Updated on April 7, 2023
In the United States, millions of patients and caregivers struggle endlessly with the multidimensional impact of autism. With diverse symptoms like social withdrawal, repetitive behavior, self-injury, stereotyped gestures, and gastrointestinal distress, therapies for autism must impact multiple neurobiological mechanisms to provide benefit to patients. Therapies that purport to address multiple symptoms simultaneously are attractive to researchers, patients, and caregivers alike. For many, gamma-aminobutyric acid (GABA) is one such therapy.
GABA is one of the brain’s core neurotransmitters responsible for inhibiting neuronal transmissions. When neurons are inhibited, they can’t transmit their electrochemical signals to other neurons as readily as they typically would.
Most people are familiar with the subjective effects of GABA in their brains owing to the sedating effect of alcohol consumption; alcohol molecules bind to GABA receptors, precipitating an inhibitory effect across the brain. As more GABA receptors are bound, this inhibitory effect increases, leading to sluggishness, sedation, relaxed muscles, uncoordinated movements, and weakening of impulse inhibition – the hallmark symptoms of being “drunk.” Cognitive ability drops, and memory consolidation is hampered. Although normal levels of GABA don’t cause these effects, they’re still responsible for helping the brain to regulate its level of arousal in multiple ways.
The relaxing effect of GABA inhibition is only half of the story, however. Individuals who are deficient in GABA are prone to the following neurological issues of over-excitability: seizures, agitation, irritability, and anxiety. These are issues that are common in autistic individuals. The rationale for using GABA supplements for autism is simple: because autism presents the same symptoms as systemically overly-excitable neurons, some believe that autistic patients don’t produce enough GABA to regulate neuronal activity.
However, autistic individuals don’t necessarily have insufficient GABA. Instead, they might not have sufficient cellular machinery necessary to utilize GABA normally. Caregivers who are looking for a new therapy to address the agitated or anxious behavior associated with autism must thus be careful when evaluating GABA as a therapeutic option and might want to explore butyric acid as a more promising alternative.
At first glance, GABA would seem to make for an effective autism therapy. Symptoms of acute agitation, anxiety, and self-harm in individuals without autism are often addressed with anxiolytic drugs like benzodiazepines, which increase the concentration of GABA in the synaptic cleft of neurons. The subsequent inhibition of neurotransmission transiently calms the patient.
This suggests that supplementation with GABA might provide a similar but lesser effect, potentially addressing the same symptoms of excitation in autism without the risks inherent with benzodiazepines. Unfortunately, GABA might not be an effective therapy for autism because autistic individuals might have neuronal defects that prevent them from effectively using additional GABA.
Autistic individuals are known to have fewer of several GABA receptor subtypes on the neurons in the prefrontal cortex. Similar aberrations are likely present in other parts of the brain. Although the cause of this phenomenon is unclear, the effect is that the neurons of autistic individuals are less inhibited by GABA than those of a neurotypical person.
This means that even if autistic individuals have sufficient GABA, their neurons would have a much lower limit on the amount of inhibition they could bring to bear when they encounter GABA. The downstream result is that some regions of the brain, like the prefrontal cortex, are habitually overstimulated, causing effects ranging from depression to stereotyped behavior. Adding GABA won’t make up for having fewer GABA receptors.
Furthermore, researchers believe that autistic individuals have malformations in the neuronal pathways that utilize GABA to inhibit other tracts of neurons. As such, even if there is a sufficient quantity of GABA ready for use and a sufficient number of receptors ready to accept the molecules, autistic individuals might not have the neurotypical neuronal connections that allow GABA to be used effectively. This would lead to a weaker than expected effect of GABA. Adding more GABA won’t change the structure of neuronal tracts, but it might cause systemic inhibition and cause intense sedation as a side effect.
There are also other issues with GABA supplements. It is generally accepted that GABA cannot cross the blood-brain-barrier. This means GABA would not be capable of addressing neurological issues by operating directly on neurons. Even when delivered to the brain directly via injection (something not done outside experimental contexts), neuronal mechanisms like the GABA reuptake protein ensure it is rapidly eliminated. Nutritional supplements claiming to offer therapeutic benefits owing to their GABA content have nonetheless shown minor beneficial effects. In a small pilot study, patients who took a GABA supplement experienced reduced levels of anxiety. As noted by the authors, this finding indicates that GABA might be able to cross the blood-brain-barrier in small quantities, although further research is needed to draw firm conclusions.
At present, there are no studies examining the efficacy of GABA supplements on autism symptoms; the above study, like others investigating GABA supplementation, was limited to neurotypical participants examined during performance of anxiogenic tasks, like mental arithmetic. The above study also found that the participants’ immune systems showed signs of suppression in the form of reduced immunoglobulin secretion—a problematic side effect that would lead to a higher risk of illness.
The gaps in the research and lingering engineering challenges regarding bioavailability mean that GABA supplements must be studied further before it can be concluded that they can help autistic patients. However, this conclusion shouldn’t dissuade patients, caregivers, and practitioners from investigating an alternative compound that might seem superficially similar. Indeed, those who are interested in a natural yet more promising therapeutic option for autism might be better served by butyric acid, a compound that has the potential to address multiple dimensions of autism at the same time, but which lacks the major drawbacks of GABA.
