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Optimize Your Glutamate

Top 9 Evidence-Based Supplements for Lowering Anxiety, Restlessness, Stress, and Distraction

Glutamate, the most abundant neurotransmitter in the human brain and body, acts as the primary excitatory neurotransmitter in the brain. As glutamate is derived from food sources, the human body contains approximately 4 pounds of glutamate, with glutamate deficiencies being a rare condition.

The average human consumes up to 20 grams of glutamate from food sources daily, as roughly 50 grams of this is made available for free form glutamate. Glutamate deficiency is rare and instead more commonly found in excess in the human body because of glutamate toxicity.

We associate glutamate toxicity with a range of mental and physical conditions ranging from dementia to anxiety to physical pain and seizures. The prevailing view is that excess glutamate can be blocked and/or balanced with increasing GABA, the primary inhibiting neurotransmitter.

For this section, we will explore how to balance glutamate by increasing presumably low levels of GABA and/or blocking excessive glutamate. Emerging evidence is likewise pointing our attention to the role of serotonin in glutamate management.

GABA operates in this action by balancing glutamate, the primary hypothalamic excitatory neurotransmitter that acts through NMDA receptors. This means it regulates our neurons from over-firing and over-stimulation.

GABA has been found to be involved in modulation of anxiety, depression, stress, anxiety, relaxation, muscle tension, convulsions, insomnia, and epilepsy. Neurons that produce GABA are called GABAergic neurons and are distributed throughout the brain.

GABA has two primary receptors called GABAA and GABAB. GABAA influences sedation, relaxation, reduced anxiety, and short-term memory inhibition.

Alcohol, benzodiazepines, and kava kava are common GABAA agonists. GABAB agonists can help with stress, general and social anxiety, depression, and muscle tension. GABAB causes less sedative, hypnotic, and memory impairment effects than GABAA.

Plants and supplements can increase GABA, and we believe all but a very few “relatively safe”. The GABA supplements that possess synthetic GABA agonists, such as phenibut, could cause dependence and should be used with high caution.

What are the Top 9 Evidence-Based Glutamate Supplements?

#1 Agmatine

Matching its very strong anecdotal support within the nootropics community, the initial agmatine studies are very promising. Agmatine, an amino acid derived from another amino acid, L-arginine, is a popular athletic performance enhancer.

I believe the antidepressant effect on serotonin is because of central glutamatergic modulation. Likewise, we also see some initial and promising evidence for cardiovascular and neuroprotection by NMDA antagonism and nitric oxide production.

Studies have used 2 to 3 grams for dosage. Many biohackers are now using it in the intranasal form and experience even better results.

#2 Kava or Kava Kava (Piper Methysticum)

Kava, one of the most psychoactive plants, is a popular Polynesian root, often used in place of alcohol. The plant was at the heart of the controversy in the 1990s when it was believed that the plant was hepatotoxic.

Since then, we discovered this was not the case when pure root parts were used and not stem and leaf. While some positive modulators of GABA (barbiturates and benzodiazepines and even alcohol) can cause dependence in some users, GABA agonizing plants, such as kava, do not meet the criteria for abuse or dependence.

#3 Valerian (Valeriana Officinalis, Valerenic Acid)

Part of the colloquially named, “Three Sisters of Sleep”, valerian when combined with hops, and purple passionflower is so effective at raising GABA activity, we have found it to be equally effective as the prescription medication zolpidem otherwise known as Ambien. In Germany, this formula is the number one sleep medication. It is likewise effective as an anti-anxiety plant for the same GABA agonist effects.

#4 Hops Humulus Lupulus

Part of the colloquially called, “Three Sisters of Sleep”, hops when combined with valerian, and purple passionflower is so effective at raising GABA activity, that it has been found to be equally effective as the prescription medication zolpidem otherwise known as Ambien. In Germany, this formula is the number one sleep “medication. It is likewise effective as an anti-anxiety plant for the same GABA agonist effects.

#5 Magnolia Bark (Magnolia Officinalis, Honokiol, Magnolol)

We have used this traditional Chinese medicinal herb to be a very popular strong anti-anxiety and sleep aid. While we still need human studies to support the vast anecdotal, animal, and in vitro evidence, it continues to perform as a very strong psychoactive plant extract.

