GABA in the Treatment of Anxiety

by Douglas Lobay, BSc, ND

Anxiety is a feeling of worry, nervousness, apprehension, fear, and generalized unease. It is one of the most common psychiatric disorders in North America. An estimated 4.8% of males and 6% of females suffer from anxiety at any given time. Up to 25% of the population may suffer from anxiety at some point in their lives. It is one of the most common conditions seen in general practice by family physicians. These conditions include generalized anxiety disorder (GAD), panic disorder, social anxiety, specific phobias, obsessive-compulsive disorder (OCD), posttraumatic stress disorder (PTSD), persistent depressive disorder (PDD), and major depression. Concomitantly, 90% of people with anxiety suffer with depression.

Some of the most widely prescribed drugs in North America used to treat anxiety are benzodiazepines. These drugs include Ativan (lorazepam), Klonopin (clonazepam), Valium (diazepam), Xanax (alprazolam), and Versed (midazolam), to name a few. These drugs are highly addictive and can create physical and psychological dependence. They can cause many of the side effects that they were intended to treat. Withdrawal effects include anxiety, insomnia, agitation, seizures, muscle spasms, sweating, drowsiness, slurred speech, respiratory depression, and cognitive and memory impairment.

Gamma-aminobutyric acid (GABA) is an excellent natural remedy for the treatment of anxiety. Despite the long-held belief that GABA does not cross the blood–brain barrier, I have found that it produces a strong, desired anxiolytic affect for most people. In this article, I discuss the chemistry and pharmacology of GABA, the blood–brain barrier, mechanism of action of GABA, laboratory studies of GABA, clinical studies of GABA, and my own personal experience with GABA as a practicing naturopathic physician.

Chemistry and Pharmacology

GABA was first discovered and isolated in Germany in 1863. It wasn’t until 1950 that its function as an inhibitory amino acid in the nervous system was identified. GABA is a four-carbon-long amino acid with a carboxylic acid group at one end carbon and a nitrogenous amine group at the other end carbon. GABA has a chemical formula of C4H9N02. Its molecular mass is 102.12 grams per mole. It is a white, crystalline powder and is freely soluble in water and partially soluble in alcohol. No LD50 value has been determined in humans. In mice GABA has a LD50 of 12,680 milligrams per kilogram.¹

GABA is synthesized from the amino acid glutamine via the enzyme glutamic acid decarboxylase (GAD). Pyridoxal-5-phosphate is required as a cofactor in the activity of the GAD enzyme. The GABA shunt can convert excess GABA back into glutamine. GABA can also be used as an intermediate molecule in the Krebs cycle.²

GABA is found in small amounts in many plants. It functions as an intracellular messenger. It was found to accumulate rapidly in plant tissue in response to biotic and abiotic stress. It may also play a role in plant metabolism and the nitrogen cycle.³ The GABA content of ginger (Zingiber officinale) is 0.0114% and turkey berry (Solanum torvum) is 0.0119%.⁴

GABA is found in many foods, including fermented foods. GABA is incorporated in chocolate, green tea, rice, soy sauce, kimchi, a Japanese fermented fish dish, Chinese pickled vegetables called pao cai, and fermented milk products, including cheese and yogurt. Bacteria such as Lactobacillus, Rhizopus, Streptomyces, and Monascus can produce GABA in the fermentation process.² Pharma GABA is the proprietary name given to GABA that has been produced by bacterial fermentation. GABA is also produced synthetically from the organic solvent pyrrolidinone. Structurally the GABA molecules produced are the same.¹

GABA is absorbed across the human intestine similarly to other amino acids. It shares a common protein transporter across the human intestinal epithelial cells. Lower pH favours increased absorption of GABA across the brush border of the intestines.⁵ In human studies, GABA is rapidly absorbed with peak absorption occurring ½ to 1 hour after oral consumption. The half-life of GABA in the blood is 5 hours. GABA and its metabolites are mainly excreted through the kidneys as 79% of a single oral dose.⁶

Blood–Brain Barrier

The blood–brain barrier (BBB) is a highly selectively permeable membrane that separates the blood from the brain extracellular fluid. It forms by close fitting capillary endothelial cells connected by tight junctions. It has high electric resistivity and prevents many charged molecules from penetrating this barrier. It allows more neutral lipid soluble molecules, gases, and water to enter the brain. There are a few regions of the brain that do not have a BBB. These areas include the pineal gland, the pituitary gland, and areas around the ventricles in the brain.⁷

