Gamma-aminobutyric acid (GABA) is a major neurotransmitter (chemical signals that are transmitted to cells) that is largely found in the central nervous system. It is an inhibitor – the most important one in the brain – which kicks in when the body experiences too much stimulation, leading one to be overly excited. Too much excitement can lead to irritability, insomnia, restlessness, seizures, and disorders with bodily movement. GABA can also be used for stress reduction, as medications like benzodiazepines activate GABA receptors, which inhibit the overabundance of chemical signals one has when overly excited, causing relaxation. As such, low GABA levels or even a decreased GABA function in the brain can lead to a multitude of psychiatric and neurological disorders, the likes of which include: depression, insomnia, epilepsy, and anxiety. Many studies indicate that GABA can be used to enhance sleep and improve relaxation by reducing excitability.
Both natural and synthetic (man-made) GABA can be purchased in North America as dietary supplements. Natural GABA is made through a vegetable fermentation process that uses Lactohacillus hilgardii – a bacteria used to prepare the famous, traditional Korean dish: kimchi.
Mechanisms of Action
GABA takes care of pre-synaptic inhibition in the motor neuron system of primary afferent fibers. It regulates the excitability of the brain through GABA receptors, which are categorized into three major groups: alpha, beta, and gamma (with subunits that further determine its pharmacological activity). For example, a select number of benzodiazepines have a tendency to strongly bind with the alpha 1 subunit, while others bind to different alpha subunits. Together with its neurological effects, GABA seems to demonstrate effects on the endocrine system. It was discovered to be able to produce a large increase in plasma growth hormone levels following a single, high dose intake of 5 g. Discovered in high concentrations in islet cells from the pancreas, GABA led to improved plasma levels of immunoreactive insulin, glucagon, and C-peptide without changing plasma glucose concentration, in 12 healthy subjects given oral doses of 5 or 10g. The significance of these endocrine effects in clinical settings are still unclear.
A Deficiency in GABA
As mentioned above, low GABA levels or functions can lead to many psychiatric and neurological disorders, such as: depression, insomnia, and anxiety. As a result of these conditions, many anti-anxiety and sleep-inducing drugs have been developed that primarily stimulate GABA receptors. Many medications include the benzodiasepine drug – diazepam (Valium), triazolam (Halcion), alprazolam (Xanax), quazepam (Doral), zolpidem tartrate (Ambien), baclofen (Kemstro and Lioresal), temazepam (Restorir), and flurazepam (Dalmane). Olfactory (perception of smell) and gustatory hallucinations (perception of taste with stimulus) have been linked to GABA levels in the brain. Treatments which cured these hallucinations involved increasing the amount of GABA in the central nervous system.
Clinical Applications of GABA
Clinical studies on the supplementation of GABA are rather limited. Studies have mainly focused on synthetic GABA analogues, e.g. Gabapentin, or other drugs which attach themselves to GABA receptors. As a result, most of the clinical applications of GABA are purely theoretical, based on word-of-mouth clinical experience or data extrapolated from drug studies. A large scale clinical study on a plethora of psycho-neurological conditions is direly needed.
GABA may be able to aid with sleep due to its effects on relaxation. In the thalamus (the part of the brain involved with sleep processes), GABAA receptors are highly active. GABA-agonist drugs like temazepam (Restoril) or zolpidem (Ambien) are used in insomnia treatment as sedatives. Gabapentin, the synthetic GABA-like drug that can increase GABA levels in one’s brain, was discovered to have improved sleep disturbances linked with the consumption of alcohol.
In an unpublished, small study, 100 mg of a natural source GABA lowered sleep latency by 20 percent, while raising the time spent in deep sleep by 20 percent.
Since an insufficient amount of GABA brain activity or reduced levels of GABA have been linked with anxiety, many anti-anxiety drugs (some of which has been in use for close to half a century), target the GABA receptor. A small early study of six subjects found the analog drug gabapentin to be effective for panic disorder. Natural relaxation therapies also help, at least in part, by enhancing one’s GABA levels. A controlled study found that GABA levels in the brain were highly increased after a 60-minute session of yoga compared to a hour long reading session. Another study found an active component of valerian, valerenic acid, regulates GABA receptors.