It as well boasts firm support for antioxidant activity and as well protection of the major organs of the body.

#6 L-Theanine

Found in the highest concentrations in matcha green tea at roughly 39 milligrams for every 2 grams, l-theanine is an amino acid found mainly in tea leaves. L-theanine sometimes referred to as just theanine, is one of the most popular supplements in the nootropics community and is often used as part of a “stack” and combined to balance out the “jitters” from caffeine or other stimulants. The dose most commonly researched and referenced is 200 milligrams, as theanine continues to be a well supported and performing focus, relaxation, and sleep compound.

#7 Acetyl-L-Cysteine (NAC)

N-Acetyl-cysteine, typically referred to as NAC, has been receiving much attention for its role in mental health. Besides being a potent liver support aid, as seen in essential hospital medicines, NAC serves as an antioxidant for the brain.

For its believed role in depression, NAC balances glutamate levels along with the growth of new brain cells. While these studies show several months to achieve effects, the evidence seems to exist for a variety of mood and cognitive disorders.

NAC appears to be neuroprotective in its NMDA antagonistic actions. This means it creates a buffer against the toxic effects of excess glutamate.

#8 Magnesium

As one of the most commonly used supplements in the world, magnesium is involved with over 300 enzymes in the human body, including cell-to-cell communication and production of ATP, DNA, RNA, and proteins. For GABA and glutamate regulation, magnesium plays a big role and is often used as a sleep and anxiety supplement, as up to 80% of humans are believed to have a magnesium deficiency, which has become more and more difficult to correct from the diet.

#9 Black Seed Oil (Nigella Sativa)

Black seed oil (Nigella Sativa), one of the world’s oldest plants native to South Asia, has been used for an array of indications, and has been affectionately been referred to as, “the cure for all diseases except for death.” While black seed oil, also known as black cumin oil, has lacked evidential support, recently it has been used with great success in the opioid community to assist in recovery, and as well has been used both anecdotally and now supported in human studies for raising acetylcholine, GABA, and serotonin levels.

We have attributed the believed mechanism for this anxiolytic and inhibitory effect to its high levels of thymoquinone.

Glutamate Top 9 Notables

Ashwagandha, Bacopa Monnieri, Glycine, Lavender, Lemon Balm, Skullcap, Taurine, Valerian, Zinc.

Glutamate Essential Cofactors


Glutamate Agonists

NMDA, AMPA, kainic acid.

Glutamate Antagonists

AP5, ketamine, CNQX, kynurenic acid.

GABA Biosynthesis

Glutamate dehydrogenase.

Glutamate Receptors

NMDA, AMPA, kainate, mGluR.

Glutamate Precursors



Adrographis, alcohol, American ginseng (Cereboost), apigenin, Asian ginseng, astragalus membranaceus, BPC-157, berberine, beta-alanine, butyric acid, COQ10, cacao, caffeine, cannabidiol (CBD), carvacrol, catalpol, chamomile, chocolate, cinnamon, clary sage, cocoa, coca leaf, creatine, curcumin, cussonia plants, cyperus plants, EGCG, eleuthero (Siberian ginseng), epimedium, fenugreek, fish oil, fo-ti, GABA, ginger, Grape Seed extract, green tea, hibiscus, holy basil, Inositol, jasmine, Korean red ginseng (Panax ginseng), L-glutamine, lactobacillus, lactobacillus brevis, lactobacillus buchneri, lactobacillus hilgardii, Lactobacillus paracasei, lactobacillus rhamnosus, licorice, luteolin, maca, matcha tea, methionine S-Adenosine (SAMe), mucuna pruriens, nefiracetam, niacin (vitamin B3), niacinamide (vitamin B3), noni, noopept, oil of oregano, oleamide, oregano, passion flower, pharma GABA, phenibut, picamilon, pregnenolone, probiotics, protein, pramiracetam, propolis, quercetin, rhodiola rosea, red sage (danshen), reishi, resistant starch, resveratrol, rosemary, shilajit, sumac, rosemary, saffron, schisandra, St. John’s wort, THC, trimethylglycine (TMG), tulsi, ubiquinol, white oolong tea.

Your Friend in Health

Mark Stein



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