DHN 374: Research and Writing in DieteticsLiterature Review Composition Assignment

Author: Chloe SapienzaAffiliation: Dietetics Student, University of Kentucky, Lexington, KentuckyDate: November 23, 2015

Title: Gamma-aminobutyric Acid (GABA) Supplementation Related to Anxiety Disorders

ABSTRACT:

With the number of Americans diagnosed with anxiety disorders climbing each year, and

the number being treated at an all time low, it is important to start looking into innovative

avenues of treatment. The purpose of this review is to evaluate how GABA supplementation can

be used to aid anxiety disorders. By looking at GABA and anxiety related to development,

GABA’s contribution to anxiety and other issues and GABA and its receptors, the different

effects GABA has on brain chemistry and how that in result may aid in anxiety relief and

perhaps prevention is shown. By taking GABA supplements and eating a diet rich in GABA the

need of drugs to increase the release of GABA-A is eradicated. Given the information presented

in this review there is a high probability that the two-thirds of people not receiving treatment will

benefit from GABA supplementation.

INTRODUCTION:

Today, anxiety disorders are the most common psychiatric illness affecting both children

and adults. The Anxiety and Depression Association of America estimates that 40 million

American adults are suffering from anxiety disorders with only one-third receiving treatment.

The term anxiety disorder is composed of many specific classes including generalized anxiety

disorder (GAD), panic disorder and panic attacks, agoraphobia, social anxiety disorder, selective

mutism, separation anxiety and specific phobias. Obsessive-compulsive disorder (OCD) and

post-traumatic stress disorder (PTSD) are also closely related to anxiety disorder. Although it is

possible for anxiety disorders to stand alone, it is common to have a co-occurring disorder or

physical illness, which can affect the severity of symptoms and make recovery more difficult.

With that being said it is crucial that treatment is broad and manages all disorders that are

present. [1]

Treatments for anxiety disorders are extremely individualized but follow one or a

combination of therapy, medication, and complementary and alternative treatment. Therapy

includes cognitive behavioral therapy, exposure therapy, acceptance and commitment therapy,

dialectical behavioral therapy, interpersonal therapy, intrapersonal therapy, and eye movement

desensitization and reprocessing. Medication includes, selective serotonin reuptake inhibitors,

serotonin-norepinephrine reuptake inhibitors, benzodiazepines, and tricyclic antidepressants.

Complementary and alternative treatment includes, stress and relaxation techniques, meditation,

yoga, acupuncture, and kava. [1]

Research suggests that anxiety disorders develop from a complex set of risk factors,

which include genetics, brain chemistry, personality, and life events. This review will focus on

brain chemistry and the relationship between gamma-aminobutyric acid and anxiety disorders.

[1]

GABA is short for gamma-aminobutyric acid. GABA is an amino acid that acts to inhibit

the transmission of nerve impulses in the central nervous system. The signaling of GABA is

mediated through two receptor classes known as GABA-A / GABA-C and GABA-B. GABA-A

and GABA-C are classified as ionotropic receptors that function directly by opening channels

that enable specific ions to stream in and out of a cell. GABA-B is a metabotropic receptor that

acts indirectly through a secondary messenger. The effect of GABA on emotional behavior relies

on the activation of these specific GABA-A receptor subtypes. [2] The GABAergic pathways

possess an inhibitory influence upon the release of neurotransmitters that are known to mediate

anxiety agent’s actions such as serotonin, noradernaline, dopamine, and glutamate. Low levels of

gamma-aminobutyric acid in the brain, plasma and cerebrospinal fluid is concerned in both

anxiety and depression pathophysiology. [3] Drugs such as benzodiazepines are used to adjust

the GABA-A receptors in patients suffering from anxiety related disorders. [2] Research has

been conducted to evaluate how increasing GABA can affect specific aspects of brain chemistry.

Gamma-aminobutyric acid can be consumed in the form of supplements and also diet.

