The Dance of Glutamate and GABA

Relevant for Mood and Behavioural Conditions: ADHD, Anxiety, Depression, Dementia, Epilepsy/Seizures, PMS, OCD, Tics & Tourette’s Syndrome

Glutamate is a highly excitatory, and excitotoxic, neurotransmitter and GABA is an inhibitory neurotransmitter. Glutamate is thus anxiety-inducing when it is too high and is involved in practically every behavioural and mood disorder. GABA is the opposite of glutamate in many respects and is necessary for relaxation and staying calm. Interestingly enough, GABA comes from glutamate. The main required nutrient for the conversion of Glutamate to GABA is vitamin B6, or pyridoxine, the active form being Pyridoxal-5’-Phosphate which is often referred to as P5P and PLP. 

If someone is deficient in vitamin B6 they can have trouble converting their glutamate into GABA. This is harmful for three main reasons:

1. Glutamate will stay high

2. GABA will be low

3. The ratio of Glutamate to GABA will be suboptimal.

This is likely why vitamin B6 has been used successfully for a wide variety of neurological conditions. Vitamin B6 is also known to lower prolactin, and since prolactin is a major antagonist to dopamine, lowering prolactin can lead to better mood and motivation. The prolactin-lowering effect of vitamin B6 is likely part of its benefit for things such as fertility, PMS and depression. Prolactin can inhibit gonadal (ovarian, testicular) function thus leading to fertility issues. 

While vitamin B6 can lower glutamate, increase GABA, lower prolactin and increase dopamine directly it can also lower glutamate indirectly. Vitamin B6 and Magnesium are required cofactors for the enzyme that turns the amino acid tryptophan into niacin (vitamin B3). If there is not enough vitamin B6 in the body then tryptophan can go down harmful pathways in the kynurenine pathway, leading to the production of the neurotoxic quinolinic acid.

“The polyunsaturated fats, DHA, EPA, and linoleic acid activate the conversion of tryptophan to quinolinic acid” -Ray Peat, Ph.D.

Quinolinic acid is implicated in many behavioural issues and disorders, including ASD, Tic disorders, ADHD and OCD. One of the reasons quinolinic acid is so harmful is that it can activate the NMDA (N-methyl-D-aspartate) receptor. Things that activate the NMDA receptor lead to an increase in the production of glutamate. So, by preventing the production of quinolinic acid, vitamin B6 and magnesium are indirectly lowering glutamate. 

Many things can activate the NMDA receptor, and in fact, there are many drugs that work by blocking the activation of NMDA. Memantine is one of these drugs, and it is approved for use in patients with dementia. Memantine is used off-label successfully for many conditions, including ADHD, OCD, anxiety and depression. Ketamine is also being studied for treatment-resistant depression, and it works by being a powerful blocker of NMDA.

Natural/OTC blockers of NMDA include but are not limited to, magnesium, zinc and agmatine. There is also some evidence that taurine can block NMDA. Interestingly, NMDA blockers like magnesium are used successfully for many of the conditions mentioned in this blog. Most of the time vitamin B6 is used in a study for a condition (ADHD, OCD, Tic’s and Tourette’s) it is used in combination with magnesium. Agmatine has been found to be useful in OCD and ADHD and even for benzodiazepine withdrawal. It is a foul-tasting amino acid and if taken orally it should be on an empty stomach, or at least away from other protein-containing foods as agmatine can compete with arginine for absorption. Contrary to what different vendors may say, agmatine is not a nitric oxide booster. In fact, it is known to inhibit nitric oxide synthase (NOS), thus leading to less nitric oxide production.

A common activator of the NMDA is ammonia. Ammonia can be created in the body when someone is eating too much protein. If you eat an excess of protein the body will use it to make glucose, but in the process of doing this ammonia is created. Protein is very important and should be eaten in sufficient amounts daily (usually this ends up being 70g-150g a day depending on how much you weigh). However, if you eat too much, or too much in one sitting, then ammonia can be produced. This is also a result of fasting or going on a low-carbohydrate diet. If you restrict the consumption of carbs your body will need to get glucose from somewhere, and this means it will get glucose from protein/amino acids. Of course, the result of this will be more ammonia. Furthermore, one of the main ways the body gets rid of ammonia is by combining it with carbon dioxide (CO2) to create urea. We create CO2 in abundance when we oxidize glucose well. In order to oxidize glucose well it is important to eat enough carbohydrates, vitamin B1, magnesium, biotin, potassium, manganese and chromium.

Vitamin B1 + magnesium are vital for the enzyme pyruvate dehydrogenase (PDH) which helps us to oxidize glucose. Biotin (Vitamin B7) and manganese are required for the enzyme pyruvate carboxylase which helps pyruvate (from glucose) turn into oxaloacetate. Oxaloacetate has been shown to be beneficial for women with PMS.

