with shedding light on GABA metabolism and gene functions. In this review, we summarize, analyze and compare all the studies that have substantially contributed to tomato GABA breeding with further discussion and proposals regarding the most recent NPBTs that could bring this process to the next level of precision and efficiency. This document also provides guidelines with which researchers of other crops might take advantage of the progress achieved in tomato for more efficient GABA breeding programs.
... Антидепрессивный эффект ГАМК обусловлен восстановлением уровня моноаминов (норадреналина, дофамина и серотонина) в гиппокампе [17]. ГАМК значительно сокращает латентность сна и увеличивает общее время фазы сна с медленным движением глаз, что указывает на ее эффективность в профилактике инсомнии [18,19]. При стрессовых состояниях ГАМК способна вызывать релаксацию, уменьшать беспокойство и модулировать работу иммунной системы [20]. ...
Article
The review sets out modern ideas about the mechanisms of action of gamma-aminobutyric acid (GABA) in the central nervous system and other organs and systems. Current experimental and clinical studies have shown that GABA has numerous effects: neuroprotective, antihypertensive, antidiabetic, antitumor, anti-inflammatory, antimicrobial, anti-allergic, hepatoprotective, nephroprotective and enteroprotective, and others, which are currently the subject for study by biologists, physiologists, and physicians. Synthetic GABA analogues are widely used in clinical practice. One of these drugs is aminophenylbutyric acid hydrochloride (Anvifen®) that has demonstrated high efficiency and safety in clinical practice.
... Received 31 October 2019; Received in revised form 19 December 2019; Accepted 3 January 2020 increase in alpha wave activity and decrease in beta wave activity in the brains of volunteers for 60 min after the intake of 100 mg GABA, suggesting that this neurotransmitter can promote relaxation and reduce anxiety (Abdou et al., 2010). Orally administered GABA, which exhibited a blood peak after 30 min, was shown to shorten the sleep latency significantly and increase the non-REM sleep time in subjects (Yamatsu et al., 2016). ...
... Badania przeprowadzone na szczurach wykazały, że podanie 60 mg GABA/kg masy ciała przywraca dobrą jakość i regularność snu [88]. Również badania kliniczne wykazały pozytywne działanie 100 mg dawki GABA na poprawę jakości snu i skróceniu czasu potrzebnego do zaśnięcia [89]. ...
... Although GABA supplementation has been reported as effective in mediating favorable behavioral outcomes in animals and people, the mechanisms by which this occurs remain largely unknown as it is unclear whether, and under what conditions, GABA may cross the blood brain barrier (BBB) (70). Hence, it is unknown whether reports demonstrating that oral administration of GABA results in a reduction of fatigue in animals (27) and human volunteers (16), as well as antidepressant-like effects (26), improved task completion (71), and anti-insomnia effects (72) (73), are due to GABA acting locally on gastrointestinal receptors in a putative gut-to-brain mechanism, are due to circulating GABA, or if some GABA does indeed cross the BBB. ...
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The study of host-microbe neuroendocrine crosstalk, termed microbial endocrinology, suggests the impact of diet on host health and microbial viability is, in part, reliant upon nutritional modulation of shared host-microbe neuroendocrine axes. In the 1990's it was first recognized that neuroendocrine pathways are major components of the microbiota-gut-brain axis, and that diet-induced changes in the gut microbiota were correlated with changes in host behavior and cognition. A causative link, however, between nutritional-induced shifts in microbiota composition and change in host behavior has yet to be fully elucidated. Substrates found in food which are utilized by bacteria in the production of microbial-derived neurochemicals, which are structurally identical to those made by the host, likely represent a microbial endocrinology-based route by which the microbiota causally influence the host and microbial community dynamics via diet. For example, food safety is strongly impacted by the microbial production of biogenic amines. While microbial-produced tyramine found in cheese can elicit hypertensive crises, microorganisms which are common inhabitants of the human intestinal tract can convert L-histidine found in common foodstuffs to histamine and thereby precipitate allergic reactions. Hence, there is substantial evidence suggesting a microbial endocrinology-based role by which the gastrointestinal microbiota can utilize host dietary components to produce neuroactive molecules that causally impact the host. Conversely, little is known regarding the reverse scenario whereby nutrition-mediated changes in host neuroendocrine production affect microbial viability, composition, and/or function. Mechanisms in the direction of brain-to-gut, such as how host production of catecholamines drives diverse changes in microbial growth and functionality within the gut, require greater examination considering well-known nutritional effects on host stress physiology. As dietary intake mediates changes in host stress, such as the effects of caffeine on the hypothalamic-pituitary-adrenal axis, it is likely that nutrition can impact host neuroendocrine production to affect the microbiota. Likewise, the plasticity of the microbiota to changes in host diet has been hypothesized to drive microbial regulation of host food preference via a host-microbe feedback loop. This review will focus on food as concerns microbial endocrinology with emphasis given to nutrition as a mediator of host-microbe bi-directional neuroendocrine crosstalk and its impact on microbial viability and host health.