GABA is the metabolic byproduct of plants and microorganism’s therefore fermented foods are

the only dietary source. Examples of such fermented foods include but are not limited to Kimchi,

kefir, miso, sauerkraut, tempeh, and yogurt. It is also found that GABA can be consumed

through Pu-Erd tea, and flavonoid rich foods such as berries, citrus fruits, apples, pears, cocoa,

and wine. [5] It is possible to take solely gamma-aminobutyric acid in pill form. While this is a

possibility it has been shown that the addition of vitamin B6, magnesium, and theanine can aid

the effects of GABA. Vitamin B6 is needed for GABA synthesis, magnesium enhances GABA

sensitivity on nerve receptors, and theanine increases GABA activity in the brain. Specifically,

ZenLife encompasses all of these natural supplements. [6] In the image below, the difference

between powder GABA supplementation and pill GABA supplementation is depicted.

Since GABA could be readily available in a dietary formula, finding evidences for its

therapeutic benefits in a wide variety of health conditions would be valuable. [7]

Key terms include but are not limited to glutamate a major excitatory transmitter in the

brain, Leonurus cardiaca and jappnicus also known as motherwort a plant in the mint family,

allostasis achieving stability or homeostasis through psychological or behavioral change,

ameliorate to make something unsatisfactory better, stria terminalis the structure in the brain

consisting of a band of fibers running along the lateral margin of the ventricular surface of the

thalamus, GATs the GABA transporters, anxiolytic a medication or other intervention that

reduces anxiety.

PURPOSE OF CURRENT REVIEW:

The objectives in the present review are to provide an integrated overview of current

knowledge regarding the link between GABA receptors and anxiety related disorders. In

addition, it is proposed that this subject has potentially promising avenues for future research.

METHODS:

The literature research articles were found using PubMed. Articles were narrowed down

using key words such as GABA, GABA and anxiety, the effects of GABA, gamma-aminobutyric

acid, how gamma-aminobutyric acid affects anxiety disorders, GABA related to anxiety

disorders. Studies of both humans and animals were used. Additional information was found

using Anxiety and Depression Association of America, Stress and Anxiety Research Society, the

Anxiety Network, and beyondblue. The specific articles were chosen based on date published,

within the last 10 years, and relativity to purpose of the review.

BODY:

The Effects of Gamma-aminobutyric Acid:

GABA and Anxiety Related to Development:

Disturbances of the gamma-amino butyric acid-ergic (GABAergic) system during post-

natal development can have long lasting consequences for later life behavior, including an

individual’s response to stress. Studies have been conducted to try and determine which post-

natal windows of sensitivity or changes in the gamma-aminobutyric acid system are associated

with which later-life behavioral outcomes. GABA influences neurodevelopmental events that

range from the rapid growth and production of cells to the establishment of mature synaptic

circuits. [9]

A study by Amaicha Mara Depino et al sought to determine whether chronic treatment

during post-natal development with the GABA-A receptor positive modulator, diazepam (DZP),

could lead to long-term dependence such as changes in anxiety-related behavior. Diazepam

increases the power of the internal inhibitory neurotransmission. Within this study were are sub-

studies conducted to arrive at the end conclusion. The first of the sub-studies took place fourteen

days after birth. A control group was created by implanting mice with osmotic pumps that

contained vehicle (5mg/kg) or diazepam (15mg/kg). This group was tested at fifteen days after

birth and twenty-seven days after birth in the open field. Measures for data include resistance to

enter the center, visits to the center, percent distance in the center, time in the border, and total

distance. It was confirmed through these control experiments that diazepam has an anti-anxiety

effect at the doses used and over time these behavioral effects diminish.

