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Citation: Almutairi, S.; Sivadas, A.;
Kwakowsky, A. The Effect of Oral
GABA on the Nervous System:
Potential for Therapeutic Intervention.
Nutraceuticals 2024,4, 241–259.
https://doi.org/10.3390/
nutraceuticals4020015
Academic Editors: Daniel Linseman
and Herbert Ryan Marini
Received: 15 February 2024
Revised: 5 April 2024
Accepted: 24 April 2024
Published: 6 May 2024
Copyright: © 2024 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
Review
The Effect of Oral GABA on the Nervous System: Potential for
Therapeutic Intervention
Shahad Almutairi, Amaya Sivadas and Andrea Kwakowsky *
Pharmacology and Therapeutics, School of Medicine, Galway Neuroscience Centre,
Ollscoil na Gaillimhe—University of Galway, H91 W5P7 Galway, Ireland;
s.almutairi1@universityofgalway.ie (S.A.); a.sivadas1@universityofgalway.ie (A.S.)
*Correspondence: andrea.kwakowsky@universityofgalway.ie; Tel.: +353-09149-3012
Abstract: Gamma-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the central
nervous system (CNS), plays a pivotal role in maintaining the delicate balance between inhibitory
and excitatory neurotransmission. Dysregulation of the excitatory/inhibitory balance is implicated
in various neurological and psychiatric disorders, emphasizing the critical role of GABA in disease-
free brain function. The review examines the intricate interplay between the gut–brain axis and
CNS function. The potential impact of dietary GABA on the brain, either by traversing the blood–
brain barrier (BBB) or indirectly through the gut–brain axis, is explored. While traditional beliefs
questioned GABA’s ability to cross the BBB, recent research challenges this notion, proposing specific
transporter systems facilitating GABA passage. Animal studies provide some evidence that small
amounts of GABA can cross the BBB but there is a lack of human data to support the role of
transporter-mediated GABA entry into the brain. This review also explores GABA-containing food
supplements, investigating their impact on brain activity and functions. The potential benefits
of GABA supplementation on pain management and sleep quality are highlighted, supported by
alterations in electroencephalography (EEG) brain responses following oral GABA intake. The
comprehensive overview encompasses GABA’s sources in the diet, including brown rice, soy, adzuki
beans, and fermented foods. GABA’s presence in various foods and supplements, its association with
gut microbiota, and its potential as a therapeutic strategy for neurological disorders are thoroughly
examined. The articles were retrieved through a systematic review of the databases: OVID, SCOPUS,
and PubMed (keywords “GABA”, “oral GABA“, “sleep”, “cognition”, “neurodegenerative”, “blood-
brain barrier”, “gut microbiota”, “supplements” and “therapeutic”, and by searching reference
sections from identified studies and review articles). This review presents the relevant literature
available on the topic and discusses the mechanisms, effects, and hypotheses that suggest oral GABA
benefits range from neuroprotection to blood pressure control. The literature suggests that oral intake
of GABA affects the brain illustrated by changes in EEG scans and cognitive performance, with
evidence showing that GABA can have beneficial effects for multiple age groups and conditions. The
potential clinical and research implications of utilizing GABA supplementation are vast, spanning
a spectrum of diseases ranging from neurodegeneration to blood pressure regulation. Importantly,
recommendations for the use of oral GABA should consider the dosage, formulation, and duration of
treatment as well as potential side effects. Effects of GABA need to be more thoroughly investigated
in robust clinical trials to validate efficacy to progress the development of alternative treatments for a
variety of disorders.
Keywords: GABA; oral GABA; gut microbiota; neurodegenerative; cognition; blood–brain barrier;
supplements; therapeutic
1. Introduction
Gamma-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter. With
widespread distribution and abundant presence in the brain and spinal cord, GABA plays
Nutraceuticals 2024,4, 241–259. https://doi.org/10.3390/nutraceuticals4020015 https://www.mdpi.com/journal/nutraceuticals
Nutraceuticals 2024,4242
a pivotal role in mediating and modulating a diverse array of central nervous system (CNS)
functions [
1
,
2
]. In the mature brain, GABA and glutamate are balanced, exerting inhibitory
and excitatory effects, respectively, and this homeostasis is vital in disease-free brain
function [
3
,
4
]. Substantiating this crucial role, a wealth of evidence points to the diverse
pharmacological effects exhibited by GABA receptor agonists and antagonists, ranging from
anxiolysis and hypnosis to muscle relaxation, amnesia, cognitive enhancement, stimulant,
and anticonvulsant activities [5].
The GABAergic system operates through two key receptors in the CNS, namely
GABAA and GABAB receptors, each contributing to synaptic inhibition. GABAA receptors
are heteropentamers, comprising more than 20 subunits [
4
–
6
]. As chloride ion channels,
these receptors are distributed throughout the CNS. In contrast, GABAB receptors utilize
G-protein-coupled mechanisms, primarily belonging to the pertussis toxin-sensitive Gi/o
family, which regulates specific ion channels and cAMP cascades. GABAB receptors
mediate slow synaptic inhibition and are critical regulators of neuronal excitability. The
varied subunit compositions of the receptor subtypes contribute to the functional versatility
of the GABAergic system, enabling fine modulation of neuronal activity [6].
GABA is synthesized through the conversion of glutamate via the action of glutamate
decarboxylase and vitamin B6. Synthesized GABA is released onto the post-synaptic ter-
minals of neurons. Despite glutamate being the precursor for GABA, in the CNS it is an
excitatory neurotransmitter, and GABA functions as an inhibitory neurotransmitter. Dys-
regulation of the glutamate–GABA balance, or the excitatory/inhibitory (E/I) balance, has
been implicated in various pathologies, including psychiatric disorders such as generalized
anxiety, schizophrenia, autism spectrum disorder, major depressive disorder, Alzheimer ’s
disease, and other dementias [4,7,8].
Decades of research bring the gut–brain axis to the forefront, an intricate and bidirec-
tional communication system integrating peripheral intestinal function with emotional and
cognitive brain centers through neuro-immuno-endocrine mediators (Figure 1). Within
this context, gut microbiota has been associated with various CNS disorders, including
dementia [
9
]. Dysbiosis of gut microbiota has been linked to the secretion of amyloid and
lipopolysaccharides (LPS), disrupting gastrointestinal permeability and the blood–brain
barrier (BBB). This disruption sets in motion inflammatory signaling pathways, leading
to neuroinflammation, neuronal injury, and ultimately neuronal death [
9
,
10
]. The gut
microbiota is a source of GABA present in the gut, but oral GABA intake needs to be
considered as well. It is vital to investigate how GABA present in the gut may affect the
brain and whether it has a direct effect by crossing the BBB or works indirectly by acting on
the enteric nervous system (ENS) or the vagus nerve [11].
Exploring the impact of dietary GABA on the brain via gut interactions and its potential
to influence the BBB directly or indirectly raises questions about the underlying mechanisms.
Nonetheless, the extent to which GABA can effectively traverse the BBB remains a subject
of ongoing debate. In a study involving rat brain grafts, fetal neocortex, or substantia
nigra was transplanted into a young adult rat cortex or striatum. This allowed examine
how the BBB lets [3H] GABA pass. Initially, [3H] GABA could cross the BBB and enter
transplanted areas, particularly the neocortex, for up to 4 weeks. In substantia nigra grafts,
the BBB became better at stopping GABA passage after 4 weeks. This suggests that the BBB
gradually forms and restricts GABA movement. In the early stages, GABA was taken up
by neurons or glia in the grafts. Ultimately, the BBB’s barrier to GABA was established
beyond four weeks. This study highlights how the BBB evolves and controls GABA access
to the brain [
12
]. On the other hand, another study conducted on rats tested the BBB’s
permeability to GABA following intraperitoneal injection and intraperitoneal GABA plus
L-Arginine (L-Arg) administration. GABA and L-Arg injected together showed a fourfold
increase in brain GABA level (383.3%) compared to untreated rats. Intraperitoneal GABA
alone showed an increased brain GABA concentration of 33%, while L-Arg alone increased
GABA concentration by 65%, compared to untreated rats. The study also observed dose-
dependent nitric oxide (NO) production in the brain when rats were injected with L-Arg,
Nutraceuticals 2024,4243
and the peak concentration of NO production was observed at 2000 mg of L-Arg. This
suggests that high NO concentrations in the brain following L-Arg administration may
increase the permeability of the BBB to peripheral GABA due to NO’s role in vasodilation.
