1. GABA Deficiency Symptoms

  2. About GABA. What Does GABA Do?

  • Major Causes of GABA Deficiency

  • GABA & The Brain & The Immune System- The role of GABA in Neuroplasticity, Myelin Formation, Intelligence, and Higher Cognitive function, and Protection Against Neurodegeneration, On the Immune System and Inflammation

  • GABA Deficiency & MS-Could GABA Deficiency Be A Secret Cause of MS?

  • GABA and the Gut/Gut-Brain Axis

  • GABA And The Sleep -Awake Cycle

       3. How To Increase GABA Naturally  and  Drugs That Increase GABA

  1. Gaba Deficiency Symptoms

          GABA deficiency symptoms (mental/emotional symptoms)

  • Anxious or panic for no reason

  • Great fear or apprehension

  • Overwhelmed for no reason

  • Reduced ability to cope with stress

  • Restless

  • Unable to relax

  • Mood swings

  • Scattered attention, memory problems

  • Feeling a lump in the throat or butterflies in the stomach

  • Worry about things and situations you never thought before

  • Short, violent temper even delusions (advanced GABA deficiencies)

  • Depression [36] or bipolar

  • Phobias

  • Motor tics

  • Insomnia or excessive sleeping, restless leg syndrome

  • Alcohol or marijuana abuse

  • Increased sensitivity (to sounds, chemicals, light, etc)

      GABA deficiency symptoms (physical symptoms)

  • Neuro and MSK (musculoskeletal): blurred vision, dizziness, tingling and numbness; migraines or seizures (in severe deficiencies), slow movements, muscle tension and weakness, muscle pain, fibromyalgia

  • Digestive: moderate/severe diarrhea or constipation with/without associated IBS, significant changes in appetite, vomiting

  • Cardiovascular: tachycardia (rapid heartbeat), palpitations, low or high blood pressure, cold hands and feet

  • Respiratory: allergies, asthma, coughing or choking

  • Genitourinary: PMS or excessive menstrual bleeding, night sweats, urinary frequency

*Symptoms often worsen when you skip a meal or try to fast

* *not all the symptoms above must be present; these symptoms may be caused by other conditions as well. The low GABA symptoms list above gives you an idea of what happens if you have a shortage of this neurotransmitter.

 

2. About GABA. What does GABA Do?

Why GABA Deficiency Is So Common

Up to one-third synapse in the brain need the neurotransmitter GABA [1].  GABA is a major inhibitory neurotransmitter of the brain, promoting a healthy brain rhythm and keeping the other neurotransmitters in check (glycine is the main inhibitory neurotransmitter in the brain stem/spinal cord). When GABA levels are not optimal the brain electricity becomes unstable, produced in bursts, and therefore affecting the entire body and emotional well-being.

For a long time, GABA and serotonin had been known as being the calming neurotransmitters- they make you more calm and relaxed, where dopamine and acetylcholine are the accelerating (excitatory) neurotransmitters.

More recently, scientists discovered that GABA is the only true calming (aka inhibitory) neurotransmitter. Serotonin, acetylcholine, and dopamine can also be excitatory or inhibitory (depending on what type of receptors they encounter).  Let’s focus on GABA and serotonin for now.  

We live in a fast pace word, always hitting the go-go button. To no surprise, more and more people experience anxiety and feeling burned out. One key underlying problem is neurotransmitter deficiency (GABA and/or serotonin). Since GABA and serotonin deficiency share so many symptoms, how can you tell which is depleted?

Generally speaking, GABA is the anti-anxiety, calm, emotionally-stable feeling neurotransmitter. Serotonin is the anti-depression, mood regulator, happy feeling neurotransmitter. You will get a better idea when you read Clara’s story, a case of GABA deficiency in a GABA dominant nature, and compare with serotonin nature I described in this article.

Also, keep in mind that it could be a shortage of both at the same time. You may need support for both serotonin and GABA at the same time. Standard treatment often uses both anti-depressant and anti-anxiety drugs together- the concept is great, but there are a lot of side effects.  There are effective, natural alternatives to correct GABA and serotonin deficiencies, which are covered in this article.