After confirming those points they determined whether early diazepam treatment could

affect adult anxiety-related behavior. This confirmation was executed by treating a separate

group of mice with diazepam (15mg/kg/day) from fourteen to twenty-eight days after birth. The

mice were subjected to behavioral testing four weeks later. Early diazepam treatment is

associated with reduced exploration in adulthood. The next sub-studies focus on the altered

benzodiazepine and gamma-aminobutyric acid binding sites in adulthood after postnatal

diazepam treatment. This was examined by subjecting brains from control and diazepam-treated

animals to autoradiography using [H]-flunitrazepam, a nonselective benzodiazepine receptor

ligand. The findings show that increased fear and anxiety related behaviors in early diazepam-

treated mice are accompanied by changes in benzodiazepine and GABA-A receptors in

amygdala and cortex. Overall the findings of this study show that excessive inhibitory

neurotransmission during postnatal development can forbid balance in the gamma-aminobutyric

acid systems. This imbalance is associated with increased behavioral inhibition in adulthood.

[10]

A second study by Ali-Akbar Salari et al, examined the developmental consequences of

GABA-A receptor activation of mice three to five days after birth and fourteen to sixteen days

after birth. Musimol, a selective agonist, was used to stimulate GABA-A receptors at five

distinct doses. The mice were tested for anxiety and depression-like behaviors as well as

hypothalamic-pituitary-adrenal axis activity during adulthood. The findings of this study were

that the early neonatal period is a more sensitive period for muscimol to evoke anxiety and that

depressive outcomes are increased in later life. Increased anxiety was found in both early and

late postnatal administration of muscimol. With that being said a higher dose was needed during

the later phase. [9]

The findings from these studies help aid in the future research of developmental

mechanisms contributing to stress-related disorders.

GABA and Effectors Contribution to Anxiety and Other Issues:

Anxiety often develops as a result of a combination of factors including family history of

mental health problems, ongoing stressful events, physical health problems, substance abuse, and

personality factors. [11] The health and well being concerns that come with anxiety are

important to note when it comes to gamma-aminobutyric acid related therapy.

Various factors such as stress, disease, caffeine, and others disrupt daily sleep patterns. In

many studies caffeine has been correlated to anxiety increasing properties. With that being said

the consumption of caffeine can have a domino effect on a persons sleep pattern, hyper

locomotion, anxiety, and impulsivity. A study done by Darine Froy N. Mabunga et al, evaluated

the constricting effect of GABA extract obtained from rice germ ferment to caffeine- induced

sleep disruption. The results showed GABA might increase the levels of melatonin and serotonin

in the brain adding to its sleep promoting properties. Rice germ fermented extracts-gamma-

aminobutyric acid (RFE-GABA) slightly neutralized the caffeine-induced hyper-locomotion and

anxiety-like behavior. This study shows promising potential benefits of RFE-GABA

administration in neutralizing caffeine’s wakeful effects and in turn anxiety amplifying effects.

[7]

It is hypothesized that stress provokes the imbalance of the autonomic nervous system

with decreased parasympathetic nervous system and increased sympathetic nervous system

activity, under activity of the gamma amino-butyric acid system, the primary inhibitory

neurotransmitter system, and increased allostatic load. With under activity of GABA comes

increased anxiety. This study focuses on the effects yoga has on these imbalances. It is proposed

that yoga based interventions support the return of optimal balance in the parasympathetic

nervous system and gamma-aminobutyric acid system. This function improves regions of the

brain that regulate response to threat, such as fear processing, emotion regulation, and defensive

reactions. The neurophysiologic model depicts the effects yoga breathing has on the transmission

of information about the state and activity of the respiratory system through wandering nerves

and brainstem relay stations to other central nervous system structures where they influence

perception, cognition, emotion regulation, somatic expression, and behavior. Evidence that yoga-

responsive anxiety disorders have low heart rate variability and low GABA activity is in

agreement with the theory that imbalances in the autonomic nervous system and GABA systems

constitute an wear and tear on the body that can be reduced by yoga-based therapies. The

conclusion of this study states that the therapeutic effects of yoga can be understood in part

through its direct effects on the autonomic nervous system and indirect effects on the GABA

system.