The authors conclude that NO contributes to increased BBB permeability to GABA [
13
].
Nevertheless, while traditional beliefs suggest that GABA may not traverse the BBB, recent
research challenges this notion. Some studies propose that GABA can indeed cross the BBB
facilitated by specific GABA-transporter systems in the brain [
13
,
14
]. These pathways could
offer a means for oral absorption of GABA and its analogs. However, while these animal
studies provide some evidence that small amounts of GABA can cross the BBB there is a
lack of human data to support the role of transporter-mediated GABA entry into the brain.
Moreover, oral administration of GABA might influence the brain via the gut–brain axis
(Figure 1). Notably, studies have shown alterations in electroencephalography (EEG) brain
responses following oral GABA intake in comparison to controls like water/L-theanine
or dextrin placebo [
15
]. However, it is important to note that the mechanism by which
oral GABA affects the brain is unclear and further research needs to be performed to
provide clarity. It is crucial to consider that experiments testing GABA’s ability to cross
the BBB employed different methodologies; this is likely one reason for the difference in
outcomes and the conflicting viewpoints. Also important to factor in possible species-
specific differences in GABA transport mechanisms and the age and disease model used in
these studies. GABA transport seems to be limited under normal physiological conditions
in the adult brain [
16
–
22
] but can increase during development [
12
,
14
] and transport can
be altered in disease conditions [19].
Nutraceuticals 2024, 4, FOR PEER REVIEW 3
Figure 1. A schematic diagram showing the proposed mechanisms contributing to the functioning
of the gut–brain axis. The mechanisms involve bidirectional communication between the gastroin-
testinal (GI) tract and the central nervous system (CNS), integrating neural pathways, immune path-
ways, as well as the endocrine pathway, and the involvement of the enteric (ENS) and autonomic
nervous (ANS) systems, including the vagus nerve. This intricate network relies on a dynamic in-
terplay of signals between gut microbiota, intestinal epithelial cells, and various components of the
nervous and immune systems. The gut–brain axis facilitates this communication and dietary GABA
might help to maintain this. Importantly, the gut microbiota, comprising trillions of microorgan-
isms, also influences this axis by producing GABA, other metabolites, and bioactive compounds.
Created in BioRender.com (hps://www.biorender.com, accessed on 5 April 2024).
Exploring the impact of dietary GABA on the brain via gut interactions and its po-
tential to influence the BBB directly or indirectly raises questions about the underlying
mechanisms. Nonetheless, the extent to which GABA can effectively traverse the BBB re-
mains a subject of ongoing debate. In a study involving rat brain grafts, fetal neocortex, or
substantia nigra was transplanted into a young adult rat cortex or striatum. This allowed
examine how the BBB lets [3H] GABA pass. Initially, [3H] GABA could cross the BBB and
enter transplanted areas, particularly the neocortex, for up to 4 weeks. In substantia nigra
grafts, the BBB became beer at stopping GABA passage after 4 weeks. This suggests that
the BBB gradually forms and restricts GABA movement. In the early stages, GABA was
taken up by neurons or glia in the grafts. Ultimately, the BBB’s barrier to GABA was es-
tablished beyond four weeks. This study highlights how the BBB evolves and controls
GABA access to the brain [12]. On the other hand, another study conducted on rats tested
the BBB’s permeability to GABA following intraperitoneal injection and intraperitoneal
GABA plus L-Arginine (L-Arg) administration. GABA and L-Arg injected together
showed a fourfold increase in brain GABA level (383.3%) compared to untreated rats. In-
traperitoneal GABA alone showed an increased brain GABA concentration of 33%, while
L-Arg alone increased GABA concentration by 65%, compared to untreated rats. The
study also observed dose-dependent nitric oxide (NO) production in the brain when rats
were injected with L-Arg, and the peak concentration of NO production was observed at
2000 mg of L-Arg. This suggests that high NO concentrations in the brain following L-Arg
administration may increase the permeability of the BBB to peripheral GABA due to NO’s
role in vasodilation. The authors conclude that NO contributes to increased BBB permea-
bility to GABA [13]. Nevertheless, while traditional beliefs suggest that GABA may not
traverse the BBB, recent research challenges this notion. Some studies propose that GABA
can indeed cross the BBB facilitated by specific GABA-transporter systems in the brain
[13,14]. These pathways could offer a means for oral absorption of GABA and its analogs.
However, while these animal studies provide some evidence that small amounts of GABA
can cross the BBB there is a lack of human data to support the role of transporter-mediated
Figure 1. A schematic diagram showing the proposed mechanisms contributing to the functioning of
the gut–brain axis. The mechanisms involve bidirectional communication between the gastrointestinal
(GI) tract and the central nervous system (CNS), integrating neural pathways, immune pathways, as
well as the endocrine pathway, and the involvement of the enteric (ENS) and autonomic nervous
(ANS) systems, including the vagus nerve. This intricate network relies on a dynamic interplay of
signals between gut microbiota, intestinal epithelial cells, and various components of the nervous
and immune systems. The gut–brain axis facilitates this communication and dietary GABA might
help to maintain this. Importantly, the gut microbiota, comprising trillions of microorganisms, also
influences this axis by producing GABA, other metabolites, and bioactive compounds. Created in
BioRender.com (https://www.biorender.com, accessed on 5 April 2024).
In Europe, GABA is utilized as an ingredient in food supplements. In 2009, the Euro-
pean Food Safety Authority (EFSA) Panel on Dietetic Products, Nutrition, and Allergies
assessed health claims regarding GABA’s impact on cognitive function. They concluded
that a definitive cause-and-effect relationship between GABA intake and the asserted cog-
nitive functions had not been firmly established [
23
]. In recent times, interest has surged in
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GABA-containing food supplements and their hypothetical impact on brain activity and
functions. A study found that consistent administration of GABA to rats and dogs, even
at doses up to 1 g/kg/day, did not exhibit any indications of toxicity [
24
]. Notably, some
research has linked GABA to reductions in blood pressure, implying a potential risk of
hypotension when used alongside antihypertensive drugs [
24
]. Oral GABA’s potential
to affect stress and sleep was examined through various studies. One of which indicated
an increased heart rate variability (HRV) and parasympathetic activity, suggesting stress
reduction [
25
]. Another study looked at GABA’s ability to affect brain wave patterns
and reported increasing alpha and decreasing beta waves suggesting relaxation [
26
]. In
addition, cortisol, and chromogranin A (CgA) level reduction in GABA consumers indi-
cates potential stress reduction, and reduced sleep latency. It is important to note that
evidence for GABA’s effect on improved sleep maintenance is limited [
27
]. Further research
is warranted to establish optimal doses of GABA and its long-term effects on stress and
sleep. GABA-enriched products as a potential food source to mitigate inflammatory re-
sponses were also proposed, offering practical applications in health and wellness. The
anti-inflammatory activity of GABA-enriched products derived from Lactobacillus fer-
mented rice bran solution exhibited inhibitory effects on the expression of inflammatory
enzymes, including inducible nitric oxide synthase and cyclooxygenase-2, and reduced
the generation of pro-inflammatory cytokines like interleukin (IL)-6, IL-1
β
, tumor necrosis
factor α, and monocyte chemoattractant protein-1 [28].
Dietary GABA encompasses foods like brown rice, soy and adzuki beans, chestnuts,
and mushrooms [
29
]. It can also be found in foods, such as tea, tomato, soybean, germi-
nated rice, and some fermented foods [
29
]. Additionally, some foods are GABA-enriched
such as cereals, sourdough breads, cheeses, and fermented sausages, which also contribute
to GABA intake [
30
,
31
]. GABA supplements, like rice bran and Sarcodon aspratus extracts,
offer additional GABA sources. As mentioned earlier, gut microbiota also plays a role in
gut GABA production and maintenance of normal gut GABA levels. Nutritional support of
the GABAergic system with GABA or GABA receptor ligands, food, and vitamins has been
suggested as treatment options for neurodevelopmental and aging-related disorders associ-
ated with GABAergic dysfunction [
32
–
34
]. Vitamin D deficiency is known to induce an E/I
imbalance and supplementation has been reported to recover impairments of the GABAer-
gic system [33,35]. These findings highlight the importance of diet in maintaining healthy
brain function and the opportunity for nutritional support to correct the E/I imbalance.
