Updated on April 10, 2023
Individuals with health issues ranging from autism to epilepsy are increasingly experimenting with dietary supplementation of gamma-amino-butyric acid (GABA), one of the body’s most important neurotransmitters. These individuals, seeking to address symptoms caused by excessive neuronal excitation, have chosen to experiment with an alternative therapy in an attempt to find relief, often after conventional therapies have failed to address symptoms or had undesirable side effects. But although some individuals might indeed find relief using GABA supplements, others are concerned about its potential side effects. Many questions remain to be answered regarding GABA’s efficacy as a supplement, and although GABA’s impact on the body is well understood, far less is known about GABA supplementation’s side effects. Individuals might wish to investigate alternatives for better therapeutic potential and known safety.
Why would a GABA supplement be included in the 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, which then interfaces with other neurons. When GABA binds to a neuron’s receptors, it triggers a signaling cascade within the neuron that results in the neuron being less prone to activate other neurons. As a result, neurons that have recently been activated by 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 addressing excessive neuronal excitation—like seizures—to supporting sleep. Other conditions, such as Parkinson’s disease, neuralgia, and autism, might also be addressed by the attenuation of excessive neuronal activation.
However, excessive GABA activity can be problematic. Other substances that promote secretion of GABA systemically, like alcoholic beverages, have a side effect profile that is nearly identical to GABA. These side effects include slower cognition, a 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 result from GABA’s core function, which makes the prospect of finding the appropriate therapeutic use for a GABA supplement very difficult. In other words, GABA supplementation will cause these side effects if it makes any physiological impact whatsoever; the only question is the degree of these side effects. At the same time, there are a number of technical concerns with GABA supplements that could curtail GABA’s potential for effectively addressing symptoms.
Although side effects are a significant concern for many individuals, GABA supplements also suffer from issues independent of their side effect profile, the most significant of which is GABA’s general lack of bioavailability. In other words, when an individual takes a GABA supplement, only a small portion of the GABA supplement is ready for their body to use. This is because GABA cannot cross the blood-brain-barrier (BBB) in sufficient quantities under normal physiological conditions, which means that it cannot reach the central nervous system unless the supplement is formulated to optimize bioavailability. Presently, prescription pharmaceutical drugs, like Gabapentin, are the only GABA formulations 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.
Although GABA in the digestive tract is biologically active and available, it does not cause systemic central nervous system inhibition. This means that a person taking a GABA supplement for a seizure disorder is less likely to find it effective than someone taking a GABA supplement for an inflammatory bowel disease. This is because GABA in the digestive tract does operate via the gut-brain axis.
The gut-brain axis includes the vagus nerve, which sends signals regarding the comfort and digestive status of the gut to the brain, among many other functions. If there is an abundance of stimulation of the vagus nerve, then it can result in anxiety and subsequent depression in the central nervous system, although 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 can have inhibitory effects in other areas the vagus nerve passes through, like the heart. In fact, stimulation of the vagus nerve is often utilized therapeutically to reduce the heart rate and normalize its pattern of beating. The inhibition of the vagus nerve can thus cause increased heart rate and anxiety—the opposite of what most individuals desiring the effects of GABA would want. As a result, it’s possible that GABA supplementation could be dangerously excitatory for individuals with heart issues.
GABA supplements can also cause issues in unlikely places. For example, GABA acts on the immune cells of the gut in an inhibitory fashion and that inhibition can 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. Although there is no research definitively linking GABA supplementation to stool-related gut infections, individuals with a weakened immune system should proceed with caution.
Although the possibilities of an abnormally fast heart rate and a weakened immune system initiated by GABA supplementation have not been confirmed by research, this does raise another important issue: GABA supplements have not been researched sufficiently to build a clinically valid side effect profile, nor have a sufficient number of individuals 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 that would have tabulated side effects in a rigorous way. Patient reports are sparse and inconsistent. This means the side effects of GABA supplements might exceed side effects that are hypothesized or be entirely different from what researchers have speculated. For individuals who would choose to be conservative with their health, GABA supplements might be too unproven to experiment with.
Furthermore, GABA supplements are highly non-specific in their effects even if they do make it into the brain. GABA is an inhibitory neurotransmitter in every context. While this makes it well-suited to reduce problems of excessive excitation like seizures, it’s likewise poorly suited for more subtle applications like addressing the behavioral symptoms of autism. This is because, in cases of disorders that are more complicated than uniformly excessive neuronal excitation, GABA supplements have the potential to exacerbate the problem. This is especially true for disorders that contain elements of both over-excitability and under-excitability, such as attention deficit hyperactivity disorder (ADHD); GABA supplements cannot guarantee the GABA molecules will be trafficked only to the anatomical structures where additional inhibition is needed, with side effects of systemic inhibition a likely result.
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, researchers with potential conflicts of interest have not reported on the side effect profile of their company’s GABA supplements. These gaps in the independent body of research might 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—although the nature of those side effects remains unclear.
Depending on the intended purpose, butyric acid can be a suitable alternative to a GABA supplement for individuals with gastrointestinal and neurological health concerns. Similar to GABA, butyric acid is a physiological molecule the body creates in large quantities to serve a variety of purposes. Like GABA, butyric acid behaves as a neurotransmitter when it is present in the central nervous system. However, 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.* And although butyric acid’s effects in the central nervous system are still under active investigation, 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 conditions, like Parkinson’s or Alzheimer’s disease.* These conditions have very high levels of neural oxidative stress, which causes an unbalanced inflammatory response. Although the link between neural inflammatory response and loss of function is complex, researchers agree that a balanced inflammatory response in the brain is generally the preferable condition. Sophisticated butyric acid supplements currently bring the prospect of helping to maintain a balanced inflammatory response to these patient populations,* with more applications being currently explored by research.
These multiple functions of butyric acid 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 maintaining mental health.* For example, in autistic individuals, 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 individuals with inflammatory bowel disease, maintaining the gut’s normal inflammatory response might reduce the frequency and severity of flare-ups, and a healthy microbiome could mean fewer symptoms owing to butyric acid’s support of gut motility.* Meanwhile, increasing the brain’s ability to compensate for oxidative stress means that butyric acid might also have broad applicability to providing nutritional support to other neurological conditions, like Parkinson’s or Alzheimer’s disease, which are associated with high levels of neural oxidative stress and, thus, the likelihood of an unbalanced inflammatory response.*
Significantly, the side effect profile of butyric acid is benign, with users primarily reporting minor stomach discomfort.* Many users find that butyric acid supplementation reduces their levels of gastrointestinal discomfort, such as constipation.* Large clinical trials documenting butyric acid’s efficacy in a handful of health conditions 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, because there is a finite amount of inhibition that butyric acid can cause in the immune cells.* Significantly, sophisticated supplements designed to optimize butyric acid’s bioavailability are now entering the market, allowing users to experience its full benefits.
Individuals who are willing to experiment with GABA supplements likely are seeking symptom relief they can’t find elsewhere, and accepting the unknowns of GABA supplementation could be worth the potential benefits. However, for those who prefer a more characterized alternative, butyric acid is likely the better choice to address these same 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 and weaknesses. In the meantime, can consider incorporating a butyric acid supplement into their management plans in a safe and highly tolerable manner.
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Watanabe M, Maemura K, Kanbara K, et al. 2002. Int Rev Cytol. 213:1-47.