... Many people report that these supplements reduced anxiety and improve sleep quality. Oral GABA has been shown to improve sleep (Yamatsu et al., 2016) and memory (Thanapreedawat et al., 2013). GABA enriched chocolate has a stress reducing effect (Nakamura et al., 2009). ...
... γ-Aminobutyric acid and GABA-rich foods can alleviate hypertension and depression in humans (Abdou et al., 2006;Ko et al., 2013;Ng'ong'ola-Manani et al., 2014;Wu and Shah, 2017). Previous studies also showed that GABA can improve the quality of sleep and could serve as a treatment for epilepsy (Cossart et al., 2005;Yamatsu et al., 2016). In addition, GABA can be used as an antidiabetic agent to control blood glucose levels (Ligon et al., 2007;Soltani et al., 2011;Tian et al., 2011;Chen et al., 2016). ...
Article
Yogurt, a functional dairy food product, is an effective medium for delivering beneficial functional ingredients. One ingredient, γ-aminobutyric acid (GABA), has growing appeal in the development of functional foods for its potential in reducing the risk of diabetes, hypertension, and stress as a bioactive agent. However, the concentration of GABA in existing food products is remarkably low. We developed a functional yogurt rich in GABA using Streptococcus thermophilus fmb5. The GABA yield of yogurt was enhanced by optimization of culture conditions using single factor and response surface methods. The results showed that culture temperature, monosodium glutamate concentration, and culture time are the 3 main factors that affect GABA yield. The optimal culture conditions were determined as follows: 38.8°C for culture temperature, 20 g/L of monosodium glutamate, and 120 h of culture time. Under the above optimal conditions, the actual yield of GABA production was maximized at 9.66 g/L, which was 1.2 times or higher than that of from any single factor treatment. The GABA concentration, viable bacteria number, and water-holding capacity of GABA-rich yogurt were stable throughout the whole storage time. The results show that producing yogurt with Streptococcus thermophilus fmb5 and the optimized culture conditions will achieve high GABA concentrations that maximize health benefits to consumers.
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Gamma-aminobutyric acid (GABA), a non-protein amino acid, possesses various health benefits and plays a signaling and defensive role in plants. Due to the low content of GABA in plant foods, scientists have made great efforts to enrich GABA in foods using various chemical, physical, and biological methods, including anaerobic treatment, cold, salt treatment, germination, microbial fermentation, crossbreeding, and innovative technologies such as ultrasound, ultraviolet, high pressure, etc. To effectively increase GABA in different foods, it is crucial to understand the underlying mechanisms and the virtues and limitations of different enrichment methods that are suitable for different foods. In this paper, we aimed to comprehensively review the recent progress on both conventional and innovative enrichment methods, the advantages and disadvantages, the associated mechanisms, and the applicable foods of these methods. We also summarized the functions of GABA in plants and microorganisms, the factors influencing GABA enrichment, the patents related to GABA enrichment, and the functional foods rich in GABA. The mechanisms of GABA enrichment mainly include modification of cell microstructure; influencing H⁺ and Ca²⁺ concentration and enzyme configuration, thereby activating glutamate decarboxylase; and regulation of gene and protein expression of enzymes involved in GABA biosynthesis and metabolism. This review will provide significant information on the production of GABA-enriched foods.