This review aims to provide a comprehensive overview of the effect of dietary GABA
and GABA supplements on the brain in both health and disease. We will explore the poten-
tial impact of GABA-containing food and GABA supplements on brain function, delving
into the proposed mechanisms of action. Additionally, we will address the intriguing
controversy surrounding GABA’s direct versus indirect influence on the brain through
the gut–brain axis. The understanding of the intricate interplay between dietary GABA,
gut microbiota, and CNS function holds great promise for unveiling novel therapeutic
strategies, including probiotic-based interventions, to address neurological disorders and
promote brain health. Through an in-depth exploration of these mechanisms, we aspire
to contribute to the advancement of the field and deepen our comprehension of GABA’s
multifaceted role in regulating brain function. Here we review articles that propose health
benefits to oral GABA in humans and animal models that can be linked to the involvement
of the nervous system.
2. The Effect of Dietary GABA on Sleep
In recent years, dietary GABA has garnered interest in sleep aids. Multiple studies
have explored its potential to enhance sleep quality and duration, shedding light on
promising approaches for better sleep. One study examined the effect of consuming
GABA-enriched rice in two groups (containing 16.8 mg GABA in a daily portion of 150 g
GABA rice vs. 4.1 mg GABA in 150 g white rice per day) of healthy middle-aged patients
with poor sleep. Participants were given the rice for 8 weeks. Enhanced sensations
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upon awakening were discovered in the GABA-enriched rice-consuming group during
both the fourth week and the tenth week of the study, in comparison to the white rice
group. However, no significant impact of GABA rice on the Visual Analog Scale (VAS)
sleepiness score was observed [
36
]. Another study using GABA-enriched rice documented
that among post-menopausal women, the ingestion of GABA rice containing 26.4 mg of
GABA three times daily resulted in the improvement of insomnia scores as assessed by
the Kupperman Menopause Index. This enhancement was notable during the fourth week
of the treatment period when compared to the control rice group [
37
]. These two studies
illustrated the positive outcome resulting from the consumption of GABA-enriched rice
among participants with poor sleep and insomnia.
Other studies took a different approach and looked at the effect biosynthetic rice
might have on sleep in disease-free elderly patients. GABA consumption improved the
maintenance and onset of sleep, and drowsiness in the morning. Recovery from fatigue
in the GABA group was seen after 4 weeks although the placebo group showed the same
result [
38
]. However, other studies illustrate the effectiveness of biosynthetic GABA.
One such investigation includes three intervention studies, conducted with notably small
sample sizes each spanning 1 to 3 weeks, delving into the impact of biosynthetic GABA
consumption on sleep quality among individuals experiencing suboptimal sleep. One
study enrolled participants scoring above 5 on the Pittsburgh Sleep Quality Index (PSQI)
and the other two involved individuals with PSQI scores exceeding 6. In the initial 1-week
intervention study, the ingestion of 100 mg GABA was delivered in the form of GABA
powder, contained in gelatin capsules. Each capsule contained 100 mg of GABA powder,
along with other components like glutamic acid, other amino acids, minerals, and water.
As opposed to a control GABA consumption led to an improvement in sensations upon
waking scores. Additionally, the results indicated a decrease in sleep onset latency and an
increase in the total duration of non-REM sleep stages (N1, N2, and N3/SWS) following the
intervention. The observed trends suggest enhancements in PSQI scores, sleep satisfaction,
and ease of falling asleep ratings, alongside the augmented duration of light non-REM sleep
and sleep efficiency within the GABA group compared to the control after the treatment
period [
37
]. This highlights GABA’s potential to positively influence sleep parameters,
making it a promising avenue for further research.
More evidence of oral GABA’s effect on sleep is exemplified in a week-long interven-
tion study focused on middle-aged individuals grappling with sleep disturbances. The
investigation unveiled a noticeable trend toward decreased sleep onset latency, specifi-
cally in the context of the 100 mg GABA capsule intake as compared to the control group.
However, when examining various parameters including PSQI total score, sleep satisfac-
tion, feelings upon awakening, ease of falling asleep ratings, along with measurements
of non-REM sleep latency, REM sleep duration, non-REM sleep duration, frequency of
awakenings, and delta wave power, no statistically significant differences emerged between
the GABA-only group and the control group [
39
]. Another study was conducted in 4 weeks
and focused on middle-aged individuals who reported struggling with poor sleep quality.
The study revealed that the intake of a 300 mg GABA tablet, as compared to a control tablet,
led to a reduction in sleep onset latency following the intervention. The researchers also
noted a decrease in N2 sleep duration as a percentage and a decline in the severity index of
insomnia (ISI). Furthermore, improvements were observed in various PSQI parameters,
including the total score, sleep quality, sleep latency, and total sleep time within the GABA
group when comparing pre-treatment and post-treatment scores. However, the study did
not state any notable differences between the GABA group and the placebo/control group.
Notably no statistically significant effects were found concerning PSQI sleep efficiency
scores, total sleep time, the percentages of stage 1 and 3 non-REM sleep, REM sleep percent-
age, wake after sleep onset (WASO) in minutes, REM sleep latency, sleep efficacy, arousal
index, apnea-hypopnea index (AHI), or respiratory distress index (RDI) [40].
Another study conducted on human subjects utilized sake yeast which has been
observed to take up GABA during the primary stage of sake brewing [
41
]. For the clinical
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trial, tablets were prepared, each containing 125 mg of sake yeast powder, approximately
equivalent to 75 mg of dry sake yeast. Participants were instructed to ingest four tablets per
day, with each tablet containing 125 mg of sake yeast powder. The tablets were taken
1 h
before bedtime, over a period of 4 days for each test condition. A placebo group was also
used for comparison. Sake yeast supplementation significantly augmented sleep quality,
evident in a robust 110% amplification of EEG delta power slow-wave sleep (SWS) is a phase
of deep sleep crucial for physical restoration and cognitive functions. The amplification
of EEG delta power in the context of sleep quality refers to an increase in the intensity or
magnitude of the brain’s electrical activity in the delta frequency range (
0.5–4 Hz
) during
the SWS stage. SWS is a phase of deep sleep crucial for physical restoration and cognitive
functions. Higher delta power indicates a greater predominance of slow-wave activity
during sleep, suggesting a deeper and more restorative quality of sleep. Moreover, the
subjective perception of sleep quality, especially in terms of ‘sleepiness upon waking’,
exhibited a notable enhancement, showcasing a significant difference compared to the
placebo (p= 0.02). These quantitative outcomes highlight the potential of sake yeast
supplementation to positively influence sleep patterns and the subjective perception of
sleep, ultimately fostering an improved overall sleep quality [42].
Other studies examined how GABA-rich foods such as Passiflora incarnata L. (Pas-
sionflower (PI)), which contains high levels of GABA, may influence behaviors and brain
function [
43
,
44
]. One study investigated the sleep-inducing effects of PI extract on ro-
dents; this included both mice and rats. The study used brain tissue samples from the
animals treated with the PI extract. They performed immunohistochemistry staining with
a c-Fos-specific antibody on the brain tissue samples of rodents and observed a notable
affected on brain activity, specifically the mammillary body region, as evidenced by in-
creased c-Fos-positive cells. Moreover, the extract influenced intracellular ROS levels
and upregulated GABA receptors and GAD1 mRNA expression, suggesting a potential
mechanism involving GABAergic signaling. Notably, the PI extract significantly increased
serum melatonin levels, a critical marker for potential sleep-inducing effects due to its
fundamental role in regulating the sleep-wake cycle, also known as the circadian rhythm.
Additionally, the extract led to prolonged immobility time and increased palpebral closing
time, further indicating its sedative or sleep-inducing properties. In conclusion, PI extract
demonstrates promising sleep-inducing effects in animal models suggesting its potential as
a natural alternative for managing sleep disorders [
44
]. Another study was conducted to
investigate the sleep-promoting effects of a mixture of GABA and 5-hydroxytryptophan
(5-HTP) specifically using ICR mice and Sprague-Dawley rats. The GABA/5-HTP mixture
was administered orally to the study subjects at specific doses, GABA at 60 mg/kg and
5-HTP at 6 mg/kg dissolved in 0.9% physiological saline. The drugs were given to the
subjects one hour before conducting the experiments related to sleep analysis using the
pentobarbital-induced sleep test. The administration of the GABA/5-HTP mixture signif-
icantly increased the sleep onset ratio by more than 65%. Additionally, in mice treated
with a hypnotic dose of pentobarbital (42 mg/kg), the GABA/5-HTP mixture significantly
reduced sleep latency and significantly prolonged the duration of sleep. These results high-
light the sleep-promoting potential of the GABA/5-HTP mixture, showcasing its ability to
enhance sleep onset and duration effectively in the study subjects [45].
