Intractable headache…could a glutamate blocker be helpful?

Intractable headaches are defined as persistent headache that is difficult to treat or fails to respond to standard and/or aggressive treatment modalities. ​

​It’s important to note that headache pain is identified as the third most common symptom in long COVID cases – and for those patients who previously experienced migraines, the headache often becomes even more difficult to treat.
 
So, what mechanisms can contribute to this? We’ve previously discussed at length the potential causes – read more about the science here: https://www.suzannegazdamd.com/blog---long-covid/long-haulers-syndrome-understanding-the-mechanisms-behind-resulting-headaches
 
But we know that spike protein shares molecular mimicry with the CGRP (calcitonin gene-related peptide) receptors, which can then incite high levels of neuroinflammation, triggering the release of more glutamate and mast cells. And this in turn fosters more endothelial dysfunction. 
 
A new study sheds additional light on why so many patients suffer with headaches after recovering from COVID. Findings noted structural changes in the periaqueductal gray (PAG), a key structure in the propagation and modulation of pain and sympathetic responses, as well as the learning and action of defensive and aversive behavior. Damage in the PAG has been associated with causing headaches. 
 
These pathways are involved in the descending control of trigeminovascular nociceptive traffic.
A trigeminovascular system is often implicated as integral to the pain, inflammation, and secondary vascular effects of migraine, linked through the NMDA/glutamate system. 
Damage here will cause dysregulation of pain pathways that could include the release of an onslaught of glutamate and other neurotransmitters.
 
In the study they found the combined glutamine and glutamate/total creatine ratio (Glx/tCr) was increased in the PAG following COVID-19 infection.

Image credit: Wikipedia, https://en.wikipedia.org/wiki/Periaqueductal_gray

Several lines of evidence indicate that both glutamate and CGRP (as my prior blog noted) are important neurotransmitters in migraine and many other neurological and psychiatric symptoms and disease states. The most abundant neurotransmitter in our brains, excessive amounts of glutamate are thought to be linked to the following conditions:
 

• Anxiety disorders
• Autism spectrum disorder
• Brain injury
• Alzheimer's disease
• Parkinson's disease
• Huntington's disease
• Multiple sclerosis
• Amyotrophic lateral sclerosis (ALS)
• Human immunodeficiency virus
• Chronic pain
• Migraine
• Chronic fatigue syndrome

 
The role of glutamate in some disorders.
 
As the primary excitatory neurotransmitter in the brain, glutamate is present in about 50% of synapses, which are the small gaps at the end of a neuron that allow a signal to pass from one neuron to the next. Glutamatergic neurotransmission has a fundamental role for neuronal plasticity, learning, and memory.  However, in pathological conditions, glutamate also can act as a neuronal excitotoxin, leading to rapid or delayed neurotoxicity.
 
As noted above, glutamate system dysfunction that leads to overproduction and overstimulation of brain cells has been linked to many psychological and neurodegenerative disorders and sometimes to the point of death.
 
The relationship between glutamate and GABA.
 
You really can’t discuss glutamate without also mentioning GABA (gamma-aminobutyric acid), another abundant neurotransmitter that lessens a nerve cell's ability to receive, create or send chemical messages to other nerve cells. Studies have shown that glutamate is the precursor of GABA.
 
Glutamate and GABA are integrally related in both form and function. They have a complex, homeostatic relationship that brings balance to the level of brain activity:
 

• While glutamate is the main excitatory neurotransmitter, GABA is the main inhibitory neurotransmitter. 
• Inhibitory neurotransmitters decrease the likelihood that a nerve impulse will fire.
• GABA normally inhibits brain activity, thereby enabling you to relax.
• When you’re low in GABA, your brain gets stuck in the “on” position and you’ll find yourself anxious, overstimulated, and overwhelmed.
• Much like the accelerator and brakes in your car work together to control speed, GABA puts the brakes on brain activity to counter glutamate’s accelerative effects. 

 
You can read more about the complex relationship of these two neurotransmitters here:
https://www.suzannegazdamd.com/blog---ms-in-the-news/the-relationship-between-glutamate-and-gaba

Image courtesy of University of Utah

​There are two main causes of excess glutamate and its resulting excitotoxicity:
 

• Too much glutamate has accumulated in the brain.
• Glutamate receptors have become overly sensitive and, consequently, are easily overstimulated.

 
Receptor oversensitivity sometimes occurs in patients with neurodegenerative disorders even when glutamate levels are not particularly high. Symptoms indicative of an elevated level of glutamate include anxiety, depression, restlessness, inability to concentrate, headaches, insomnia, fatigue, and increased sensitivity to pain. Chronic excitotoxicity due to a persistent excess of glutamate is a key element in neurodegenerative conditions such as Alzheimer’s, Parkinson’s, multiple sclerosis, and other disorders.
 