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The use of areca nuts (areca) in the form of betel quids constitutes the fourth most common addiction in the world, associated with high risk for oral disease and cancer. Areca is a complex natural product, making it difficult to identify specific components associated with the addictive and carcinogenic properties. It is commonly believed that the muscarinic agonist arecoline is at the core of the addiction. However, muscarinic receptor activation is not generally believed to support drug-taking behaviour. Subjective accounts of areca use include descriptions of both sedative and stimulatory effects, consistent with the presence of multiple psychoactive agents. We have previously reported partial agonism of α4-containing nicotinic acetylcholine receptors by arecoline and subsequent inhibition of those receptors by whole areca broth. In the present study, we report the inhibition of nicotinic acetylcholine receptors and other types of neurotransmitter receptors with compounds of high molecular weight in areca and the ability of low molecular weight areca extract to activate GABA and glutamate receptors. We confirm the presence of a high concentration of GABA and glutamate in areca. Additionally, data also indicate the presence of a dopamine and serotonin transporter blocking activity in areca that could account for the reported stimulant and antidepressant activity. Our data suggest that toxic elements of high molecular weight may contribute to the oral health liability of betel quid use, while two distinct low molecular weight components may provide elements of reward, and the nicotinic activity of arecoline contributes to the physical dependence of addiction.
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At present, the problem of the impact of dietary characteristics on the quality of human sleep is most acute, since it is necessary to have a sufficient level of wakefulness, which is provided by a full-length sleep, for harmonious interaction with the outside world in an urbanized society. Also, the quality of sleep is important factor too, because if the sleep is fragmented, then no matter how long it is - it will not give enough energy. For the quality of sleep, an important role is played not only by the sleep hygiene that a person adheres to, but also by the characteristics of the diet, which can affect the representation of certain phases and stages of sleep. The purpose of this review is to discuss the data of the most significant studies of the influence of dietary supplements on the quality and duration of sleep.
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Research and development of functional food materials and functional foods with the goal of "contributing to the maintenance and improvement of people’s health through food" were conducted. Phosphoryl oligosaccharides of calcium (POsCa), highly branched cyclic dextrin (HBCD), and α-glucosylhesperidin (Hsp-G) were synthesized using enzymes, and POsCa was utilized for caries prevention, HBCD increased endurance performance, and Hsp-G improved poor blood circulation, which could be put into practical use. Subsequently, based on the knowledge and experience gained from these studies, the research was expanded. In oral hygiene, we have developed biscuits for the elderly that are easy to chew and swallow, and tablets that suppress halitosis by removing tongue coating using protease. Research on glycemic control derived from endurance performance studies has led to the development of rice crackers for diabetics and the research on persimmon polyphenols found they suppress postprandial blood glucose. The knowledge of autonomic nerves gained in research on blood circulation led to the development of stress-reducing chocolate using GABA and the search for ornithine that promotes sleep. In addition, a study on the post-growth health of offspring born from undernourished mother based on the DOHaD theory found that cross-generational nutrition was very important.
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Insomnia can be a serious problem diminishing quality of life for Veterans and military populations with and without posttraumatic stress disorder (PTSD). Sleep disturbances are one of the symptoms of PTSD but even after evidence-based PTSD treatments, insomnia symptoms often remain. The primary approaches for treating insomnia are cognitive behavioral therapy for insomnia (CBT-I) and pharmacotherapy. However, each of these treatments has drawbacks. Complementary and Integrative Health (CIH) approaches such as mindfulness meditation, mantram meditation, yoga, and tai chi may provide alternative treatments for insomnia in military populations. This paper provides a brief review of studies on CIH interventions for sleep disturbances in Veterans. It also proposes possible mechanisms by which CIH practices may be effective, including increasing hippocampal volume and gamma-aminobutyric acid acid (GABA). Finally, the acceptability of CIH approaches among Veterans is discussed.