In a double blind, unpublished comparison study (so as to prevent experimenter bias and placebo effects) a natural source of GABA (PharmaGABA) was found to produce relaxation as indicated by changes in brain wave patterns, heart rate, and the diameter of the pupil, in addition to reduction of the stress markers salivary cortisol and chromogranin A (adrenal stress marker).
To measure brain wave activity, an electroencephalogram (EEG) is used. Alpha waves are generated while in a relaxed state, unlike beta waves which are found in stressful situations that make it difficult to focus on mental concentration. As a result, the ratio between alpha-to-beta waves is used as a measure of relaxation and increased concentration. For the most part, the bigger the discrepancy between the alpha-to-beta ratio, the more relaxed and aware the person is.
A pilot experiment carried on at the University of Shizuoka in Japan involved 13 healthy volunteers: six females and seven males roughly between the ages of 21-35. A couple of hours before the study began, the subjects were instructed not to eat, drink, or use any form of tobacco. EEG readings were recorded prior and after each of the three consumptions of 200 mL distilled water: (1) only distilled water; (2) distilled water mixed with 100 mg of natural GABA (PharmaGABA, in this case); (3) distlled water mixed with 200mg L-theanine (an amino acid extracted from green tea that can cause an increase in alpha-brain waves).
The administration of the tests were separated by seven day intervals. EEG recordings were acquired while the subject was quietly resting with eyes closed, and were done before administration, then starting from 0, 30, and 60 minutes after each administration for a period of five-minutes. The subject’s alpha and beta waves were determined as a percentage and pre and post-administration values were examined. The ratio between alpha-to-beta were determined as a ratio between alpha and beta percentages. The inclusion of GABA produced enormous increases on two factors: increasing alpha waves, and decreasing beta waves, causing a large increase in the alpha-beta wave ratio.
A different study brought forth more evidence that natural GABAs can help reduce stress. While blindfolded, eight subjects (between 25-30) with acrophobia (the fear of heights) were administered either 200 mg of a natural GABA (PharmaGABA) or a placebo pill prior to crossing a long walking suspension bridge that extended over a 150-foot canyon. Salivary secretory immunoglobulin A (sIgA) was determined from samples taken prior to crossing, halfway across, and once they were off the bridge.
Secretory IgA is a necessary antibody in saliva that assists in fighting off infections. Being relaxed will cause a large increase (P<0.001) in sIgA levels, while conversely, being under stress will cause a decrease in sIgA. In this experiment, sIgA was lowered by approximately 35 percent in subjects that were part of the control group. In the GABA group, however, sIgA levels maintained salivary levels at the halfway point and showed an increased level upon finishing the walk. To offset any potential discrepancies caused by the effect of saliva quantity (as a dry mouth can be caused by stress), the final concentrations of sIgA were determined in mcg/mL.
Utilizing the same suspension bridge but different subjects (n=13), a second study was conducted which yielded results in favor of GABAs ability to decrease markers of stress. The subjects took 200 mg of natural source GABA and had a 20 percent drop in salivary levels of chromogranin A (an adrenal stress marker) at the mid-way point of the bridge relative to the starting values; the control group saw a 20 percent boost in chronogranin A.
The process that most anti-epileptic drugs utilize either a direct or indirect method to increase GABA levels. These drugs act by increasing GABAergic inhibition (some examples include: phenobarbiral, valproate, and benzodiazepines), inhibiting GABA reuptake (tiagabine), improving synaptic concentrations of GABA through restriction of gamma-aminobuty rate transaminase (vigabatrin), and improving brain synaptic GABA whilst lowering neuronal influx of calcium ions (gabapentin).
Used particularly for the treatment of epilepsy during childhood, the ketogenic diet is theorized to work through GABAergic mechanisms. Ketosis improves brain metabolism of acetate, later to be converted to glutamine via glial cells. The glutamine is then used by GABAergic neurons and turned into GABA. EEG recordings in healthy human subjects that were on a ketogenic diet produced patterns that are in line with an increased amount of GABA activity.
