Patients with issues ranging from autism spectrum disorder to epilepsy are increasingly experimenting with dietary supplementation of gamma-amino-butyric acid (GABA), one of the body’s most important neurotransmitters. These patients, seeking to address symptoms caused by excessive neuronal excitation, have chosen to experiment with unproven treatments in an attempt to find relief, often after conventional therapies failed to address their symptoms or had undesirable side effects. But while some patients may indeed find relief using GABA supplements, some patients are concerned about the potential side effects that supplementation may have. Unfortunately, many questions remain to be answered regarding GABA’s usage as a supplement. Though GABA’s impact in the body is well-understood, far less is known about the efficacy or side effects of GABA supplements, and patients may wish to investigate alternative supplementation for greater therapeutic potential and known safety.
The Physiological Role of GABA
Why would patients want to include a GABA supplement in their diet in the first place? The reasoning behind using GABA stems from its physiological purpose as the body’s primary inhibitory neurotransmitter. In the brain, neurons release GABA at their synaptic clefts where they interface with other neurons. When GABA binds to a neuron’s receptors, it triggers a signaling cascade within the neuron which results in the neuron being less prone to activate other neurons. As a result, neurons which have recently been exposed to GABA require stronger or more consistent stimuli from other neurons before they will activate and send their electrochemical signal elsewhere in the brain or the body. The applications of inhibitory neurotransmission range from preventing disorders of excessive neuronal excitation—like seizures—to aiding the induction of sleep. Other pathologies, such as Parkinson’s disease, neuralgia, and autism, might also be improved by attenuation of excessive neuronal activation.
However, excessive GABA activity can be problematic. Chemicals that promote secretion of GABA systemically, like ethanol, have a side effect profile that is nearly identical to GABA. These side effects include slower cognition, reduced level of consciousness, sleepiness, slack muscle tone, poor motor coordination, and lowered social inhibitions. Significantly, there is no way to avoid these side effects because they are the result of GABA’s core function, which makes the prospect of finding the correct therapeutic dose for a GABA supplement very difficult. In other words, GABA supplementation will cause these same side effects if it makes any physiological impact whatsoever; the only question is the degree of those side effects. At the same time, there are a number of technical concerns with GABA supplements which may curtail their potential for effective treatment of symptoms.
GABA Supplements Face Considerable Obstacles
While side effects are a significant concern for many patients, GABA supplements also suffer from issues independent of their side effect profile, the most significant of which is its general lack of bioavailability. In other words, if patients take a GABA supplement, only a small portion of that supplement is ready for their body to use. This is because GABA cannot cross the blood-brain-barrier (BBB) in high quantities under normal physiological conditions, which means that it cannot reach the central nervous system unless the supplement has been formulated specifically to optimize bioavailability. Presently, prescription pharmaceutical drugs like Gabapentin are the only formulations of GABA that are confirmed to reliably cross the BBB in significant concentrations. This is in part because formulating supplements to cross the BBB is expensive, leading many manufacturers to neglect this critical project. As a result, most of the GABA content from these supplements ends up digested by the stomach and rendered useless, with the remainder used by the digestive tract.
GABA in the digestive tract is biologically active and available but does not cause systemic central nervous system inhibition. This means that patients taking GABA supplements for their seizure disorder are less likely to find it effective than those taking GABA supplements for an inflammatory bowel disease. This is because GABA in the digestive tract operates via the gut-brain axis. The gut-brain axis contains the vagus nerve, which sends signals regarding the comfort and digestive status of the viscera to the brain, among many other functions. If there is an abundance of stimulation of the vagus nerve, it can cause anxiety and subsequent depression in the central nervous system, but the inverse is not necessarily true; heavy inhibition of the vagus nerve’s transmissions does not heavily inhibit the central nervous system uniformly. However, it may have inhibitory effects in other areas that the vagus nerve passes through, like the heart. In fact, stimulation of the vagus nerve is used therapeutically to reduce the heart rate and normalize its pattern of beating. The inhibition of the vagus nerve may thus cause increased heart rate and anxiety—exactly the opposite of what most patients pursuing the effects of GABA would want. As a result, it’s possible that GABA supplementation could be dangerously excitatory for patients with heart issues.
GABA supplements may also cause issues in unlikely places. GABA acts on the immune cells of the gut in an inhibitory fashion and that inhibition may be excessive. Excessive inhibition of the immune cells in the gut results in weakening the adaptive immune system’s ability to respond to threats. In the context of the gut, the adaptive immune system constantly faces these threats as a result of the microbes incorporated into stool matter. While there is no research definitively linking GABA supplementation to stool-related gut infections, patients with weakened immune systems should proceed with caution.
The possibilities of an abnormally fast heart rate and weakened immune system prompted by GABA supplementation have not been confirmed by research, but this raises another important issue: GABA supplements have not been researched sufficiently to build a clinically valid side effect profile, nor have a sufficient number of patients used GABA supplements to build an anecdotal side effect profile. In fact, there are very few systematic investigations into the effectiveness of GABA supplements and even fewer consistent clinical trials which would tabulate side effects in a rigorous way. Patient reports are sparse and inconsistent. This means that the side effects of GABA supplements may exceed those which are hypothesized or be entirely different than what researchers have speculated. For patients who would rather be conservative with their health, GABA supplements may thus be too unproven to experiment with.
Furthermore, GABA supplements are highly nonspecific in their effects even if they can make it into the brain. GABA is an inhibitory neurotransmitter in every context. This makes it well-suited to reduce problems of excessive excitation like seizures but poorly suited for more subtle applications like addressing the behavioral symptoms of autism. This is because, in cases of disorders which are more complicated than uniformly excessive neuronal excitation, GABA supplements have the potential to exacerbate the problem. This is especially true for disorders which contain elements of both over-excitability and under-excitability such as attention deficit hyperactivity disorder (ADHD); GABA supplements cannot guarantee that the GABA molecules will be trafficked only to the anatomical structures where extra inhibition is needed and side effects of systemic inhibition will likely result.