European Leonurus cardiaca and East Asian Leonurus japonicus, extracts from the mint

family, have been traditionally used in the treatment of neurological disorders such as anxiety,

depression, nervousness, and as a sedative for insomnia. Current experiments show that the

neurological mechanism of L. cardiaca and L. japonicus may be based on their interaction with

the GABA site to the GABA-A receptor while the benzodiazepine site most likely does not

contribute to this effect. Both L. cardiaca and L. japonicus extracts bind to the gamma-

aminobutyric acid site of the rat GABA-A receptor with a high binding affinity. With that being

said, binding to the GABA site of the GABA-A receptor is likely mode of action of both

Leonurus species. With the presented GABA-A receptor binding studies at the GABA- and

benzodiazepine- sites for L. cardiaca and L. japonicus, positive in vitro evidence for their well-

documented traditional anxiety reducing and sedative indications in traditional European

herbalism and TCM/Kampo, were generated for the first time (Rauwald HW et al. 1108). [12]

Although GABA is the major inhibitory neurotransmitter in the brain, it is also produced

in other sites including the pancreas beta cells and immune cells. A study by Gerald J.

Prud’homme et al, focused on three aspects of GABAergic interaction in the immune system.

These three factors include the expression of GABA, GABA receptors and the relevant

GABAergic molecular machinery, the in vitro response of immune cells to GABA or other

agonists, and therapeutic applications of GABA in autoimmune diseases. Findings from research

show the GABA treatment gives promise for the improvement of pancreas cell transplantation.

In patients chronically treated with immunosuppressive drugs for other reasons, GABA might

improve pancreas-cell survival and function. As mentioned in previous studies several drugs

mediate the pharmacological effects by promoting the activation of the GABA-A receptor. Said

drugs include, benzodiazepines, barbiturates, general anesthetics, and some antiepileptic drugs.

While this study confirmed that immune cells possess all the molecular components of a

GABAergic system and GABA has an anti-inflammatory action, it is important to note that more

research needs to be done on humans. One of the major limitations is the ability of most

GABAergic drugs to pass through the blood-brain barrier. While this trait is important to treat

neurological disease, such as anxiety, it can be undesirable for other diseases. [13]

GABA and its Receptors:

The root of all function of gamma-aminobutyric acid is through its receptors. The ion

channel pores are mostly located behind the structure that allows a neuron to pass a signal to

another neuron (postsynaptic), are coupled with Cl- channels, and mediate fast restriction of the

synapse. The receptors that require a secondary messenger (metabotropic) are coupled to guanine

nucleotide- binding proteins and form a heterodimer of GABA-AB1. These receptors regulate

neurotransmitter release by weakening Ca2+ streaming via voltage-activated Ca2+ channels and

by increasing K+ delivery. For many years a key target for anxiety inhibiting drug creation has

been GABA-A. GABA-B receptor drug baclofen is used for the treatment of jerkiness and

skeletal muscle rigidity. It has shown to reverse anxiety associated with alcohol withdrawal,

panic disorder, post-traumatic stress and traumatic spinal cord lesions in clinical studies without

abuse potential. [14] These receptors are currently categorized in cognitive, anxiety, and

depressive phenotypes. A study by Chelsea R. Katen and Stephen L. Boehm II focuses on

whether GABA-B1a and GABA-B1b isoforms contribute differently to behaviors in isoform

knockout mice. The role of B1 isoforms on test of unconditioned anxiety and anxiety following

stress were conducted by putting the animals under social stress and maternal separation with

unpredictable stress. This research supports an isoform specific role in behavior. GABA-b

isoform knockout mice show a broad spectrum of isoform-specific behaviors. Global B1 and B2

subunit knockout studies have signified deficits in animals that do not express GABA-B

receptors. There are times where these deficits are isoform specific such as the role of B1a in

hyperactivity, seizure activity, protection of depressive phenotypes and memory maintenance,

whereas B1b is involved in susceptibility to depression like phenotypes and impaired memory

formation. It would be beneficial to enhance upon this study with studies conducted to look at

how isoforms and pre-exposure alters neurotransmitter signaling of dopamine, glutamate, and

other systems of interest. [15]