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Increased oxidative stress and inflammation cause abnormal sleep regulation. Sulforaphane, which is derived from glucoraphanin, has antioxidant and anti-inflammatory effects; however, its effects on sleep are unknown. Therefore, a randomized, double-blind, parallel-group, placebo-controlled study was conducted to explore the effects of sulforaphane on sleep quality. Eighteen healthy adults who reported poor sleep quality consumed broccoli sprout capsules (30 mg glucoraphanin) or placebo capsules for 4 weeks. The visual analogue scale questionnaire on sleep quality (4.8 ± 1.6 vs. 6.4 ± 1.9) and area under the curve of melatonin concentration (109.7 ± 80.0 pg/mL・h vs. 143.5 ± 79.9 pg/mL・h) were significantly increased and prostaglandin D2 levels at 21:00 (44.2 ± 24.6 pg/mL vs. 20.2 ± 15.5 pg/mL) were significantly decreased in the sulforaphane group, although there were no significant differences between the groups. These suggest that sulforaphane may improve sleep quality by increasing melatonin and anti-inflammatory activity.
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The direct neurotropic and neurotoxic effect of the SARS-CoV-2 virus on the central nervous system, as well as the stressful effect of various factors of the COVID-19 pandemic, contribute to the development of the so-called post-COVID syndrome. The clinical picture of the syndrome includes asthenic, anxiety-asthenic, and depressive manifestations. When prescribing psychopharmacotherapy to patients who have undergone COVID-19, it is recommended to assess the potential benefits and risks in the aspect of using drugs not only with therapeutic antiasthenic and anxiolytic properties, but with minimally expressed undesirable effects and adverse drug interactions.
Chapter
GABA is a novel potent bioactive amino acid, non-proteinaceous in nature and comprising of four carbon units. Its role as an inhibitory neurotransmitter of the neuronal cortex is well known and it had proven its effects on central nervous system. Recent studies reveal that this neurotransmitter is also able to act as a hypotensive agent, anti-diabetic and as tranquilizer. Besides this, GABA is also a bioactive compound of food, pharmaceutical, and feed industries. It is present in beans, pulses, milk, green, black, and oolong tea, as well as in fermented foods including kefir, yogurt, and tempeh and other dairy products. It is normally synthesized in the plant from Glutamate and nowadays various advanced strategies are being used for enhanced production of GABA. The reason for this may be accounted for use of GABA as a supplement to treat high blood pressure, stress, and anxiety, and sleep, as well as to stimulate the body's natural growth hormone, often by athletes. This chapter would focus on the production of GABA, its effects on humans as neurotransmitter along with the physiological effects being studied recently. The chapter will also cover various types of food containing GABA and later it deals with the strategies being adopted for large scale production of GABA.
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Gamma aminobutyric acid (GABA) is known as an important inhibitory neurotransmitter in the human brain. Recent studies have proved the beneficial effects of GABA on human health. It has been reported that in people who use GABA supplements, the factors affecting the life quality negatively such as psychological problems, insomnia and immune problems have decreased. Studies in this field have shown that lactic acid bacteria (LAB) can produce GABA. For this reason, interest in LAB producing GABA is steadily increasing. It is stated that GABA produced by natural LAB has almost no side effects compared to synthetically created ones. It is also suggested that GABA-producing LAB, which is isolated from especially in Far East countries foods, should be used to develop functional foods. More research needs to be done in order to proceed in this newly developing area, and the undiscovered features of GABA need to be investigated. In this review, the importance of GABA is addressed and the studies about GABA are examined.
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Gamma aminobutyric acid (GABA) is known as an important inhibitory neurotransmitter in the human brain. Recent studies have proved the beneficial effects of GABA on human health. It has been reported that in people who use GABA supplements, the factors affecting the life quality negatively such as psychological problems, insomnia and immune problems have decreased. Studies in this field have shown that lactic acid bacteria (LAB) can produce GABA. For this reason, interest in LAB producing GABA is steadily increasing. It is stated that GABA produced by natural LAB has almost no side effects compared to synthetically created ones. It is also suggested that GABA-producing LAB, which is isolated from especially in Far East countries foods, should be used to develop functional foods. More research needs to be done in order to proceed in this newly developing area, and the undiscovered features of GABA need to be investigated. In this review, the importance of GABA is addressed and the studies about GABA are examined.