This set of studies delved into exploring the potential of dietary GABA as a sleep aid,
encompassing both human and animal research. One study primarily targeted middle-aged
individuals grappling with poor sleep, comparing the consumption of GABA-enriched
rice to white rice. The results showed an improvement in awakening sensations for the
GABA group during specific weeks, although no significant changes in sleepiness scores
were observed. Another study involving post-menopausal women revealed that GABA
rice consumption led to better insomnia scores compared to a control group. The effects
of biosynthetic GABA on sleep were also investigated in elderly patients, showcasing
improved sleep maintenance and onset as well as increased morning alertness. However,
it is important to note that placebo effects were also evident in these cases. Differing
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results emerged from smaller studies focusing on biosynthetic GABA, some demonstrating
improved wakefulness scores and non-REM sleep stages, but not consistently across all
sleep parameters. Studies involving middle-aged individuals indicated trends toward
reduced sleep onset latency with GABA capsules, although not consistently significant
effects on various sleep metrics were observed.
In summary, the potential impact of dietary GABA on sleep quality appears promising,
showing potential benefits in terms of awakening sensations and specific aspects of sleep in
both human and animal studies. However, the results varied across studies and parameters,
possibly influenced by differences in the source and administration methods of GABA
and the specific groups (e.g., health status, age, sex, ethnicity) on which the studies were
conducted. Factors such as the short duration of the studies and variations in participant
numbers may have contributed to the diverse outcomes observed. Further research and
standardized methodologies are essential to better understand the potential of GABA as a
sleep aid.
3. Effects of Dietary GABA on Anxiety
A study on the oral effect of GABA in rats explored alterations in anxiety-related
behavior using stress models and behavioral tests. In the open field test, emotional stress led
to a notable 84% reduction in center time compared to controls. However, GABA at 1 mg/kg
and 2 mg/kg increased center time significantly (t =
−
3.384, p= 0.002 and
t = −5.256,
p< 0.001,
respectively). Notably, GABA at 2 mg/kg also increased the distance traveled
in the center (t =
−
3.342, p= 0.002). Locomotor and exploratory behaviors showed no
significant differences among groups. In the elevated plus maze test, stressed rats spent less
time in open arms, while GABA at 2 mg/kg markedly increased this duration (
t = −4.225,
p< 0.001
). Entries into open arms decreased in stressed rats but were improved by GABA
at
2 mg/kg
. Regarding blood composition, it was noted that plasma NO metabolites
nitrate and nitrite (NOx) levels were higher in stressed rats and the 0.5 mg/kg GABA
group compared to controls (t =
−
4.828, p< 0.001 and
t = −3.219
,p= 0.003, respectively).
However, GABA at 1 mg/kg and 2 mg/kg reduced plasma NOx levels significantly
(
t = 2.349, p= 0.025
and t = 3.219, p= 0.003). In the frontal cortex, NOx levels were lower
in stress-exposed rats (t = 2.300, p= 0.028), but GABA doses showed a dose-dependent
increase. Correlation analysis revealed grooming in the open field negatively correlated
with NOx levels (p< 0.01), as did open field movement time (p< 0.01). In the elevated plus
maze, the anxiety index negatively correlated with NOx levels (p< 0.01). In conclusion, oral
GABA supplementation exhibited anxiolytic potential. GABA’s influence on NOx levels
correlated with behavioral changes, suggesting complex interactions that need to be further
studied to be understood [46].
Another study explored the effect of GABA-enriched chocolate on humans to assess
stress using heart rate variability and salivary CgA. The first experiment examined the
heart rate variability (HRV) using two measures of heart rate variability (HRV): LF/HF
and HFnu, after people had 10 g of GABA-enriched chocolate (28 mg GABA) or placebo.
After 14 min of a task (about 31–34 min after eating), both the GABA chocolate and placebo
groups had higher LF/HF values compared to before eating (p< 0.05). Around
6.5–9.5 min
after the task (about 36.5–39.5 min after eating), the LF/HF value was significantly lower in
the GABA chocolate group compared to placebo (p< 0.05). At ECG-1 (14 min post-task),
HFnu values in both groups were lower compared to before eating (p< 0.05). At
6.5–9.5 min
after the task and at 12–15 min after the task (about 36.5–39.5 min and
42–45 min
after
eating), the GABA chocolate group had higher HFnu values than placebo (
p< 0.05
). The
other experiment tested for changes in salivary CgA after participants had GABA-enriched
chocolate (28 mg GABA) or placebo. In the placebo group, the levels of salivary CgA were
significantly higher at 30 min and 50 min after eating compared to before eating (p< 0.05).
In the GABA chocolate group, there were no significant differences between these times.
While the 30-min salivary CgA level in the GABA chocolate group was a bit lower than in
the placebo group (p= 0.060) [47].
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4. Effects of Dietary GABA on Pain Modulation
The GABAergic system in the CNS plays a significant role in pain modulation. Over
nearly three decades, extensive research has delved into the intricate interplay of GABAer-
gic transmission in pain perception and mediation, covering acute, inflammatory, neu-
ropathic, and chronic pain [
1
]. This understanding has propelled the exploration of oral
GABA supplementation as a potential therapeutic approach for pain management. Nu-
merous studies have highlighted the critical association between reduced GABAergic tone,
characterized by diminished GABA activity within the spinal cord, and heightened pain
sensitivity, particularly in neuropathic pain models [
48
]. This reduction stems from dis-
rupted GABA synthesis, loss of GABA-producing spinal neurons, and alterations in GABA
transport mechanisms, culminating in compromised inhibitory effects and heightened
neural excitability within the CNS, ultimately amplifying pain perception. Pharmaceuticals
structurally resembling GABA, such as gabapentin and pregabalin, have demonstrated
efficacy in pain management by modulating specific central nervous system channels, miti-
gating neural excitation, and alleviating pain [
1
,
48
]. Although they do not directly bind to
GABA receptors, they influence GABA-associated pathways, presenting promising options
for pain relief [
49
,
50
]. In parallel, a burgeoning area of research explores the neuromodula-
tory potential of microbial-derived GABA, particularly in the context of visceral pain [51].
Certain commensal bacterial species, including GABA-producing Bifidobacterium dentium,
have been investigated for their ability to modulate colonic sensory afferent excitability
and influence pain perception within the gastrointestinal tract [
52
]. Further research in
this domain holds promise for innovative nutritional interventions and microbiome-based
therapeutics targeting abdominal pain and related conditions. Additionally, studies have
shed light on the pivotal role of GABAergic neurons, especially parvalbumin (PV) in-
terneurons, in mitigating anxiety induced by chronic inflammatory pain [
53
]. GABAergic
activity within the anterior cingulate cortex (ACC) has been shown to alleviate anxiety-
like behaviors associated with chronic inflammatory pain, underscoring the potential of
GABAergic signaling as a therapeutic modality for managing both chronic pain and its
consequential anxiety [
53
]. Furthermore, intriguing findings have revealed a complex
interplay between thalamic GABA levels and altered cortical brain rhythms in individuals
experiencing chronic neuropathic pain [
54
]. Although conventional expectations of reduced
GABAergic activity in chronic pain were not fully confirmed, the correlation observed
between thalamic GABA and modified cortical rhythms provides valuable insights into the
neural mechanisms contributing to chronic pain perception. In conclusion, the collective
research underscores the potential of GABAergic modulation, whether through oral GABA
supplementation or microbial-derived GABA, as a promising avenue for pain management.
Understanding GABA’s role in pain perception and exploring therapeutic interventions
targeting the GABAergic system offer exciting prospects for alleviating a spectrum of pain
disorders. Continued research endeavors are imperative to fully unlock the therapeutic
potential of GABAergic interventions in the field of pain management.