A study by Malgorzata Frankowska et al evaluates the effects of GABA-B receptor

ligands in animal models predictive of antidepressants and anti-anxiety activities. This study was

performed on a group of male rats using the drugs (R)-baclofen, CGP 7930, diazepam

hydrochloride, imipramine hydrochloride, SKF 97541, and SCH50911. The tests conducted

include the forced swimming test (FST), elevated zero-maze (EZM), and locomotor activity

measurement. Overall the results from this study do not support the concept that GABA-B

receptor antagonists may be regarded as potential antidepressant drugs, while drugs of these

receptors display anti-anxiety activity. [16]

A key component to the GABAergic transmission is GABA transporters (GATs). GATs

control the duration and intensity of GABAergic activity. The major subtype that is present at

both synaptic and extra synaptic sites in the brain is GAT1. It has been shown that a deficiency

of this subtype can lead to increased extracellular GABA levels which in turn results in over

activation of GABA-A receptors. The results of this study show that drugs that can regulate the

function or expression of GAT1 with subsequent adjustments of the GABAergic system may

have therapeutic value in the treatment of mental illnesses such as anxiety disorders. [17]

The central nucleus of the amygdala (CeA) and the bed nucleus of stria terminalis

(BNST) are extremely interconnected, especially due to the fact that they receive information

from and project to similar structures. Another key feature is that they are both largely

GABAergic. Even though these two are composed of many similarities it is important to note

that manipulation of corticotrophin releasing factor (CRF) has immense differences of effect on

fear and anxiety behavior. These differences are dependent on which structure is targeted.

Corticotrophin releasing factor plays a complex and critical role in anxiety and fear memory. It is

suggested that hyper activation of CRFergic cells through deletion of GABAergic receptors is

associated with increased anxiety. The results of this study show that corticotrophin releasing

factors in the bed nucleus of stria terminalis contributes to anxiety behavior while corticotrophin

releasing factor in the amygdala contributes to fear memory processing. [18]

GABAergic stimulation of the amygdala plays part in the expression of fear. The

examination of contribution from GABAergic mechanisms operating in the amygdala nuclei in

low and high anxiety rats (after repeated pretreatment with corticosterone and after midazolam, a

benzodiazepine,) sheds light on whether animals overly vulnerable to fear would be more

sensitive to the effects of corticosterone on amygdala nuclei activity and fear memory. It is also

evaluated to whether this effect is accompanied by changes in the local expression of markers of

neuronal and GABAergic system activity. Results of the current study show that chronically

administered corticosterone increased anxiety like behavior in the open field and decreased body

weight gain in both groups tested. The data collected suggests that individual differences in local

amygdala GABAergic activity may determine the strength of emotional behavioral responses. [2]

In 35-40% of depressed patients, plasma GABA levels have been reported to be low.

Anxiety is the main basis for association with low cerebrospinal fluid gamma-aminobutyric acid

(CSF GABA). With regards to this study the

relationship is confined to psychic anxiety and not

psychomotor agitation or physical anxiety. Because

there was no data to support low CSF GABA to

psychomotor agitation or physical anxiety it is said that

these forms of anxiety may be mediated through other

mechanisms or neurotransmitters. This data was

acquired through lumbar puncture and analytic procedures. [4] The image below depicts the

difference between a normal brain and a

brain affected by anxiety disorder.

Normal Brain Brain Affected by Anxiety Disorder

CONCLUSIONS:

As anxiety rates continue to rise, the condition remains one of the most common

psychological illnesses. As such, more research is being conducted to combat the growing

numbers of diagnosis. It is important to start studying the effects of these supplements now so

there can be an extended time period of effect. Also with that being said it would be helpful for

more human subjects to be tested upon.

While more research is being conducted now than ever before it is important to note the

need of more studies to be more done before registered dietitians and practitioners can

implement GABA alone as a treatment plan.

REFERENCES:

1. Anxiety and Depression Association of America. Understanding the Facts. Updated November 3, 2015. http://www.adaa.org/understanding-anxiety. Accessed October 1, 2015.