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To explore the optimum condition of γ -aminobutyric acid (GABA) accumulation in germinated tartary buckwheat, effects of some factors including aeration treatment, physiological indexes, air flow rate, culture temperature, and pH value of cultivating solution under hypoxia on GABA in germinated tartary buckwheat were investigated. The results showed that the dark cultures with distilled water at 30°C, 2 days, and aeration stress with 1.0 L/min air flow rate at 30°C were optimal for GABA accumulation. Under these conditions, the predicted content of GABA was up to 371.98 μ g/g DW. The analysis of correlation indicated that there was a significant correlation ( P < 0.01 ) between GABA accumulation and physiological indexes. Box-Behnken experimental analysis revealed that optimal conditions with aeration treatment for GABA accumulation in germinated tartary buckwheat were air flow rate of 1.04 L/min, culture temperature of 31.25°C, and a pH value of 4.21. Under these conditions, the GABA content was predicted as high as 386.20 μ g/g DW, which was close to the measured value ( 379 . 00 ± 9.30 μ g/g DW). The variance analysis and validation test suggested that this established regression model could predict GABA accumulation in tartary buckwheat during germination.
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Objectives. (1) To assess sleep patterns and parameters of sleep quality among Chilean college students and (2) to evaluate the extent to which stimulant beverage use and other lifestyle characteristics are associated with poor sleep quality. Methods. A cross-sectional study was conducted among college students in Patagonia, Chile. Students were asked to complete a self-administered questionnaire to provide information about lifestyle and demographic characteristics. The Pittsburgh Sleep Quality Index (PSQI) was used to evaluate sleep quality. In addition, students underwent a physical examination to collect anthropometric measurements. Results. More than half of students (51.8%) exhibited poor sleep quality. Approximately 45% of study participants reported sleeping six hours or less per night and 9.8% used medications for sleep. In multivariate analysis, current smokers had significantly greater daytime dysfunction due to sleepiness and were more likely to use sleep medicines. Students who reported consumption of any stimulant beverage were 1.81 times as likely to have poor sleep quality compared with those who did not consume stimulant beverages (OR:1.81, 95% CI:1.21-2.00). Conclusions. Poor sleep quality is prevalent among Chilean college students, and stimulant beverage consumption was associated with the increased odds of poor sleep quality in this sample.
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Background Sleep is an important physiological process for humans. University students in most resource limited countries often report poor sleep quality due to changing social opportunities and increasing academic demands. However, sleep quality among university students has not been studied in Ethiopia. Thus, this study assessed sleep quality and its demographic and psychological correlates among university students. Methods A cross-sectional survey was conducted in two universities in Ethiopia. Multistage sampling procedures were used to enroll 2,817 students into the study. A self-administered structured questionnaire including the Pittsburgh Sleep Quality Index (PSQI), the Depression Anxiety Stress Scale-21, the Perceived Stress Scale (PSS) and selected modules of the World Health Organization STEPS instrument was used for the study. This research included 2,551 students. Frequency, median, mean with standard deviation and 95% confidence interval were used to characterize sleep quality and other variables. Analysis of variance and binary logistic regression procedures were also used. Result The prevalence of poor sleep quality (total PSQI score > 5) was 55.8% (1,424). Female students (adjusted odds ratio (AOR) 1.23; 95% CI: 1.00, 1.57), second year (AOR 2.91; 95% CI: 2.1, 4.02) and third year students (AOR 2.25; 95% CI 1.62, 3.12) had statistically significant higher odds of poor sleep quality. Perceived stress level and symptoms of depression and anxiety were strongly associated with sleep quality. Conclusion A substantial proportion of university students are affected by poor sleep quality. If our results are confirmed in prospective studies, health promotion and educational programs for students should emphasize the importance of sleep and mental health.
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γ-Aminobutyric acid (GABA) is a kind of amino acid contained in green tea leaves and other foods. Several reports have shown that GABA might affect brain protein synthesis, improve many brain functions such as memory and study capability, lower the blood pressure of spontaneously hypertensive rats, and may also have a relaxation effect in humans. However, the evidence for its mood-improving function is still not sufficient. In this study, we investigated how the oral intake of GABA influences human adults psychologically and physiologically under a condition of mental stress. Sixty-three adults (28 males, 35 females) participated in a randomized, single blind, placebo-controlled, crossover-designed study over two experiment days. Capsules containing 100 mg of GABA or dextrin as a placebo were used as test samples. The results showed that EEG activities including alpha band and beta band brain waves decreased depending on the mental stress task loads, and the condition of 30 min after GABA intake diminished this decrease compared with the placebo condition. That is to say, GABA might have alleviated the stress induced by the mental tasks. This effect also corresponded with the results of the POMS scores.
