Glutamate is the most abundant neurotransmitter in the brain and periphery.
Cells can make glutamate from glutamine or alpha-ketoglutarate.
There are genetic variants that impact glutamate levels a bit, but overall, glutamate levels are tightly controlled by multiple pathways.
Altered glutamate signaling is implicated in schizophrenia, OCD, and migraines.
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What is glutamate?
Glutamate is the major excitatory neurotransmitter in the central nervous system (CNS). It’s important for learning, memory, and mood, but it’s not as well-known as other neurotransmitters like dopamine or serotonin.
As an excitatory neurotransmitter, glutamate is essential for learning, attention, and focus – but too much glutamate causes too much stimulation in the brain. A balance between stimulation and inhibition is needed.
Let’s look at the research on how glutamate is synthesized, what receptors it binds to, and why it is so important for cognitive function.
How glutamate is synthesized:
Glutamate is the most abundant free amino acid in the brain.[ref] As an excitatory amino acid, glutamate levels are strictly controlled by several mechanisms. Glutamate can be synthesized from multiple sources and can also be converted into other neurotransmitters or amino acids. These pathways interact to keep glutamate levels at the right balance.
Here’s a graphical overview of the synthesis pathways:
Glutamate from glutamine:
Glutamate can be synthesized from the amino acid glutamine with the help of the enzyme glutaminase (GLS and GLS2 genes). This conversion releases a molecule of ammonia (NH3). In neurons, glutamate is then packaged into synaptic vesicles by vesicular glutamate transporters (VGLUTs) and stored in the presynaptic terminal before release.
The conversion of glutamine to glutamate is a two-way street. Glutamate can also be converted to glutamine with the addition of a molecule of ammonia (NH3).
Glutamine is the most abundant free amino acid in the body. In addition to being used to synthesize glutamate, glutamine is incorporated into many proteins and can be used for nucleotide synthesis. It is considered “conditionally essential,” meaning that most of the time the body can make enough glutamine, but during times of stress (illness, etc.), the demand for glutamine may be such that it is needed from food or supplements.[ref]
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If you are being treated for a psychiatric disorder, please consult your doctor before taking any supplements or even changing your diet. If you have questions about supplements and drug interactions, your pharmacist or doctor should be able to help.
Glutamate in foods:
Glutamate is found in many (most) packaged, processed foods that contain flavor enhancers such as MSG, hydrolyzed protein, yeast extract, and aspartame. Glutamate, or glutamic acid, is associated with the umami taste. Glutamate is also found naturally in higher levels in soy sauce, fish sauce, aged cheese, and Marmite. Lower levels of glutamate can be found in tomatoes, anchovies, walnuts, dried fruit, and peas.
Glutamine in foods:
Glutamine can be found in many foods. It is found in higher amounts in animal protein, eggs, and dairy products, but it is also abundant in vegetables and grains. [ref] Athletes may benefit from supplemental glutamine. Studies show that glutamine supplements post-workout help with fatigue and immune suppression.[ref]
Supplements that interact with glutamate:
Agmatine: Glutamate levels in the hippocampus increase when animals are chronically exposed to opioids. Agmatine was able to attenuate the increased glutamate levels due to chronic opioid administration.[ref] Agmatine also helps with neuropathic pain by blocking NMDA glutamate receptors.[ref]
Riboflavin (vitamin B2):
Riboflavin can reduce the release of glutamate from nerve terminals.[ref] This may be why riboflavin is effective in preventing migraines in some people.[ref]
Saffron: A review of animal studies found that saffron “appears to be able to regulate glutamate levels, reduce oxidative stress, and modulate Aβ and tau protein aggregation.”[ref]
N-acetylcysteine (NAC):
NAC has been shown to reduce neuronal glutamate release. Animals show that this is due to the cysteine replacing glutamate in glial cells, which impacts the amount of glutamate in the synaptic cleft. NAC may also be reducing neuroinflammation and thus impacting glutamate levels.
In people addicted to cocaine, NAC decreases glutamate levels, and in people with schizophrenia, NAC is being investigated as an add-on to current medications.[ref]
Nigella Sativa (Black Cumin Seed): Nigella Sativa seed has been used for thousands of years as a natural remedy and for food preservation. In animal models of epilepsy, Nigella sativa has antiepileptic effects. A study in rats showed that Nigella sativa increased glutamate and GABA in different areas of the brain.[ref] I’m not exactly sure how the study would apply to humans, but I included it to show that Nigella sativa could be affecting amino acid neurotransmitter levels, including glutamate.
Lowering glutamate with a low-glutamate diet:
A low-glutamate diet is described in research studies as a whole food diet that restricts free glutamate and aspartate. Essentially, it eliminates foods that contain flavor enhancers such as MSG, hydrolyzed protein, yeast extract, and aspartame. Glutamate, or glutamic acid, is associated with umami taste. Many packaged foods, such as flavored pasta, flavored rice, Hamburger Helper-type boxed meals, and condensed soups, have hydrolyzed protein and yeast extract as flavor enhancers. A low-glutamate diet also eliminates soy sauce, fish sauce, aged cheese, Marmite, and other natural sources of glutamate. Tomatoes, dried fruit, and peas are also eliminated.[ref]
Brain fog reduced by a low-glutamate diet: A double-blind, placebo-controlled clinical trial showed that a low glutamate diet for one month significantly improved cognitive function in people suffering from brain fog and Gulf War Illness.[ref] Neuroinflammation is likely playing a role in Gulf War Illness, and it’s interesting that just switching to a low-glutamate diet was enough to significantly change cognitive function.
Anxiety and Psychiatric Symptoms: A study also showed that a 1-month low-glutamate diet reduced severe psychological symptoms. The researchers did crossover challenges using MSG vs. placebo to show that it was the change in glutamate (rather than just the elimination of junk food). [ref]
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About the Author: Debbie Moon is a biologist, engineer, author, and the founder of Genetic Lifehacks where she has helped thousands of members understand how to apply genetics to their diet, lifestyle, and health decisions. With more than 10 years of experience translating complex genetic research into practical health strategies, Debbie holds a BS in engineering from Colorado School of Mines and an MSc in biological sciences from Clemson University. She combines an engineering mindset with a biological systems approach to explain how genetic differences impact your optimal health.