While GABA is considered the classical, the most important anti-anxiety neurotransmitter, there are also many other ones involved in the development of anxiety- serotonin was mentioned above, as well as opioid peptides, endocannabinoids, neuropeptide Y, oxytocin and corticotropin-releasing hormone (CRH) [2].

Serotonin is made in specific areas of the brain. On the other hand, GABA producing neurons are widespread throughout the entire brain.

The precursors of GABA are glucose (the predominant precursor) [3], as well as pyruvate and the amino acid glutamine.

Glutamine → Glutamate  →  GABA  

                             ↑                         ↓

              Citric Acid Cycle ←    Succinate semialdehyde (SA)        

The excitatory neurotransmitter glutamate will be the topic of another article. The conversion glutamate → GABA requires GAD (the enzyme glutamic acid decarboxylase) and vitamin B6 (the active form of B6 is p5p).

Technical: GABA production is a result of energy produced in the brain in so-called GABA shunt. Glucose is metabolized for energy and one of the byproducts — glutamate- is converted into GABA as needed. Once the GABA is utilized, it then converts into succinate semialdehyde —> TCA, leading to conversion into glutamate. Glutamate is the salt form of the amino acid glutamic acid.

A few important things worth mentioning.  Supplementing with glutamine can be used to raise GABA levels, but should be taken always with vitamin B6 as well as magnesium, zinc. Otherwise, glutamine supplementation may fail to raise GABA, but rather convert/raise the levels of glutamate (note: excess glutamate is a major issue not only in MS [4], but in many conditions as well). Next, you have to look into other reasons that decrease the conversion glutamine to GABA such as inflammation, autoimmunity, impaired gut microbiome, chronic stress, etc.

GABA is produced not only by the neurons but also by immune cells as well as in other organs (pancreas, pituitary, testes, gastrointestinal tract, ovaries, placenta, uterus and adrenal glands) [5]

Causes of GABA deficiency:

  • Some cases are associated with a genetic inability to synthesize GABA [6] . Most cases of GABA deficiency, however, are related to :

  • Stress (chronic stress increases the cortisol, epinephrine, and norepinephrine, in addition to making the body produce more glutamate/less GABA) [7] , causing chronic GABA deficiency [8], blood sugar imbalances, diet, food intolerances (especially gluten and dairy), altered gut microbiome and autoimmune conditions (especially MS, type 1 diabetes, psoriasis and rheumatoid arthritis ) [9]. 

  • Lack of sleep causes GABA deficiency, which further aggravates sleeping problem- it is a vicious cycle, creating more GABA shortage and more sleeping issues over time [10]

  • Nutrient deficiencies: Magnesium deficiency is common, affecting as many as 70-80% of the population. Correcting this deficiency could improve GABA levels because magnesium plays a key role in binding and activating GABA receptors, and increases the body’s ability to use GABA in an effective way. [11] 

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GABA & The Brain & The Immune System

GABA & The Brain. Back to the question: What does GABA do? let s start with its role in the brain. GABA is mostly searched and known as a neurotransmitter in the brain. During the early developmental stage, GABA is an excitatory neurotransmitter, playing a key role in the formation of new neurons (neurogenesis). In the mature brain, GABA act in an inhibitory neurotransmitter, opposing the excitatory glutamate (glutamate and GABA work together to keep the proper inhibitory-excitatory balance in the mature brain). GABA is involved in neuroplasticity, and GABA producing neurons seem to work closely with the myelin-producing cells (called oligodendrocytes), especially in the hippocampus area of the brain. Furthermore, oligodendrocytes have GABA receptors are formed in the same area of the brain. GABA promotes higher cognitive function and intelligence [12]. GABA works closely with other neurotransmitters and hormones, influencing the production of serotonin and melatonin [13]. Dopamine, norepinephrine, and histamine. Of course, GABA has a very close relationship with glutamate

GABA protects the brain against neurodegeneration; in case of neuron injury, GABA limits the injury and promotes the repair of the brain cells.GABA system is involved in various brain conditions- from traumatic brain injuries and stroke to anxiety, depression, and schizophrenia [14]. 

Recent studies found that the immune system has the ability to synthesize and release GABA. This neurotransmitter has severe effects on the immune cell, having an impact on inflammatory cytokines.