The idea that GABA does not cross the BBB is largely based on a 1971 experiment on adult mice and rabbits. Radiolabeled GABA was injected intraperitoneally and intraventricularly to the test animals. No significant amount of GABA that was injected intraperitoneally showed up in the brains of the mice or rabbits. The researchers concluded that GABA does not cross the BBB. This conclusion persists today based upon this single study. However, some important question about the permeability of the BBB to GABA remain. This study was done in mice and rabbits, not humans. It was with intraperitoneally injected GABA, not from oral consumption. Certain metabolites of GABA were identified in the brain of these test animals and throughout other parts of the body, but this was not followed up.⁸

There are some novel ways of enhancing GABA absorption across the BBB. The addition of L-arginine to GABA for oral consumption dramatically increased GABA concentration in the brain in rats. GABA concentrations in the brain showed a fourfold increase, or 383%, following the addition of L-arginine in a dose dependent manner. The researchers concluded that L-arginine increased the permeability of the BBB to peripheral GABA.⁹ A synthetic combination of GABA and niacin called picamilon was developed in the former Soviet Union in 1969. One study showed that picamilon was rapidly absorbed, penetrated the BBB, and released GABA that was able to bind GABA receptors in various parts of the brain.¹⁰ In another study, the permeability of the BBB to GABA in the region of an epileptic focus was assessed in laboratory animals. GABA was given intravenously, and any change in epileptic spike activity on an EEG was measured. The infusion of GABA significantly increased the permeability of GABA around the epileptic focus and decreased the EEG seizure activity.¹¹

Mechanism of Action

GABA is the major neuroinhibitor of the central nervous system. At least 20%, although estimates say as high as 50%, of all neurons in the central nervous system have GABA receptors. It is important to note that GABA is not just confined to the central nervous system; it is also widely found in peripheral neurons, and muscle tissue. GABA is found in liver, kidney, lung, stomach, pancreas, ovaries, testes, and eyes.¹ Stimulation of GABA receptors causes relaxation and calmness throughout the body.¹² Anxiety is created when there is an imbalance between excitatory neurotransmitters such as glutamine, adrenaline, and other catecholamines and inhibitory neurotransmitters such as GABA.¹³

GABA is released from presynaptic neurons and binds to postsynaptic GABA receptors. Two specific GABA receptors have been identified; GABA-A and GABA-B. GABA-A receptors regulate chlorine ion inflow and outflow. When the GABA-A receptor is stimulated, a conformational change occurs across the protein ion channel that allows the influx of negatively charged chlorine ions into the cell. A corresponding outflow of potassium ion occurs. The net effect is a negative charge of the postsynaptic neuron. The result of this negative hyperpolarization of the cell is that there is no depolarization and no electric impulse generated. The postsynaptic nerve is therefore inhibited and does not fire. The GABA-B receptor is a G-protein coupled receptor that opens in response to GABAergic stimulation.¹⁴

Laboratory Studies

A GABA-containing rice-germ ferment extract was administered to mice pretreated with caffeine. Doses of 10, 30, and 100 milligrams per kilogram were given to the mice. A dose-dependent response was observed to counter the stimulating effects of caffeine. The researchers concluded that the supplement countered the sleep disturbance induced by caffeine without affecting general locomotor ability in the mice.¹⁵

The effect of GABA-enriched soybean on blood pressure was investigated in male hypertensive rats. Ten-week-old rats were given diets containing graded levels of GABA-enriched soybean for 8 weeks. The systolic blood pressure in the rats fed 0.15% GABA diet was significantly lower at the first week and maintained lower values for 4 weeks as compared with the 0% GABA control. No effect on blood pressure was found in the 0.03 and 0.3% GABA diets. The results suggest that there exists an appropriate dietary GABA level to get a blood–pressure lowering effect.¹⁶

Another study investigated the neuronal effects of GABA in the common fruit fly. GABA administration increased sleep time, decreased nighttime activity, increased GABA levels at both 1 and 12 hours following intake, and modulated nighttime activity, sleep episodes, and total duration of sleep.¹⁷

GABA enhanced the catabolism of serotonin to N-acetylserotonin, a precursor to melatonin in rats. GABA is believed to be involved in the synthesis of melatonin and may exert a regulatory effect on sleep and reproductive function.¹⁸