2. Jembrek MJ and Vlainic J. GABA receptors: pharmacological potential and pitfalls. Current pharmaceutical design. 2015.

3. Li AW and Adam Plaznik. GABAergic control of the activity of the central nucleus of the amygdala in low- and high-anxiety rats. Neuropharmacology. 2015; 99: 566-576.

4. Ende G. Proton Magnetic Resonance Spectroscopy; Relevance of Glutamate and GABA to Neuropsychology. Neuropsychology Review. 2015; 25(3): 315-325.

5. Li AW and Currier D. Anxiety in major depression and cerebrospinal fluid free gamma-aminobutyric acid. Depression and Anxiety the official journal of ADAA. 2014; 31(10): 814-821.

6. Livestrong. A List of Foods with the Highest GABA. Updated April 19, 2015. http://www.livestrong.com/article/478780-a-list-of-foods-with-the-highest-gaba/#page=1 Accessed November 20, 2015

7. Overcoming Your Anxiety. Natural Anxiety Remedies. Updated 2015. http://overcomingyouranxiety.net/naturalanxietyremedies/ Accessed October 1, 2015.

8. Li AW and Se Young Choung. Treatment of GABA from Fermented Rice Germ Ameliorates Caffine-Induced Sleep Disturbance in Mice. Biomolecules & Therapeutics. 2015; 23(3): 268-274.

9. Li AW and RP Brown. Effects of yoga on the autonomic nervous system, gamma-aminobutyric-acid, and allostasis in epilepsy, depression, and post-traumatic stress disorder. Medical Hypotheses. 2012; 78(5): 571-579.

10. Li AW and Judith R. Homberg. Activation of GABA-A receptors during postnatal brain development increases anxiety-and depression-related behaviors in a time- and dose-dependent manner in adult mice. European Neuropsychopharmacology. 2015; 25: 1260-1274.

11. Li AW and Cornelius Gross. GABA homeostasis contributes to the developmental programming of anxiety- related behavior. Brain Research. 2008; 1210: 189-199.

12. beyondblue. The Facts> Anxiety. Updated November 3, 2015. https://www.beyondblue.org.au/the-facts/anxiety Accessed October 1, 2015.

13. Li AW and Kuchta K. GABAA Receptor Binding Assays of Standardized Leonurus cardiaca and Leonurus japonicus Extracts as Wells as Their Isolated Constituents. Planta Medica. 2015; 81(12-13): 1103-1110.

14. Li AW and Qinghua Wang. Immunological GABAergic interactions and therapeutic applications in autoimmune diseases. Autoimmunity Reviews. 2015; 14(11): 1048-1056.

15. Li AW and Victoria B. Risbrough. The GABAB receptor positive modulator BHF177 attenuated anxiety, but not conditioned fear, in rats. Neuropharmacology. 2015; 97: 357-364.

16. Chelsea R. Kasten and Stephen L. Boehm II. Identifying the role of pre-and postsynaptic GABAB receptors in behavior. Neuroscience & Biobehavioral Reviews. 2015; 57: 70-87.

17. Li AW and Malgorzata Frankowska. Effects of GABA-B receptor ligands in animal tests of depression and anxiety. Pharmacological Reports. 2007;59: 645-655.

18. Li AW and Jian Fei. Reduced anxiety and depression-like behaviors in mice lacking GABA transporter subtype 1. Neuropsychopharmacology. 2007; 32: 1531-1539.

19. Georgette M. Gafford and Kerry J. Ressler. GABA and NMDA receptors in CRF neurons have opposing effects in fear acquisition and anxiety in central amygdala vs bed nucleus of the stria terminalis. Hormones and Behavior. 2015; In Press: 1-7.

20. The Brain from Top to Bottom. Anxiety Neurotransmitters. http://thebrain.mcgill.ca/flash/d/d_04/d_04_m/d_04_m_peu/d_04_m_peu.html Accessed October 1, 2015.