“The GABA/glutamate ratio may also play a major role in the emotional symptoms of PMS. Oxaloacetate supplementation can reduce glutamate levels in the brain via a process known as “glutamate scavenging”. In addition, oxaloacetate supplementation has been shown to increase GABA levels in animal models. By both lowering glutamate and increasing GABA levels, the GABA/glutamate ratio is altered, which may also help to alleviate emotional symptoms experienced by women during PMS.”

-Oxaloacetate reduces emotional symptoms in premenstrual syndrome (PMS): results of a placebo-controlled, cross-over clinical trial

By oxidizing glucose well, we can make more CO2 and thus get rid of ammonia better. You can also take things that chelate ammonia, such as Ceylon cinnamon and lithium. Lowering ammonia is something that has been shown to be very good for the brain, including in people with dementia. By lowering ammonia, we can have less NMDA activation, which means less glutamate. Lithium Orotate is another supplement that seems to be able to help normalize glutamate levels, and it seems to be very beneficial for many mood and behavioural related issues, including aggression and irritability. The typical dose of lithium orotate is in the range of 1-40mg a day, usually in divided doses.

Vitamin B6 can be low for many reasons, a common one is high estrogen. Men and women can have high levels of estrogen, leading to a quick loss of vitamin B6. The birth control pill depletes vitamin B6. In a magnesium-deficient body, vitamin B6 does not work as well. Magnesium is bound to ATP (energy) primarily. When the body does not have adequate levels of ATP being produced, we lose magnesium rapidly. Hypothyroidism also makes us lose magnesium rapidly. Improving the metabolism (thyroid function, ATP production) is a necessary requirement for the body to retain magnesium. Thus, it is a good idea for people who are suffering from some of the conditions mentioned (ADHD, Epilepsy, Tics, PMS) to potentially experiment with vitamin B6 (P5P form) and magnesium, but if they have poor thyroid function and high estrogen, supplementation may not be particularly useful. Parasitic infections can also lower vitamin B6 levels. 

Deficiencies of molybdenum and manganese can also cause glutamate sensitivity so try to consume enough of those minerals. Liver, mussels, maple syrup and legumes like peas are good sources.

In addition to vitamin B6 and magnesium, things that have been found to be useful for ADHD are theanine, phosphatidylserine, taurine, Gingko Biloba, vitamin B1, Pantetheine (vitamin B5) and doing things that can regulate blood sugar, prevent hypoglycemia and improve thyroid function. Tics and Tourette’s can be helped by vitamin B6, magnesium, Vitamin D, taurine and theanine. OCD can be benefited from all of these, and also Myo-inositol and NAC. Epilepsy can be improved with vitamin B6, magnesium, theanine, and progesterone (a lot of progesterone can also be converted to the neurosteroid allopregnanolone which is a potent anti-convulsant).

It is important to note, that not everyone will do well on vitamin B6. Ways to reduce the chances of adverse effects are to avoid pyridoxine HCL, this cheap form of vitamin B6 must be converted to the active P5P, however, pyridoxine HCL is shown to inhibit the conversion of itself into P5P. So, while small doses of pyridoxine HCL may be safe, higher doses would likely have some negative effects. Taking very high doses of P5P is not necessary or recommended, most people can do well between 10-60mg a day of P5P. Magnesium isn’t absorbed that well orally, even when you use good types such as magnesium taurate, glycinate, malate and threonate. So, in addition to taking oral magnesium capsules, it would be a good idea to also drink magnesium water (magnesium bicarbonate). You can also take magnesium baths to get magnesium in through the skin as well as taking it orally.

I get my magnesium products from LifeBlud, and you can use discount code DEAN for any orders from LifeBlud. If you want to use progesterone, the company Ona’s has good products such as their Luna Oil (as progesterone oil should be dissolved in vitamin E, like their product) for Ona’s you can also use discount code DEAN. 

To find out about how one can test their vitamin B6 status, look into Chris Masterjohn Ph.D. who has articles on substack and YouTube videos about this. You can also work with Chris one-on-one to talk about if vitamin B6 is right for you. When I personally take some extra isolated P5P, I usually also take a B complex (with all of the 8 B vitamins). I use Energi+ from LifeBlud for my B-complex. 

TLDR: Vitamin B6 + Magnesium can help directly and indirectly decrease glutamate and increase GABA leading to better outcomes in a wide variety of conditions such as Anxiety, Depression, OCD, ADHD, Epilepsy, PMS, ASD, Tics and Tourette’s Syndrome. 

*None of this is medical advice. I am not a medical professional, always talk to your doctor*

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BTW: I am a frequent guest on the podcast “Stuff Your Doctor Should Know”.

Discount code DEAN works at:

1. Ona’s Naturals (progesterone oil, topical progesterone and pregnenolone creams)

2. LifeBlud (Magnesium products, Taurine, Theanine, B vitamins, Methylene Blue)

3. Health Natura (oral pregnenolone, Methylene Blue)

4. Saturee (skin care products, desiccated liver, aged Cascara Sagrada)

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