Clinical Studies

The effects of orally administered GABA on relaxation and immunity during stressful events was investigated in humans in two different studies. In the first study, the effect of GABA intake was evaluated in 13 different subjects on their brain wave activity. After 60 minutes of GABA consumption, there was a significant increase in alpha waves and a corresponding decrease in beta waves. These findings denote that GABA not only induces relaxation but also reduces anxiety. The second study was conducted to see the relaxant and anxiolytic effects of GABA intake on immunity in stressed volunteers. Eight acrophobic subjects were divided into two groups: placebo and GABA-treated individuals. All subjects were crossing an elevated suspension bridge. Immunoglobulin A (IgA) levels were monitored during the bridge crossing. The placebo group showed a marked decrease in IgA levels, while the GABA-treated group showed significantly higher levels. It was concluded that GABA worked as a natural relaxant and its effects could be seen within 1 hour of administration to induce relaxation and diminish anxiety. Moreover, GABA administration could enhance immunity during stressful conditions.¹⁹

In a double-blind, randomized, controlled trial, 7 healthy subjects were assigned a tablet containing GABA or placebo. Parameters including heart rate, blood pressure, stroke volume, cardiac output, and heart rate variability were measured. Heart rate and heart rate variability significantly increased in the control tablet group, but not in the GABA-treated group. There were no significant differences between GABA and placebo in blood pressure, stroke volume, cardiac output, and total peripheral resistance. In conclusion, these results suggest the possibility that single administration of a vegetable tablet containing GABA suppresses the sympathetic nervous system.²⁰

In another randomized, single-blind, placebo-controlled, crossover study, 63 adults of 28 males and 35 females were studied over 2 days. Capsules containing 100 milligrams of GABA or 100 milligrams of dextrin as placebo were used as the test agent. The results showed that EEG activity, including alpha and beta waves, was decreased depending on the level of mental stress task. GABA also decreased the scores on the profile of mood states (POMS) test used to evaluate the response to stress.²¹

Another study investigated the effects of oral GABA administration on temperature regulation during rest and exercise in humans. On two occasions, 8 athletic men rested for 20 minutes then cycled for 30 minutes at 65% of VO2 max. An electrolyte replacement sports drink was given before the start of the rest period. On one occasion, the athletes were given a plain sports drink and on the other occasion the same sports drink with a 1000 milligrams of GABA added. Esophageal temperature, sweat rate, and circulating plasma catecholamine levels were inhibited in the GABA-treated group. The effects observed were because GABA was believed to attenuate the sympathetic nervous system during exercise.²²

Other Potential Clinical Uses

GABA has been used as an ergogenic aid for body builders and weight lifters. Blocking GABA degradation has been shown to affect growth hormone (GH) secretion. GABA neurons are found in the hypothalamus and pituitary gland. GABA can have a dual effect on GH secretion. It can have an inhibitory and excitatory effect on GH secretion depending on its release from the hypothalamus or pituitary gland.²³ Orally administered GABA has been shown to increase human growth hormone levels.²⁴

Oral consumption of GABA significantly increased circulating insulin levels: 1.6 times with a single dose and 2.0 times with a repeated dose. GABA also increased circulating glucagon levels only under fasting conditions. The potential therapeutic benefits of using GABA in the treatment of diabetes is exciting. GABA is also produced in beta pancreatic cells. It is believed to function as an intra-islet messenger and regulator of pancreatic islet function.²⁵

GABA supplementation increased sperm motility and kinematic activity in 22 sperm samples.²⁶

Internet User Feedback

Patient feedback has been a practical way of assessing the benefits and side effects of oral GABA consumption. An informal Internet search of Amazon and iHerb sites providing customer feedback is consistent with what I see in clinical practice. In rating GABA for effectiveness, 54% to 59% of respondents gave 5 stars; 19% to 22%, 4 stars; 3% to 4%, 2 stars; and 6% to 11%, 1 star. Approximately half of the 1- and 2-star-rated products showed lack of effectiveness. Other noted side effects included fatigue, tiredness, lack of sleep, inability to fall asleep, restless sleep, anxiety, panic attacks, shortness of breath, asthmalike symptoms, irritation in throat and mouth, tingling or itching throughout the body, headache, depression, and irritability.