5. Neuroprotective and Cognition-Enhancing Effects of Dietary GABA
GABA has calming and inhibitory properties, preventing excessive neuronal activity
and playing a critical role in the regulation of neural signaling. The potential neuroprotec-
tive properties of GABA have garnered significant interest, suggesting its ability to reduce
neuronal damage and cell death by counteracting excitotoxicity, a process wherein exces-
sive glutamate activity leads to cellular harm [
55
,
56
]. GABA achieves this by promoting
inhibitory actions and mitigating overstimulation of neurons, thus potentially preserving
neuronal integrity and function, providing a potential avenue for neuroprotection in vari-
ous neurological conditions, such as traumatic brain injury (TBI) and neurodegenerative
diseases [
55
,
56
]. However, further research is imperative to fully comprehend and harness
the neuroprotective potential of GABA. In the context of TBI, neurotransmitter dynamics
significantly contribute to the injury’s pathophysiological cascades [
55
]. Following TBI
and in neurodegenerative diseases, disruptions in glutamate and GABA levels, along with
Nutraceuticals 2024,4249
alterations in the expression of specific receptors and transporters, perturb the intricate
balance between neuronal excitation and inhibition [
55
]. GABA critically modulates excita-
tory pathways in the brain. However, the loss of GABA-producing cells post-TBI and in
neurodegenerative diseases, and the remodeling of the glutamate and GABA receptor and
transporter systems in neurodegenerative diseases disrupt this equilibrium, resulting in
heightened cell injury and apoptotic processes [
4
,
55
,
57
,
58
]. Excitotoxicity—characterized
by excessive glutamate activity—is a pivotal contributor to cellular damage in these neu-
rological disorders [
57
–
59
] (Figure 2). Furthermore, several studies suggest that targeted
interventions focusing on GABAergic pathways and comprehending the nuanced shifts
in GABA receptor function hold promise for neuroprotective strategies against TBI and
neurodegenerative diseases [
32
,
55
,
56
]. High levels of glutamate can induce damage to the
GABA system, including perturbed receptor subunit expression, clustering, and malfunc-
tioning of the GABARs, contributing to the pathogenesis of various neurological disorders,
such as autism spectrum disorder, AD, epilepsy, ischemic conditions, and Huntington’s
disease [
4
,
60
–
62
]. The synaptic pool of GABAARs is finely controlled by the regulation
of receptor internalization, recycling, and lateral diffusion. In disease conditions, these
mechanisms are disrupted leading to the weakening of synapses and malfunctioning of
GABAergic neuronal transmission [
61
] (Figure 2). Oligodendrocytes also express GABA
receptors, which play a crucial role in their survival and differentiation. These cells are ex-
ceptionally vulnerable to excitotoxicity triggered by glutamate, leading to their dysfunction
and cell death. Glutamate overactivation primarily targets ionotropic glutamate receptors,
such as AMPA and kainate receptors, in oligodendrocytes, resulting in sustained calcium
influx that disrupts mitochondrial function, triggering the generation of reactive oxygen
species (ROS) and initiating apoptotic pathways ultimately leading to oligodendroglia and
neuronal death [63] (Figure 2).
A study performed on rats aimed to explore the effects of orally supplemented glu-
tamate and GABA on learning and memory performance, as well as to examine their
influence on the levels of these amino acids in the brain. Three groups of rats were sub-
jected to oral supplementation with either drinking water (control group) or a suspension of
tablets containing GABA or glutamate for a duration of four weeks. Cognitive performance
was assessed through behavioral tests, including the Novel Object Recognition test, Morris
Water Maze, and Passive Avoidance test, measuring recognition, spatial reference, and
aversive memory, respectively. Additionally, the levels of GABA, glutamate, and acetyl-
choline (ACh) were quantified in the rat hippocampus. The results indicated that chronic
oral administration of GABA or glutamate tablets significantly impacted brain function,
leading to alterations in GABA and glutamate content in the rat hippocampus. Specifically,
glutamate supplementation was found to enhance memory performance by increasing
acetylcholine (ACh) levels, distinguishing its effects from those of GABA [64]. A different
study looking at mice with memory impairment induced by scopolamine (Sco) and ethanol
(EtOH) examined the effect of fermented Laminaria japonica (FL), a type of sea tangle used
in food, which is rich in GABA and is believed to boost cognitive function and potentially
help treat common neurodegenerative disorders. The study was conducted on mice using
the passive avoidance (PA) and Morris water maze (MWM) tests to assess memory impair-
ment induced by Sco and EtOH. The study also analyzed ACh and acetylcholinesterase
(AChE) activity, as well as the expression of muscarinic acetylcholine receptor (mAChR),
cAMP response element binding protein (CREB), and extracellular signal-regulated kinases
1/2 (ERK1/2) in the hippocampus. Immunohistochemical analysis was performed, and
biochemical blood analysis measured alanine transaminase (ALT), aspartate transaminase
(AST), triglyceride (TG), and total cholesterol (TC) levels. The study included seven groups:
a control group, three Sco-induced dementia groups, three EtOH-induced dementia groups,
a positive control group administered donepezil (Dpz), and an FL (50 mg/kg) treatment
group. In support of the impact of dietary GABA on the CNS, FL50 significantly reduced
AST and ALT levels induced by EtOH. FL50 treatment improved step-through latency time
in the PA test and reduced escape latency times in the MWM test for Sco- and EtOH-induced
Nutraceuticals 2024,4250
dementia. FL50 reversed the anticholinergic effects of Sco and EtOH by decreasing AChE
activity and increasing ACh concentration. FL50 also increased ERK1/2 protein expression
and p-CREB (ser133) in hippocampal tissue. In conclusion, these findings suggest that FL
may be an effective intervention for Sco- and EtOH-induced dementia, demonstrating the
potential to reverse cognitive impairment and neuroplastic dysfunction [65].
Nutraceuticals 2024, 4, FOR PEER REVIEW 10
Figure 2. Pathological alteration in cells expressing GABA and glutamate receptors induced by ex-
citotoxic mechanisms that lead to cell death. The process involves excessive glutamate release and
activation of NMDA, AMPA, and kainate receptors, leading to an excessive influx of Ca2+ which
induces a variety of pathological mechanisms including PICK1-mediated AMPAR endocytosis, in-
creased JNK activation, mGluRa1 truncation and deficient LTD, impaired synaptic function and
subsequently resulting in neuronal death. Elevated cytoplasmic Ca2+ prompts mitochondrial Ca2+
uptake, which potentially leads to ROS production, ATP inhibition, GABA receptor clustering and
recycling deficit, remodeling, and malfunctioning, and excitotoxic cell death. Abbreviations: GABA
type A alpha 1 subunit containing receptor (a1-GABAR), GABA type A alpha 5 subunit containing
receptor (a5-GABAR), N-methyl-D-aspartate receptor (NMDAR), alpha-amino-3-hydroxy-5-me-
thylisoxazole-4-propionic acid receptor (AMPAR), kainic acid receptor (KAR), voltage-dependent
calcium channel (VDCC), metabotropic glutamate receptor (mGluR), protein interacting with C ki-
nase 1 (PICK1), reactive oxygen species (ROS), adenine triphosphate (ATP). Created with BioRen-
der.com (hps://www.biorender.com, accessed on 21 March 2024).
A study performed on rats aimed to explore the effects of orally supplemented glu-
tamate and GABA on learning and memory performance, as well as to examine their in-
fluence on the levels of these amino acids in the brain. Three groups of rats were subjected
to oral supplementation with either drinking water (control group) or a suspension of
tablets containing GABA or glutamate for a duration of four weeks. Cognitive perfor-
mance was assessed through behavioral tests, including the Novel Object Recognition test,
Morris Water Maze, and Passive Avoidance test, measuring recognition, spatial reference,
and aversive memory, respectively. Additionally, the levels of GABA, glutamate, and ac-
etylcholine (ACh) were quantified in the rat hippocampus. The results indicated that
chronic oral administration of GABA or glutamate tablets significantly impacted brain
function, leading to alterations in GABA and glutamate content in the rat hippocampus.
Specifically, glutamate supplementation was found to enhance memory performance by
increasing acetylcholine (ACh) levels, distinguishing its effects from those of GABA [64].