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A reduction in core temperature and an increase in the distal-proximal skin gradient (DPG) are reported to be associated with shorter sleep onset latencies (SOL) and better sleep quality. Ramelteon is a melatonin MT-1/MT-2 agonist approved for the treatment of insomnia. At night, ramelteon has been reported to shorten SOL. In the present study we tested the hypothesis that ramelteon would reduce core temperature, increase the DPG, as well as shorten SOL, reduce wakefulness after sleep onset (WASO), and increase total sleep time (TST) during a daytime sleep opportunity. Randomized, double-blind, placebo-controlled, cross-over design. Eight mg ramelteon or placebo was administered 2 h prior to a 4-h daytime sleep opportunity. Sleep and chronobiology laboratory. Fourteen healthy adults (5 females), aged (23.2 +/- 4.2 y). Primary outcome measures included core body temperature, the DPG and sleep physiology (minutes of total sleep time [TST], wake after sleep onset [WASO], and SOL). We also assessed as secondary outcomes, proximal and distal skin temperatures, sleep staging and subjective TST. Repeated measures ANOVA revealed ramelteon significantly reduced core temperature and increased the DPG (both P < 0.05). Furthermore, ramelteon reduced WASO and increased TST, and stages 1 and 2 sleep (all P < 0.05). The change in the DPG was negatively correlated with SOL in the ramelteon condition. Ramelteon improved daytime sleep, perhaps mechanistically in part by reducing core temperature and modulating skin temperature. These findings suggest that ramelteon may have promise for the treatment of insomnia associated with circadian misalignment due to circadian sleep disorders.
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The study examined the prevalence and correlates of insomnia in a representative sample (n=3030) from the general population of Japan. Using a structured questionnaire, we found that the overall prevalence of insomnia during the preceding month was 21.4%, including difficulty initiating sleep (DIS: 8.3%), difficulty maintaining sleep (DMS: 15.0%), and early morning awakening (EMA: 8.0%). Multiple logistic regression analysis showed that older age, being unemployed, lack of habitual exercise, poor perceived health, psychological stress, and being unable to cope with stress were associated with an increased prevalence of insomnia. These findings indicate that the prevalence of insomnia in the general population of Japan is comparable to that reported in Western countries, and that insomnia is associated with multiple psychosocial factors.
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The effect of orally administrated gamma-aminobutyric acid (GABA) on relaxation and immunity during stress has been investigated in humans. Two studies were conducted. The first evaluated the effect of GABA intake by 13 subjects on their brain waves. Electroencephalograms (EEG) were obtained after 3 tests on each volunteer as follows: intake only water, GABA, or L-theanine. After 60 minutes of administration, GABA significantly increases alpha waves and decreases beta waves compared to water or L-theanine. These findings denote that GABA not only induces relaxation but also reduces anxiety. The second study was conducted to see the role of relaxant and anxiolytic effects of GABA intake on immunity in stressed volunteers. Eight acrophobic subjects were divided into 2 groups (placebo and GABA). All subjects were crossing a suspended bridge as a stressful stimulus. Immunoglobulin A (IgA) levels in their saliva were monitored during bridge crossing. Placebo group showed marked decrease of their IgA levels, while GABA group showed significantly higher levels. In conclusion, GABA could work effectively as a natural relaxant and its effects could be seen within 1 hour of its administration to induce relaxation and diminish anxiety. Moreover, GABA administration could enhance immunity under stress conditions.