Personal Clinical Experience

I have been using GABA in my clinical practice as a naturopathic physician for 24 years. I have found it to be an excellent remedy for anxiety and allied anxiety related disorders. I have tried Pharma GABA and synthetic GABA and have found no difference between them. I have used GABA alone and found that, for most people, the effects are dose dependent. A typical adult dose is between 100 and 500 milligrams of GABA per capsule. I have found that when I combine GABA with anxiolytic herbs, it seems to work better. I have had GABA products manufactured with herbs including kava kava (Piper methysticum), valerian (Valerian officinalis), hops (Humulus lupulus), and passionflower (Passiflora incarnata). Patient feedback is excellent with the combined product. I typically use 400 to 500 milligrams of synthetic GABA and mix it 100 to 200 milligrams of kava kava. Patients are instructed to typically take 1 to 2 capsules 1 to 2 times per day as needed. The GABA product combines well with melatonin for poor sleep quality and insomnia. Patients appear not to be addicted to the product, as the case may be with prescription benzodiazepines. And although not typically as strong as the benzodiazepines, most patients like the results of the combined product. I have also used GABA as a muscle relaxant and for the treatment of chronic pain conditions such as fibromyalgia. In terms of adverse side effects, my patient feedback is almost identical to the Internet feedback. I have found that for about 50% to 60% of patients, the product is excellent for the treatment of anxiety. For 10% to 20%, the GABA product doesn’t seem to produce the desired effect. And 5% to 10% of patients experience some adverse side effects such as tingling throughout the body, shortness of breath, or increased anxiety and insomnia. For less than 5% of patients, GABA seems to bring the opposite of its desired effect. I believe it to be a genetic polymorphic aberration, with GABA’s being an excitatory amino acid instead of inhibitory. For these patients, GABA does not have its desired anxiolytic effects, and deleterious effects disappear after its use is discontinued.

Conclusion

GABA is an excellent nonpharmaceutical alternative in the treatment of anxiety. I have briefly discussed the chemistry and pharmacology of this amino acid neurotransmitter. I have provided some information on the BBB and mechanism of action of GABA. I have offered some ideas why GABA may cross the BBB, producing some desired effects. I have provided some laboratory and clinical studies supporting the use of GABA as a centrally acting anxiolytic. I have then discussed my personal experience of using GABA in private practice. I provide some generalized dosing instructions and some insight of combining it with other herbal anxiolytics. I conclude that GABA is very beneficial in the treatment of anxiety and can be easily combined with other appropriate therapies.

Notes

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15. Mabunga DF. Treatment of GABA from fermented rice germ ameliorates caffeine-induced sleep disturbance in mice. Biomol Ther. 2015 May 23(3):268–274.

16. Shizuka F et al. Antihypertensive effect of gamma aminobutyric acid enriched soy products in spontaneously hypertensive rats. Biofactors. 2004;22(1–4):165–167.

17. Hong KB et al. Sleep-promoting effects of GABA/5HTP mixture: Behavior change and neuromodulation in an invertebrate model. Life Sci. 2016 Feb 24 301:36–39.

18. Balemans MGM et al. The Influence of GABA on the synthesis of N-acetylserotonin, melatonin, O-acetyl-5-hydroxytryptophan and O-acetyl-5-methoxytryptophol in the pineal gland of the male Wistar Rat. Reprod Nutr Develop. 1983;23:151–160.

19. Abdou AM et al. relaxation and immunity enhancement effects of gamma amino-butyric acid (GABA) administration in humans. Biofactors. 2006; 26(3):201–208.

20. Okita Y et al. Effects of vegetable containing gamma aminobutyric acid on the cardiac autonomic nervous system in healthy young people. J Physiol Anthropol. 2009;28(3):101–107.

21. Yoto A et al. Oral intake of gamma-aminobutyric acid affects mood and activities of the central nervous system during stress conditions induced by mental stress. Amino Acids. 2012 Sep;43(3):1331–1337.

22. Miyazawa T et al. Effect of oral administration of GABA on temperature regulation in humans during rest and exercise at high ambient temperature. Osaka City Med J. 2009 Dec;55(2):99–108.

23. Powers M. GABA supplementation and growth hormone response. Med Sport Sci. 2012; 59:36–46.

24. Powers ME et al. Growth hormone isoform responses to GABA ingestion at rest and after exercise. Med Sci Sports Exerc. 2008 January;40(1):104–110.

25. Passariello N et al. A possible role of gamma-aminobutyric acid in the control of the endocrine pancreas. J Clin Endocrinol Metab. 1982 Jun;54(6):1145–1149.

26. Calogero AE et al. effects of gamma-aminobutyric acid on human sperm motility and hyperactivation. Mol Hum Reprod. 1996 2(10):733–738.

Dr. Douglas Lobay, BSc, ND

103B-1980 Cooper Road

Kelowna, BC, V1Y 8K5

dglslby@shaw.ca