A different study looking at mice with memory impairment induced by scopolamine (Sco)
and ethanol (EtOH) examined the effect of fermented Laminaria japonica (FL), a type of sea
tangle used in food, which is rich in GABA and is believed to boost cognitive function and
potentially help treat common neurodegenerative disorders. The study was conducted on
mice using the passive avoidance (PA) and Morris water maze (MWM) tests to assess
memory impairment induced by Sco and EtOH. The study also analyzed ACh and acetyl-
cholinesterase (AChE) activity, as well as the expression of muscarinic acetylcholine re-
ceptor (mAChR), cAMP response element binding protein (CREB), and extracellular sig-
nal-regulated kinases 1/2 (ERK1/2) in the hippocampus. Immunohistochemical analysis
was performed, and biochemical blood analysis measured alanine transaminase (ALT),
Figure 2. Pathological alteration in cells expressing GABA and glutamate receptors induced by
excitotoxic mechanisms that lead to cell death. The process involves excessive glutamate release
and activation of NMDA, AMPA, and kainate receptors, leading to an excessive influx of Ca
2+
which induces a variety of pathological mechanisms including PICK1-mediated AMPAR endocyto-
sis, increased JNK activation, mGluRa1 truncation and deficient LTD, impaired synaptic function
and subsequently resulting in neuronal death. Elevated cytoplasmic Ca
2+
prompts mitochondrial
Ca
2+
uptake, which potentially leads to ROS production, ATP inhibition, GABA receptor clustering
and recycling deficit, remodeling, and malfunctioning, and excitotoxic cell death. Abbreviations:
GABA type A alpha 1 subunit containing receptor (a1-GABAR), GABA type A alpha 5 subunit con-
taining receptor (a5-GABAR), N-methyl-D-aspartate receptor (NMDAR), alpha-amino-3-hydroxy-5-
methylisoxazole-4-propionic acid receptor (AMPAR), kainic acid receptor (KAR), voltage-dependent
calcium channel (VDCC), metabotropic glutamate receptor (mGluR), protein interacting with C kinase
1 (PICK1), reactive oxygen species (ROS), adenine triphosphate (ATP). Created with BioRender.com
(https://www.biorender.com, accessed on 21 March 2024).
Another study conducted on memory-impaired mice examined the impact of fer-
mented foods high in GABA. The study was initiated by employing a 12% (w/v) concen-
tration of monosodium glutamate (MSG) for the fermentation process to produce GABA
using the lactic acid bacteria Lactobacillus sakei B2-16, which was originally isolated from
kimchi. The conversion yield of GABA from MSG was determined, and the highest yield
was observed with this bacterial strain. For the
in vivo
experiments, mice were adminis-
tered Sco to induce memory impairment. The memory recovery effects of GABA were
assessed through PA tests. Various concentrations of GABA were tested, and a significant
improvement in long-term memory recovery was noted at a concentration of 46.69 mg/mL,
reducing the recovery time from 132 to 48 s. Subsequently, a fermentation broth containing
46.69 mg/mL of GABA was used to assess the dose-dependent memory enhancement,
with a notable 85% improvement observed at a concentration of 667 mg/mL. In summary,
the study demonstrated that GABA obtained from MSG fermentation, particularly with
Lactobacillus sakei B2-16, could enhance memory recovery in mice subjected to Sco-induced
memory impairment. The findings suggest the potential use of GABA as a natural and
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functional substance obtained from fermentation processes for various purposes, including
cognitive enhancement [66].
A study conducted on mice aimed to investigate the protective effects of a freeze-dried
powder derived from a fermentation milk whey containing a high-yield GABA strain
(FDH-GABA) against D-galactose-induced brain injury and gut microbiota imbalances in a
prematurely aged mouse model. The mice received subcutaneous injections of D-galactose
to simulate premature aging. The effects of FDH-GABA were assessed by measuring
antioxidant activities, anti-inflammatory markers, autophagy, PI3K/AKT/mTOR signaling
pathway alterations, neurotransmitter levels, and changes in intestinal microorganisms.
Compared to the control group, FDH-GABA-treated mice exhibited improved antioxidant
stress, reduced inflammation, enhanced autophagy, inhibition of the PI3K/AKT/mTOR
signaling pathway, restored neurotransmitter levels, and recovery of intestinal flora di-
versity. Pathological observations confirmed the protective effects of FDH-GABA against
damage to the brain and intestine in D-galactose-induced aging mice. These findings
suggest that FDH-GABA intervention provides a means to alleviate neurodegenerative
changes associated with aging in this mouse model [67].
Evidence of oral GABA delivery on cognitive performance in humans is limited.
Administration of an oral dose of 800 mg GABA to participants performing a stop-change
task led to an enhanced action selection [
68
]. Oral administration of the same dose of GABA
also enhanced attentional processing. While spatial attention was unaffected by GABA,
performance in the temporal attention task was significantly improved [
69
]. The acute
effects of an 800 mg dose of GABA on cognitive flexibility in healthy young adults were also
explored. GABA intake decreased cognitive flexibility during task switching, but there was
no effect on Stroop task accuracy suggesting a nonlinear or U-shaped relationship between
GABA intake and cognitive performance [
70
]. In a randomized, double-blinded, placebo-
controlled, crossover trial the same GABA dose increased visual search time compared
to the placebo but did not affect visual search accuracy, temporal attention, or visual
working memory precision [
71
]. Furthermore, the GABA-enriched fermented Laminaria
japonica intake provided a protective effect against cognitive impairment associated with
dementia [
72
]. The treatment significantly improved scores in the K-MMSE, numerical
memory test, Raven test, and iconic memory, compared to the placebo group. These studies
discussed highlighted oral GABA as a potential neuroprotective and cognitive-enhancing
pharmacological intervention. However, further research is required to provide convincing
evidence. All studies have several limitations, including small sample size, administration
of a single dose of GABA, examination of the effect at a single time point, assessment of a
specific age group of participants, and a limited number of indicators of cognitive function.
6. Other Effects of Oral GABA
Several articles discussed a variety of oral GABA-induced effects on CNS and their
potential to treat disease conditions. For example, multiple studies conducted in both ani-
mals and humans examined the effect of oral GABA on blood pressure. Regarding animal
models, one study focused on assessing the blood-pressure-lowering effects of GABA and
GABA-enriched fermented milk product (FMG) through low-dose oral administration in
spontaneously hypertensive (SHR/Izm) and normotensive Wistar–Kyoto (WKY/Izm) rats.
The FMG, a non-fat fermented milk product produced by lactic acid bacteria, contained
GABA derived from milk protein during fermentation. A single oral dose of GABA or
FMG (5 mL/kg; 0.5 mg GABA/kg) resulted in a significant (p> 0.05) reduction in blood
pressure in SHR/Izm rats from 4 to 8 h post-administration, without affecting WKY/Izm
rats. The hypotensive activity of GABA exhibited dose dependency, ranging from 0.05
to 5.00 mg/kg in SHR/Izm. Chronic administration of experimental diets to SHR/Izm
revealed a significantly slower increase in blood pressure compared to the control group at
1 or 2 weeks after initiating the GABA or FMG diet, respectively (p> 0.05), maintaining
this difference throughout the feeding period. The time profile of blood pressure changes
due to FMG administration mirrored that of GABA. FMG did not inhibit the angiotensin 1-
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converting enzyme, and a peptide-containing fraction from reverse-phase chromatography
in FMG lacked a hypotensive effect in SHR/Izm rats. The findings indicate that low-dose
oral GABA exerts a hypotensive effect in SHR/Izm, and the hypotensive action of FMG is
attributed to GABA [73].
Another study conducted on rats employed an experimental approach to investigate
the potential antihypertensive effects of GABA in spontaneously hypertensive rats (SHR),
utilizing acute and chronic administration studies. The GABA-rich tomato cultivar ‘DG03-9’
and purified GABA were administered orally to SHR, and blood pressure measurements
were conducted using the tail-cuff method. In the acute administration study, ‘DG03-9’
exhibited a substantial and dose-dependent reduction in systolic blood pressure (SBP) in
SHR. Notably, the 10 g/kg dose of ‘DG03-9’ demonstrated a significant antihypertensive
effect at 4 h, 6 h, and 8 h post-administration, compared to the control group (p< 0.01).
Similarly, the 2 g/kg ‘DG03-9’ dose showed a significant antihypertensive effect at 6 h
and 8 h after administration (p< 0.01). These findings were supported by the observation
that the maximal decrease in SBP occurred at 8 h after administration, with SBP values
of
159.5 ±1.7 mmHg
for the 10 g/kg ‘DG03-9’ group (p< 0.01). To discern the specific
contribution of GABA to the antihypertensive effects, a comparative analysis was con-
ducted between ‘DG03-9’ and an equivalent amount of purified GABA administered alone.