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We investigated the effects of γ-aminobutyric acid (GABA) on the stress, sleep, and urination of elderly people. Thirty-eight elderly people were given chocolates with 100 mg of GABA or placebo chocolates for four weeks. Salivary cortisol levels were measured as a stress indicator and a questionnaire survey about sleep and quality of life (QOL) was conducted. The GABA group showed only a small rise of cortisol level after 2 and 4 weeks, on the contrary, the placebo group showed significant increase of cortisol. The questionnaire survey showed that there was an improvement in the quality of sleep from the point of view of onset and maintenance of sleep, drowsiness in the morning, and recovering from fatigue in the GABA group after 4 weeks. Furthermore, the frequency of night urination significantly decreased in the GABA group. From the observation, we confirmed that GABA has an effect of easing stress, improving quality of sleep, and decreasing frequency of night urination.
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To treat sleep bruxism (SB), symptomatic therapy using stabilisation splints (SS) is frequently used. However, their effects on psychological stress and sleep quality have not yet been examined fully. The objective of this study was to clarify the effects of SS use on psychological stress and sleep quality. The subjects (11 men, 12 women) were healthy volunteers. A crossover design was used. Sleep measurements were performed for three consecutive days or longer without (baseline) or with an SS or palatal splint (PS), and data for the final day were evaluated. We measured masseter muscle activity during sleep using portable electromyography to evaluate SB. Furthermore, to compare psychological stress before and after sleep, assessments were made based on STAI-JYZ and the measurement of salivary chromogranin A. To compare each parameter among the three groups (baseline, SS and PS), Friedman's and Dunn's tests were used. From the results of the baseline measurements, eight subjects were identified as high group and 15 as low group. Among the high group, a marked decrease in the number of bruxism events per hour and an increase in the difference in the total STAI Y-1 scores were observed in the SS group compared with those at baseline (P < 0·05). No significant difference was observed in sleep stages. SS use may be effective in reducing the number of SB events, while it may increase psychological stress levels, and SS use did not apparently influence sleep stages.
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We studied the psychological stress-reducing effect of chocolate enriched with gamma-aminobutyric acid (GABA), on stress induced by an arithmetic task using changes of heart rate variability (HRV) and salivary chromogranin A (CgA). Subjects ingested 10 g chocolate enriched with 28 mg GABA (GABA chocolate); 15 min after the ingestion, subjects were assigned an arithmetic task for 15 min. After the task, an electrocardiogram was recorded and saliva samples were collected. HRV was determined from the electrocardiogram, and the activity of the autonomic nervous system was estimated through HRV. The CgA concentration of all saliva samples, an index for acute psychological stress, was measured. From HRV, those taking GABA chocolate made a quick recovery to the normal state from the stressful state. The CgA value after the task in those taking GABA chocolate did not increased in comparison with that before ingestion. From these results, GABA chocolate was considered to have a psychological stress-reducing effect.
Article
Despite the prevalence of sleep complaints among psychiatric patients, few questionnaires have been specifically designed to measure sleep quality in clinical populations. The Pittsburgh Sleep Quality Index (PSQI) is a self-rated questionnaire which assesses sleep quality and disturbances over a 1-month time interval. Nineteen individual items generate seven "component" scores: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medication, and daytime dysfunction. The sum of scores for these seven components yields one global score. Clinical and clinimetric properties of the PSQI were assessed over an 18-month period with "good" sleepers (healthy subjects, n = 52) and "poor" sleepers (depressed patients, n = 54; sleep-disorder patients, n = 62). Acceptable measures of internal homogeneity, consistency (test-retest reliability), and validity were obtained. A global PSQI score greater than 5 yielded a diagnostic sensitivity of 89.6% and specificity of 86.5% (kappa = 0.75, p less than 0.001) in distinguishing good and poor sleepers. The clinimetric and clinical properties of the PSQI suggest its utility both in psychiatric clinical practice and research activities.
Article
Plasma levels of gamma-aminobutyric acid (GABA) appear to be altered in affective disorders and alcoholism. Plasma levels of GABA were not affected by menstrual cycle, exercise, gender, gut flora, nor by cholinergic stimulation by bethanechol. An obvious peripheral source for plasma GABA could not be demonstrated.