Studies suggest that oral GABA supplementation can be beneficial for epilepsy. Both animal and clinical studies have looked into the effect of a combination of phosphatidylserine (PS) and GABA in the treatment of many types of seizure disorders.
A pilot experiment involving 42 subjects known to have drug-resistant epilepsy (10 of which have absence seizures) discovered that a combination of upping doses of GABA (1500/2500 mg daily) and PS (to 300/500 mg daily) – in different capsules – led to a significant, dose-dependent drop in absence seizures, however not in complex or simple partial seizures. Another small study examined the result of one single concentrated dose of both GABA and PS on nine epileptic subjects with convulsions linked with intermittent photic stimulation (e.g. A strobe light). The doses were: 3 g GABA with 600mg PS and 3 g GABA with 1200 mg PS. Neither of these doses yielded any improvements. The researchers concluded that it is likely that a one-time large concentrated dose is insufficient in achieving positive results.
Liposomes of phosphatidylserine as well as GABA were discovered to benefit both penicillin- and insoniazid-induced seizures in animal studies. In the latter study, both phosphatidyletheanolamine and liposomes of GABA were ineffective.
Movement Disorders: Tourette Syndrome, Parkinson’s Disease, Tardive Dyskinesia
It is no surprise that GABAergic pathways are included in the pathophysiology of a variety of movement disorders since it is the priary inhibitory neurotransmitter. A synthetic GABA analogue, Baclofen, produces antispasmodic effects and has benefitted children with Tourette syndrome. Zolpidem and gabapentin, which are GABA-agonists, have been shown to benefit patients suffering from Parkinson’s disease, while vigabatrin (gamma-vinyl-GABA), another GABA-agonist, has provided benefits for tardive dyskinesia and a variety of other movement disorders. Though no clinical research has been done on GABA for movement disorders, testing supplemental GABA seems sensible, considering the plethora of evidence implicating these conditions are likely the cause of poor GABA-pathway signaling in the pathophysiology.
Preclinical studies indicating that GABA levels are lowered in patients who suffer from depression has caused an interest in determining the role of GABA for depression. Since the proposition of GABAergic dysfunction leading to mood disorders, a variety of antidepressant drugs appear to be effective for depression by increasing GABA activity in the brain.
A study conducted in 2006 which utilized magnetic resonance spectroscopy (MRS) discovered low occipital-lobe GABA levels immediately after birth, suggesting GABA has a possible roll in depression from an early age. Similarly, another study using MRS discovered low occipital GABA levels from patients that were chronically depressed, even whilst taking medication or during depression-free periods. The authors of the study concluded that the changes might possibly represent an area of neurobiological vulnerability to constantly recurring depressive episodes.
Even though patients who suffered from various forms of depression were found to have low GABA levels, and despite GABAergic drugs offering effective treatment of depression, as of now no studies have been conducted to determine the effectiveness of GABA for treating depression.
Side Effects and Toxicity
Even though synthetic GABA-agonist drugs have the potential to cause significant side effects, ranging from dizziness and drowsiness to addiction, natural GABA usage is virtually without any side effects. This discrepancy in safety may be due to the brain’s limited capacity to hold excessive amounts of GABA, as a result of an inefficient efflux of GABA across barrier between blood and brain. LD50 tests on natural GABA using dosing of 5,000 mg/kg on rats suffered no mortality, showing an LD50 > 5,000 mg/kg in rats.
A standard dosage of GABA for sleep disorders or anxiety is 100-200 mg as much as three times daily. A small subset of individuals with epilepsy may benefit from taking dosages of GABA from 1,500-2500 mg daily.
Cautions and Warnings
GABA has not been tested for safety during pregnancy and, due to its influence on neurotransmitters, cannot be recommended during pregnancy or lactation.
If you are not sure whether GABA is for you, please consult your doctor before using. If you are currently on medication, be sure to ask your doctor whether it is acceptable to take GABA in addition to the other medications you are taking. All of the information provided above is for informative purposes only and should not be taken over a medical professional’s advice.
Photo credit: Sponge
Article of interest: GABA Side Effects