The results revealed that both the GABA-rich tomato cultivar and purified GABA exerted
similar and significant antihypertensive effects at 4 h, 6 h, 8 h, and 24 h after administration
(
p< 0.05
). The similarity in the antihypertensive responses between ‘DG03-9’ and GABA
alone underscores the pivotal role of GABA in mediating the observed blood pressure
reduction. Furthermore, the chronic administration study investigated the sustained anti-
hypertensive effects of ‘DG03-9’ over 4 weeks. The results indicated that the GABA-rich
tomato cultivar, when included in the diet, did not significantly affect body weight, food
intake, or water consumption. However, chronic administration of ‘DG03-9’ demonstrated
a sustained antihypertensive effect, highlighting its potential as a long-term intervention
for hypertension. In conclusion, this study provides compelling evidence that GABA,
particularly derived from the GABA-rich tomato cultivar ‘DG03-9’, exerts significant and
dose-dependent antihypertensive effects in SHR. The acute and chronic administration
studies underscore the potential therapeutic implications of GABA in mitigating hyperten-
sion, suggesting avenues for further exploration in the context of dietary interventions and
functional foods [74]. The aforementioned studies provide insight into the possible use of
oral GABA for blood pressure modulation.
Importantly, the antihypertensive effects of dietary GABA have also been demon-
strated in human intervention trials. In a randomized, placebo-controlled, single-blind trial
conducted at the Cardiovascular Disease Center, Tokyo Metropolitan Police Hospital in
Japan, the study aimed to investigate the potential effects of a newly developed fermented
milk product containing GABA, denoted as FMG, on the blood pressure of individuals with
mild hypertension. The study enrolled a total of 39 participants diagnosed with mild hyper-
tension, comprising 16 women and 23 men, with an age range of
28–81 years
and a mean
age of 54.2 years. The intervention involved a 12-week period during which participants
were randomly assigned to daily intake of either FMG or a placebo (weeks 1–12), followed
by 2 weeks of no intake (weeks 13 and 14). Throughout the trial, peripheral blood pressure
and heart rate measurements were systematically collected at weeks 0, 2, 4, 8, 12, and 14.
The study findings revealed a significant reduction in blood pressure within 2 to 4 weeks of
FMG intake, and this reduction was sustained throughout the 12-week intervention period.
Specifically, the FMG group exhibited a mean decrease of
17.4 ±4.3 mmHg
in systolic BP
and 7.2
±
5.7 mmHg in diastolic blood pressure after
12 weeks
, with both values differing
significantly from baseline levels (p< 0.01). Furthermore, the systolic blood pressure of
the FMG group differed significantly from the placebo group (p< 0.05). Other parameters,
including heart rate, body weight, and various hematological and blood chemistry vari-
ables, showed no significant variations between the FMG and placebo groups throughout
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the study. The results suggest that FMG may contribute to lowering blood pressure in
individuals with mild hypertension [75].
Another study explores the potential blood pressure-lowering effects of GABA, through
the consumption of a cheese naturally enriched in GABA. Two GABA-producing strains,
Lc. lactis ssp. lactis ULAAC-A23 and ULAAC-H13 were used in the study. Cheese manu-
facturing involved the inoculation of raw milk with these strains along with Lactococcus
lactis ssp. cremoris W62 and standard Cheddar cheese production procedures were followed
with modifications for enhanced GABA production. The experimental Cheddar cheeses
containing GABA were produced in two batches and compared with placebo cheeses.
Composition analyses, including fat, protein, sodium, energy, moisture, and pH, were
conducted for both types of cheese. In the cheeses used for the clinical study, the GABA
concentration in those containing strain Lc. lactis ssp. lactis ULAAC-H13 was 16 mg of
GABA per 50 g compared to 0.12 mg in placebo cheeses. The clinical study involved 23 men
with slightly elevated blood pressure. A randomized, placebo-controlled, double-blind,
parallel design was employed, where participants were assigned to consume either GABA-
enriched cheese or placebo cheese daily for 12 weeks. Blood pressure, heart rate, body
weight, and waist circumference were recorded at regular intervals. The cheese characteris-
tics, microbiological changes, proteolysis, and hardness were assessed to ensure the quality
and consistency of the GABA-containing cheeses. In the clinical study, GABA-enriched
cheese consumption led to a significant decrease in blood pressure within 2 to 4 weeks,
with a sustained reduction throughout the 12-week intervention. The mean decrease after
12 weeks was
17.4 ±4.3 mmHg
in systolic blood pressure and 7.2
±
5.7 mmHg in diastolic
blood pressure. No significant changes were observed in heart rate, body weight, or other
metabolic parameters. The GABA group showed a statistically significant difference in
systolic blood pressure compared to the placebo group. The study demonstrates the suc-
cessful production of Cheddar cheese enriched with GABA-producing strains, resulting
in a significant increase in GABA concentrations. Consumption of this GABA-enriched
cheese by individuals with slightly elevated blood pressure led to a notable reduction in
blood pressure. The findings suggest that GABA-enriched cheese may be a promising non-
pharmacological intervention for managing hypertension [
76
]. Hypertension is a disease
that ranges in gravity and can be complicated by further cardiovascular issues. There might
be a potential avenue for oral GABA in combination with other antihypertensive drugs
however this needs to be researched to determine effectiveness and safety as well as dosage
and possible side effects.
A study explored the potential of dietary GABA in managing depression [
77
]. The
influence of GABA-enriched fermented milk was examined on crucial neurotransmitters
5-hydroxytryptamine, norepinephrine, and dopamine in the mouse hippocampus essential
for mood regulation using enzyme-linked immunosorbent assay (ELISA). The results
indicated a positive impact, suggesting potential antidepressant effects of GABA-enriched
food by enhancing these neurotransmitter levels. This finding highlights that GABA-
enriched fermented milk is a promising avenue for mitigating depressive symptoms by
targeting key components of mood regulation [77].
A study examined the potential of dietary GABA in obesity prevention [
78
]. Two
hundred male C57BL/6 mice were divided into two study groups. In Study I, mice were
categorized into a control group, a diet-induced obesity (DIO) group, and a diet-induced
obesity-resistant (DIO-R) group based on body weights after a 20-week high-fat diet (HFD).
The method of GABA administration in the study involved incorporating GABA into the
drinking water of mice. In Study II, three groups of mice on an HFD received different
doses of GABA through their drinking water (0.2%, 0.12%, and
0.06% g/mL
). The admin-
istration of GABA via drinking water allowed for convenient and controlled delivery of
the compound to the mice throughout the 20-week experiment. In Study II, mice were
assigned to a control group, an HFD group, and three HFD groups receiving different
doses of GABA. Body weights, water intake, fasting blood glucose (FBG), plasma lipid
profiles, oxidative stress markers, and thyroid-related parameters were assessed. DIO mice
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exhibited a significant increase in body weight compared to the control group (p< 0.05).
GABA administration in HFD mice led to a dose-dependent reduction in body weight gain.
FBG levels were elevated in DIO mice, while GABA-treated groups showed improved
blood glucose levels. In terms of plasma lipid status, DIO mice displayed elevated levels of
total cholesterol, LDL-C, and triacylglycerol (TG) compared to controls. GABA administra-
tion attenuated these lipid abnormalities, with a significant reduction in TC, LDL-C, and
TG levels. Oxidative stress assessment revealed that DIO mice displayed increased ROS
production and decreased antioxidant enzyme activities. GABA administration led to a
dose-dependent reduction in ROS levels and restoration of antioxidant enzyme activities.
Additionally, DIO mice exhibited elevated plasma thyroid-stimulating hormone (TSH)
levels, suggesting HPT axis dysfunction. GABA administration showed a trend toward
normalization of TSH levels, indicating a potential role in mitigating thyroid dysfunction
associated with obesity. This study highlights the beneficial effects of GABA administra-
tion in mitigating obesity, improving glucose homeostasis, restoring lipid profiles, and
modulating oxidative stress and thyroid function in HFD-induced obese mice. Impor-
tantly, there is a growing number of studies supporting the anti-obesity effects of GABA in
HFD mice
[79–81]
. These findings provide valuable insights into the complex interactions
between oral GABA, obesity, and associated metabolic dysregulations [78–81].