Although GABA is an organic acid, other organic acids might be more effective therapeutic options for autism. Butyric acid is one such option. Although laymen might believe that butyric acid is similar to gamma-aminobutyric acid owing to its name, butyric acid is distinctly different from GABA, as is its physiological role. Produced in the gut, butyric acid is used by the body to feed helpful gut microbiota and signal white blood cells.*
Butyric acid might also be considered a neurotransmitter, although its capacity in this role requires further research. Interestingly, in the capacity of immune cell signaling, GABA and butyric acid share similar purposes; both inhibit the ability of white blood cells to up-regulate inflammatory response by reducing the ability of white blood cells to secrete proinflammatory molecules.* Butyric acid has more to offer autistic individuals than only the down-regulation of inflammatory response, however.
Researchers have determined that autistic individuals typically have markedly lower concentrations of butyric acid in their intestines than is found in healthy patients. This might be a contributing factor to autistic patients’ consistent symptoms of gastrointestinal distress. But the benefits of butyric acid aren’t limited to gastrointestinal health; researchers believe butyric acid could be effective at simultaneously addressing the GI tract’s inflammatory response and addressing behavioral symptoms in autism patients.* The rationale is that by down-regulating the activity of gastrointestinal white blood cells, which are causing an excessive inflammatory response, the patient’s gut-brain axis will be less overstimulated, resulting in a concomitant drop in overstimulation of the patient’s brain.*
Modulating the level of stimulation in the gut-brain axis is critical. The gut-brain axis is the primary conduit of nerves connecting the gut to the brain’s sensory cortices. In short, when patients experience nausea or distress in their intestines, it’s the gut-brain axis that relays that information to the brain and links it to initiating compensatory behavior.
Too much actuation of the gut-brain axis leads to over-stimulation of the areas of the brain that process the sensory input. Patients could thus experience agitation, self-injurious behavior, and overanxiousness. Butyric acid therapy thus holds promise for keeping the gut-brain axis from causing problems elsewhere.*
There is another major reason butyric acid is an appealing therapeutic option: unlike GABA, butyric acid can reliably cross the blood-brain-barrier.* Although butyric acid administered orally would initially act on the gastrointestinal tract, after the butyric acid is distributed through the patient’s bloodstream it would eventually reach the brain. After reaching the brain, butyric acid’s beneficial effects could include better orientation of attention, inhibition of motor tics, and improved emotional regulation—areas in which autistic individuals often struggle.* *These benefits are the result of butyric acid reducing the propensity of the white blood cells to up-regulate the inflammatory response.
Autistic individuals are thought to have high levels of inflammation in their brains, which contributes to cognitive and behavioral symptoms. When inflammation in the brain increases, general brain function decreases. The deficits of brain function that are the most noticeable in terms of patient symptoms occur in the frontal lobe and include symptoms like difficulty concentrating and regulating emotions.
Maintaining the brain’s normal inflammatory response is therefore a pathway to addressing a handful of different autism symptoms. Butyric acid weakens the ability of white blood cells to up-regulate the brain’s inflammatory response by inhibiting their ability to retransmit chemical signals that tell them to secrete proinflammatory molecules.* The systemic impact is that the brain’s normal level of inflammatory response is maintained.* For the moment, measuring the concentration of proinflammatory molecules in the brain isn’t possible with living patients.
Exciting new research is in the process of establishing a definitive account of butyric acid’s benefits for autistic individuals, and the initial evidence is more than sufficient to make a comparison with GABA. Although GABA suffers from a number of immutable physiological barriers to being an effective therapeutic option for addressing autism symptoms, butyric acid takes advantage of a variety of different mechanisms to aid autistic patients more effectively.* Furthermore, whereas the GABA supplements on the market are unproven in the scientific literature, butyric acid is already produced to a high standard of quality and is supported by a growing body of literature.
Butyric acid is known to be effective in aiding the GI tract’s inflammatory response in multiple contexts.* As shown by a 2011 study published in the Cellular Metabolism journal, butyric acid inhibits an autoimmune response in the event of compromised colon cells.* When colon cells are compromised by excessive inflammatory response or malnutrition—both of which are likely to occur in autistic individuals—they begin a process known as autophagy, in which the cells on the inside of the colon wall are broken down and consumed for energy.
As shown in the 2011 study, adding butyric acid to the colonocytes inhibits this destructive behavior.* The inflammatory response is suppressed as a result, and negative externalities like intestinal discomfort or constipation are ameliorated.* These benefits carry over directly to autistic patients who struggle with these symptoms.*
Mouse studies have also reliably linked the beneficial effects of butyric acid to behavioral autism symptoms. In one such mouse study, a group of mice was artificially induced to have symptoms that mimicked autism. Then, the mice were split into several groups and given either placebo or compounds containing butyric acid and similar chemicals. The researchers subsequently introduced the mice to neurotypical mice they had not associated with before.
The neurotypical mice in the control group interacted with the new neurotypical mice for an average of 300 seconds, whereas the autism model mice who had received the placebo interacted with the neurotypical mice for 20 percent less time. When the researchers tested the autism model mice that had received the butyric acid-containing compound, the mice socialized with the others for just under 290 seconds—an improvement of roughly 50 seconds compared to the mice that didn’t receive the therapy. With the addition of butyric acid, the mice were able to socialize 95 percent as long as neurotypical mice.Although the results in the mouse models don’t imply similar results will occur in human patients, the results do show that the implications of there being similar successful therapy in humans are substantial. Clinical trials in humans are ongoing, and soon researchers should be able to determine if similar results occur in human patients. If patients and caregivers are eager to utilize this therapeutic option before the clinical data is available, then they can easily and safely do so.
Tesseract Medical Research provides analysis of the most intriguing, impactful, and innovative autism research, including the gastrointestinal and neurological aspects of the condition.
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