Technical: cells of the immune system produce GABA and express GABA-A ion channels, GABA transporters, and the GABA-B receptor. The old theory that GABA-A channels only fully activated by millimolar concentrations of GABA is untrue. Recent studies found that extrasynaptic channels can be activated by million times lower GABA concentrations compared with their synaptic counterparts and may be saturated by nano to micromolar GABA concentrations. Submicromolar GABA concentrations are found around neurons in the brain, as well as within the pancreatic islets and in blood [15]. 

GABA Deficiency and MS- Could GABA Deficiency Be A Secret Cause of MS? 

GABA levels in the blood are decreased in people with   MS [16]. Low levels of  GABA in the brain is found in progressive multiple sclerosis (when compared with healthy controls) and the levels of these neurotransmitters are associated with physical disability [17]. Another study found a correlation between GABA and glutamate levels and the degree of disability [18]. 

Increasing the brain GABA concentration ameliorated paralysis in EAE (animal models of MS), by inhibiting the onset of inflammation, according to another study [19].  Drugs that improve GABA are used to treat MS symptoms- from anxiety and sleeping problems to tremor [20], neuropathic pain (tingling and numbness) [21]  or urinary symptoms [22]. 

 

The concept of using GABA as a biomarker of neurodegeneration in MS had emerged, however, it does require special imaging/MRI techniques [23]. 

GABA multiple sclerosis link? There are significant changes in neurotransmitters in multiple sclerosis.  I covered in other articles serotonin, dopamine, norepinephrine deficiencies associated with MS and histamine excess associated with MS. Acetylcholine deficiency and glutamate excess are also linked with MS, I will write about them in the next articles.  Could be a neurotransmitter responsible for multiple sclerosis? Scientists do not know which came first- the disease or the neurotransmitter imbalance. What is known, however, is that a vicious cycle is created and one aggravates the other: neurotransmitter deficiency plays a role in the development of symptoms and makes symptoms worse, and inflammation and autoimmune attack contributes to neurotransmitter deficiency. I should note that not everyone with MS will have the same deficiencies- for one person could be GABA, for another one could be dopamine. 

GABA and the Gut/Gut-Brain Axis

What does GABA do in the gut?  GABA is an important neurotransmitter (and hormone)in the gut as well, working closely with other neurotransmitters and hormones to maintain digestive function [24], [25]. 

You have a second brain in the gut- the enteric nervous system (ENS). The nerve cells of the ENS of the gut have plenty of GABA receptors.

Overall, GABA regulates gastrointestinal activity including GI motility, secretion, and gut inflammation [26], as well as transient lower esophageal sphincter relaxation and visceral pain [27].

The abnormal gut microbiome (which is often found in autoimmune diseases, infections, taking certain drugs)  is a major risk factor to develop GABA deficiency [29], [30]

 

Technical: GABA promotes increased motility and secretion via GABA-A receptors; there is also inhibition via GABA-B receptors. GABA and  GABA-A receptor analogs influence the release of acetylcholine, gastrin, and somatostatin.GABA receptors also modulate 5-HT release from the gut, histamine release from mast cells,  as well as gastric mucous secretion and prostaglandins released from interstitial cells. GABA-B receptor agonist baclofen (which is used for muscle spasms in MS), also has anti-ulcer activity [31] and inhibits the formation of cancerous cells and tumor growth in the digestive tract [32]. 

GABA And The Sleep -Awake Cycle

What does GABA do for your sleep? As a primary inhibitory neurotransmitter in the brain, GABA has a crucial role in the sleep awake regulation- including circadian rhythm, falling asleep, maintaining the sleep, generating slow-wave (deep ) sleep. Sleeping pills (benzodiazepines) specifically work by modulating GABAA receptor and are highly effective to treat insomnia short term [33] (do notice they work only short term!).

GABA-A receptors aren’t the only ones that promote sleep. Scientists discovered more recently the  GABAC receptors which are more sensitive to GABA than GABA-A receptors or  GABA-B receptors. Drugs that target GABA-C receptors are currently researched, especially to improve sleep, visual and cognitive problems. They seem to be more selective,  safer and needed in lower disease compared with the drugs that target GABAA receptors [34], [35].

You can read my next article about ways to improve GABA levels- naturally or with prescription meds.