Butyric Acid as an Alternative to GABA
Given the information that is currently known (and that which remains unknown), the research community has not yet formed a consensus on the merits or risks of GABA supplementation. As stated in the abstract of a recent review on the effects of GABA supplements, “There is some evidence in favor of a calming effect of GABA food supplements, but most of this evidence was reported by researchers with a potential conflict of interest.” Likewise, these researchers with potential conflicts of interest have not reported on the side effect profile of their company’s GABA supplement products. These gaps in the independent body of research may be addressed with time. For now, however, it is safe to say that because GABA is a biologically active molecule in every tissue that it contacts, there will be some sort of side effect from supplementation—but the nature of those side effects remains unclear.
Depending on the intended purpose, butyric acid may be a suitable alternative to a GABA supplement for patients with gastrointestinal disorders and neurological pathologies. Much like GABA, butyric acid is a physiological molecule which the body creates in large quantities to serve a handful of purposes. Like GABA, butyric acid behaves as a neurotransmitter when it is present in the central nervous system. In contrast to GABA, butyric acid is primarily confined to the gut, where it acts as a nutrient source for the microbiome and behaves as a regulator of immune cells and genes that code for oxidative stress, with neurotransmitter activity occurring as a tertiary function. Butyric acid’s effects in the central nervous system are still under active investigation, but it appears to lack the uniformly inhibitory effects of GABA. Instead, butyric acid behaves as a modulator of activity, preventing conditions of over or under-excitability.
Additionally, increasing the brain’s ability to compensate for oxidative stress means that butyric acid might also have broad applicability to other diseases, like Parkinson’s or Alzheimer’s disease. In these conditions, researchers have found very high levels of neural oxidative stress, which causes inflammation. The link between neural inflammation and loss of function is complex, but researchers agree that less inflammation in the brain is generally better than more. Sophisticated butyric acid supplements currently bring the prospect of reduced inflammation to these patient populations, with more applications being currently explored by research.
These multiple functions have a broad range of potential health implications. For example, with a healthy microbiome, researchers hypothesize that there will be less activation of the gut-brain axis which would contribute to chronic anxiety or depression. For patients with autism spectrum disorder, attenuated gut-brain axis activation and reduced neural oxidative stress could address a broad range of characteristic symptoms, including providing a more stable behavioral baseline. For people with inflammatory bowel disease, reducing the gut’s propensity for inflammation may reduce the frequency and severity of flare-ups and a healthy microbiome could contribute to fewer symptoms of irritable bowel syndrome owing to butyric acid’s improvement of gut motility. Meanwhile, increasing the brain’s ability to compensate for oxidative stress means that butyric acid might also have broad applicability to other conditions, like Parkinson’s or Alzheimer’s disease, which are associated with high levels of neural oxidative stress and, thus, inflammation.
Significantly, the side effect profile of butyric acid is benign, with users primarily reporting minor stomach discomfort. However, many users find that butyric acid supplementation reduces their levels of gastrointestinal inflammation, easing constipation as a result. Large clinical trials documenting butyric acid’s efficacy in a handful of disorders are forthcoming—another notable difference between it and GABA supplements. Importantly, butyric acid does not prevent the immune cells of the gut from responding to threats like GABA supplements might, as there is a finite amount of inhibition which butyric acid can cause in the immune cells. Significantly, there are now sophisticated supplements designed to optimize bioavailability entering the market, allowing users to experience the full benefits of butyric acid.
Patients who are willing to experiment with GABA supplements likely require symptom relief that they can’t find elsewhere and accepting the many unknowns of GABA supplementation may be worth the potential therapeutic benefits which these patients experience. However, for those who prefer a more characterized alternative, butyric acid is likely the better choice to address symptoms. Like GABA supplementation, butyric acid’s history of use is in its infancy, but forthcoming clinical trials will help clinicians and patients understand the nature of these two therapies and shed light on their strengths. In the meantime, patients may wish to incorporate butyric acid into their treatment plans to alleviate symptoms in a safe and highly tolerable manner.
Boonstra E, de Kleijn R, Colzato LS, Alkemade A, Forstmann BU, et al. 2015 Neurotransmitters as food supplements: the effects of GABA on brain and behavior. Front. Psychol. 6:1520. https://www.frontiersin.org/articles/10.3389/fpsyg.2015.01520/full
Pituch A, Walkowiak J, Banaszkiewicz A. 2013. Butyric acid in functional constipation. Prz Gastroenterol. 8(5):295-8. https://www.ncbi.nlm.nih.gov/pubmed/24868272
Roopa Bhat, Robert Axtell, Ananya Mitra, Melissa Miranda, Christopher Lock, et al. 2010. Inhibitory role for GABA in autoimmune inflammation. PNAS, 200915139. http://www.pnas.org/content/early/2010/01/27/0915139107/tab-article-info
Shyamaladevi N, Jayakumar AR, Sujatha R, Paul V, Subramanian EH. 2002. Evidence that nitric oxide production increases gamma-amino butyric acid permeability of blood-brain barrier. Brain Res Bull. 57(2):231-6. https://www.ncbi.nlm.nih.gov/pubmed?Db=pubmed&Cmd=ShowDetailView&TermToSearch=11849830
Watanabe M, Maemura K, Kanbara K, Tamayama T, Hayasaki H. 2002. GABA and GABA receptors in the central nervous system and other organs. Int Rev Cytol. 213:1-47. https://www.ncbi.nlm.nih.gov/pubmed/11837891?report=docsum&format=text