7. The Effect of GABA Produced by the Gut Microbiota
Dysbiosis of the gut microbiota has been linked to various neurological disorders,
including anxiety, depression, autism spectrum disorders, and neurodegenerative disorders
such as Alzheimer’s and Parkinson’s disease [
82
,
83
]. The potential of targeting the gut
microbiota through personalized dietary interventions, probiotics, prebiotics, and fecal
microbiota transplantation (FMT) was suggested as a promising approach to managing
and treating neurological disorders [
84
,
85
]. In several studies the biosynthetic potential
of specific gut-resident bacteria to produce GABA was investigated, offering potential
avenues for modulating gut microbiota to support health. Bacterial strains isolated from
the human gastrointestinal tract revealed that certain strains of Lactobacillus and Bifi-
dobacterium exhibited the enzymatic capability to convert monosodium glutamate (MSG)
into GABA [
82
]. Lactobacillus brevis strain DPC6108 demonstrated the highest efficiency in
GABA production, achieving a complete conversion of MSG to GABA [
82
]. These findings
shed light on the biosynthetic potential of specific gut-resident bacteria to produce GABA,
presenting promising avenues for modulating the gut microbiota to support health and
enhance overall well-being [
82
]. In previous studies, the gut–brain axis and its role in
influencing neurological disorders were explored, emphasizing the potential of the gut
microbiota as a therapeutic target in neurology [
11
]. Studies highlighted the intricate bidi-
rectional communication between the gut and the brain, mediated by neural, endocrine,
immune, and metabolic pathways, underscoring the potential of the gut microbiota in
modulating this axis.
GABA is known to play a pivotal role in regulating mood and emotional responses. A
study examined the gut microbiota and its correlation to GABA in patients with major de-
pressive disorder (MDD). Quantitative analysis of the gut microbiota composition revealed
a positive correlation between the abundance of Bacteroides and GABA levels. Individuals
with higher concentrations of Bacteroides exhibited elevated GABA levels in the fecal sam-
ples, suggesting a potential modulatory effect of this gut bacterium on GABA production.
To further elucidate the relationship between Bacteroides and GABA, additional
in vitro
experiments were conducted. Fecal samples with varying Bacteroides concentrations were
incubated, and subsequent analyses demonstrated a dose-dependent increase in GABA
production. This experiment provided mechanistic insights into the observed correlation,
suggesting that Bacteroides might influence GABA levels, and this can occur through
direct or indirect pathways in the gut. The neurobiological implications of these findings
were underscored by correlating GABA levels with functional magnetic resonance imaging
(fMRI) data. Individuals with higher GABA levels exhibited distinct patterns of functional
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connectivity within the neural circuits associated with depression, including alterations in
the left dorsolateral prefrontal cortex (DLPFC) and the default mode network (DMN). In
summary, the study not only identified a potential link between Bacteroides abundance
and MDD but also shed light on the intricate relationship between gut microbiota, partic-
ularly Bacteroides, and GABA. These findings contribute to a deeper understanding of
the complex interactions within the gut–brain axis and provide a foundation for future
research exploring microbiota-mediated effects on neurotransmitter systems in the context
of mental health [
37
]. Another study looked at the
in vitro
and
in vivo
effects of certain
GABA-producing bacteria strains. Quinoa yogurt beverages (B-SP1, B-20194, and B-T6B10)
were subjected to fermentation using Lactobacillus rhamnosus SP1, Weissella confusa DSM
20194. A two-year double-blind randomized placebo-controlled trial involved 423 pregnant
women, receiving either a placebo or daily supplementation of Lactobacillus rhamnosus
HN001 from 14–16 weeks of gestation to 6 months postpartum. Modified versions of the
Edinburgh Postnatal Depression Scale and State-Trait Anxiety Inventory were employed to
measure anxio-depressive states. The trial assessed the impact of Lactobacillus rhamnosus
HN001 on depression and anxiety symptoms, maintaining a rigorous methodology. De-
pression scores were monitored even after controlling for potential confounding factors.
The clinical trial demonstrated the significant impact of Lactobacillus rhamnosus HN001
supplementation on depression and anxiety symptoms in postpartum women. The probi-
otic group exhibited a markedly lower prevalence of depression and anxiety symptoms
compared to the placebo group. Importantly, depression scores remained consistently
lower, even after adjusting for potential confounding variables, providing robust evidence
of the enduring effects of probiotic supplementation. The substantial GABA production
observed in quinoa yogurt beverages, coupled with the persistent attenuation of depression
and anxiety symptoms in the clinical trial, underscores the therapeutic promise of these pro-
biotics. The findings provide a solid foundation for further targeted studies, emphasizing
the need for exploration in individuals with diagnosed mental health disorders [86].
A study examined the impact of two Bifidobacterium adolescentis strains—namely,
IPLA60004 (GABA-producing) and LMG10502T (non-GABA-producing)—cultured daily
in an MRSc medium. C3H/HeJ mice were divided into vehicle, probiotic (IPLA60004),
and control (LMG10502T) groups, subjected to a 14-day oral gavage regimen. Fecal sam-
ples, blood, and colonic contents were collected at intervals for analysis. IPLA60004
administration induced a distinctive gut microbiota modulation, marked by increased
representation of beneficial genera such as Lactobacillus and Roseburia, contrasting with
the effects observed with LMG10502T. Notably, IPLA60004 treatment led to a reduction
in serum glutamate levels. Bacterial suspensions, containing approximately 10
8
CFU per
day, were administered in sterilized milk. High-performance liquid chromatography was
employed to determine glutamate and GABA concentrations in feces and colonic contents.
Additionally, 16S rDNA sequencing revealed specific microbiome changes associated with
IPLA60004 administration. Bifidobacterial administration did not affect animal growth, and
both strains demonstrated similar recoverable bifidobacterial levels. Metabolite analysis
in colonic contents showed no significant differences in GABA and MSG concentrations
among treatment groups. However, the probiotic group exhibited lower total short-chain
fatty acids, attributed to reduced acetic and butyric acids. Fecal and colonic microbiota
profiling revealed dynamic changes over the intervention period, with IPLA60004 inducing
higher abundances of Lactobacillus and Roseburia at late stages. Notably, Bifidobacterium
representation was elevated in groups receiving IPLA60004 or LMG10502T compared to
the vehicle group. Colonic content analysis at the end of the intervention showed no
significant differences in alpha diversity but revealed distinctive beta diversity profiles,
indicating unique microbiota compositions for control and probiotic groups. These findings
highlight the potential modulatory effects of GABA-producing probiotics on gut microbiota
and metabolic profiles, providing insights into their therapeutic implications [
87
]. Further
research in this burgeoning field is essential to unravel the intricate mechanisms underlying
Nutraceuticals 2024,4256
the gut–brain axis and harness its potential for therapeutic interventions in neurological
disorders [11].
8. Conclusions
The increasing interest in dietary GABA as a treatment avenue for neurological dis-
orders stems from its role as a neurotransmitter regulating brain activity and its natural
occurrence in certain foods. Recent research indicates therapeutic potential for neurological
conditions through the consumption of GABA-rich foods and supplements, with studies
delving into their impact on depression, anxiety, blood pressure, sleep, and cognitive
disorders. Notably, certain strains of Lactobacillus rhamnosus bacteria, renowned for GABA
production, exhibit antidepressant effects in animal and human studies. While promising
in animal models, translating these findings to humans necessitates robust clinical trials
to validate efficacy and safety across diverse populations. Investigating strain specificity,
individual variability, mechanisms of action, optimal dosage, and treatment duration are
critical aspects requiring exploration. Additionally, specificity to various neurological
disorders, including Alzheimer’s and Parkinson’s diseases, warrants targeted studies to
elucidate the broader applicability of GABA-based interventions. Further understanding of
the microbiota–gut–brain axis and human metagenomic studies focusing on GABA-related
genetic factors will collectively contribute to evidence-based dietary interventions in clinical
settings. Collaborative efforts addressing these challenges are pivotal for advancing our
comprehension of dietary GABA’s therapeutic role in neurological disorders.
Author Contributions: Conceptualization, S.A., A.S. and A.K.; methodology, S.A., A.S. and A.K.;
writing—original draft preparation, S.A., A.S. and A.K.; writing—review and editing, A.S. and A.K.;
supervision, A.K.; project administration, A.K.; funding acquisition, S.A. and A.K. All authors have
read and agreed to the published version of the manuscript.
Funding: Health Research Board Summer Scholarship.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Conflicts of Interest: The authors declare no conflicts of interest.
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