Article
1 The onset and duration of action of benzodiazepines after single oral doses depend largely on absorption rate and extent of distribution, respectively. 2 The rate and extent of accumulation during multiple dosage depend on elimination half-life and clearance. A framework is proposed for classification of benzodiazepines according to elimination half-life. 3 Long-acting benzodiazepines have half-life values usually exceeding 24 hours. Drugs in this category have long-acting pharmacologically active metabolites (often desmethyldiazepam), accumulate extensively during multiple dosage, and may have impaired clearance in the elderly and those with liver disease. 4 Intermediate and short-acting benzodiazepines have half-life values from 5-24 hours. Active metabolites are uncommon. Accumulation during multiple dosage is less extensive than with the long-acting group, and diminishes as the half-life becomes shorter. Age and liver disease have a small influence on metabolic clearance. 5 The half-life of ultrashort acting benzodiazepines is less than 5 hours. These drugs are essentially non-accumulating. 6 Pharmacokinetic classification may assist in understanding of differences among benzodiazepines, but does not explain all of their clinical actions.
Article
1 Twelve volunteers, of mean age 60 years, took part in a double-blind, balanced cross-over study, to compare effects of chlormezanone 400 mg and nitrazepam 5 mg on electrophysiologically-recorded and subjectively-rated sleep. 2 In the first week of administration nitrazepam caused a significant shortening of the time to fall asleep, but following withdrawal subjects took longer to fall asleep than during the baseline period. 3 Both chlormezanone and nitrazepam initially caused increase of sleep duration and less interruption of sleep by wakefulness. By the third week, for chlormezanone this effect was no longer significant, and for nitrazepam there was a significant decline in the effect. There was no statistically significant difference between the two drugs for these measures. 4 The drugs differed little in their effects on the amount of the various sleep stages, except that nitrazepam significantly reduced the duration of slow wave sleep, whereas chlormezanone had no significant effect on slow wave sleep. Both drugs reduced the amount of REM sleep in the first 6 h of sleep but only nitrazepam reduced the percentage of the time spent in REM sleep of the whole night. 5 Subjects' own ratings of sleep quality showed that both of the drugs improved sleep, but following withdrawal it was only after nitrazepam that there was impairment of the quality of sleep. Neither drug affected subjective alertness in the morning.
Article
Plasma gamma-aminobutyric acid (GABA) levels are decreased in some patients with depression, mania and alcoholism. Medications which increase plasma GABA improve symptoms of mood disorders and can decrease aggression. We examined the relationship between plasma GABA and aggressiveness on the Buss-Durkee Hostility Inventory in 77 psychiatrically healthy adults. In subjects selected for having a first-degree relative with primary unipolar depressive disorder (FH+, n=33), plasma GABA was negatively correlated with aggressiveness (beta=-0.338, P=0.036), as was age (beta=-0.483, P=0.005). A relationship between plasma GABA levels and aggressiveness was not observed in subjects with no such family history (FH-, n=44). Moreover, FH+ subjects had significantly lower plasma GABA concentrations than FH- subjects. These data suggest that low GABA levels may correlate with some aspects of aggressiveness and may be genetically regulated.
Article
Losses of gamma-aminobutyric acid (GABA) have been variably demonstrated in Alzheimer's disease (AD) and may be related to the presence of behavioral and psychological symptoms of dementia (BPSD) in AD. Our objective was to assess the relationship between plasma GABA (pGABA) levels and specific BPSD in patients with severe AD. pGABA levels and BPSD were measured in 14 institutionalized AD patients (8M/6F, mean age +/- S.D. = 85.6 +/- 4.5 years) with severe cognitive impairment (Mini-mental State Examination score = 4.5 +/- 4.6) and prominent behavioral disturbances (Neuropsychiatric Inventory (NPI) score = 33.4 +/- 23.6). pGABA was positively correlated with depression and apathy scores on the NPI and negatively correlated with age. Apathy and age were independent predictors of pGABA levels. The final stages of AD are associated with GABAergic changes, which may contribute to depression and apathy in AD.
Behavioral correlates of GABAergic disruption in Alzheimer’s disease
  • K L Lanctot
  • N Herrmann
  • L Rothernburg
  • G Eryavec
  • KL Lanctot
Lanctot KL, Herrmann N, Rothernburg L, Eryavec G. Behavioral correlates of GABAergic disruption in Alzheimer's disease. Int. Psychogeriatr. 19: 151-158 (2007)