Using sophisticated imaging processes (depicted in the following visuals) to better understand disease progression in MS, scientists identified glutamate concentrations had increased in active, enhancing lesions, and remained normal by contrast in chronic lesions infiltrated by inflammation. According to these researchers, other experimental studies also suggest that increased inflammation is likely related to the presence of glutamate in active lesions because these types of lesions show high glutaminase expression. Therefore, conducting imaging in diagnosed MS patients could prove extremely valuable for detecting changes in glutamate concentration that imply inflammation has already begun to impact the central nervous system. And earlier detection could help direct more effective treatment strategies!

Glutamate concentrations in multiple sclerosis. In Glutamate concentrations (mmol/L) in the white matter shown here, with differences between patients and healthy controls. 
(A) Chemical-shift imaging using echo time (TE)-average point resolved spectroscopy (PRESS) at 3T, which is an editing technique used to highlight glutamate signal; warmer colors show higher glutamate concentrations, whereas cooler colors show lower metabolite concentrations.
(B) Differences in glutamate concentrations between all patients with multiple sclerosis, each multiple sclerosis group, and healthy controls. MS = multiple sclerosis. SPMS = secondary-progressive multiple sclerosis. RRMS = relapsing-remitting multiple sclerosis. CIS = clinically isolated syndrome 
Source: Chen, Y. et al. Magnetic resonance imaging of glutamate in neuroinflammation Radiology of Infectious Disease. 2016. https://www.sciencedirect.com/science/article/pii/S235262111530015

How to restore the balance of glutamate levels.
 
There are several ways that we can help reduce or block glutamate when it is out of balance. For example, I previously detailed the effects of glutamate in MS progression and the potential for use of memantine in disease therapies. In addition to memantine, which is prescribed for its properties that may reduce abnormal brain activity, there are other glutamate-blocking medications such as:
 

• CGRP inhibitors–block glutamate

The regulated release of neurotransmitters, such as glutamate and CGRP, is controlled by voltage-dependent calcium channels, including P/Q- type channels.  

• Amantadine is a weak antagonist of the NMDA-type glutamate receptor, increases dopamine release, and blocks dopamine reuptake.
• Lamotrigine is a sodium channel blocker that inhibits the neuronal release of glutamate.
• Topiramate is a broad-spectrum anticonvulsant that in addition to antagonizing glutamate receptors enhances the effects of the inhibitory neurotransmitter GABA; reduces the activity of voltage gated sodium and calcium channels; and blocks calcium influx into cells.
• Zonisamide reduces calcium-dependent, potassium-evoked extracellular glutamate release. 
• Ketamine is a selective antagonist of the NMDA receptor.

 
The N-methyl-D-aspartate (NMDA) receptor is a receptor of glutamate, the primary excitatory neurotransmitter in the human brain. It plays an integral role in synaptic plasticity, which is a neuronal mechanism believed to be the basis of memory formation.
 
Glutamate-blocking supplements.
 
In addition to the use of prescription medications, there are supplements that may also positively impact the levels of glutamate. Note that as with any other type of supplement, always choose a high-quality product from a reputable source to ensure it contains the active ingredient.

• Magnesium blocks the NMDA receptors.

Magnesium is an activity-dependent blocker of NMDA receptors that studies have shown to be involved in both pain transmission and cortical spreading depression.
Magnesium concentration influences serotonin receptors, nitric oxide synthesis and release, NMDA receptors, and a variety of other migraine related receptors and neurotransmitters. The available evidence suggests that up to 50% of patients during an acute migraine attack have lowered levels of ionized magnesium.
Dosage - 400-600 mg daily
 

• Vitamin B2 or riboflavin has direct and indirect ameliorating effects on glutamate excitotoxicity which we know can increase migraine pain. Riboflavin plays a key role in cellular energy production in the body. Its role in mitochondrial energy metabolism suggests it may be effective in migraine. From the evidence available it is well tolerated and potentially effective as a preventive treatment for migraine.  Riboflavin suppresses the cortical neuronal endogenous release of glutamate via reduction in the activity of presynaptic voltage-gated calcium channels, inhibiting the exocytosis of glutamate vesicles.

Dosage - 400 mg twice daily
 

• Vitamin B6 (pyridoxine) is a cofactor to make GABA in the brain. GABA is synthesized in the cytoplasm of the presynaptic neuron from the precursor glutamate by the enzyme glutamate decarboxylase, an enzyme which uses vitamin B6 as the cofactor.

Dose 10-50 mg daily. (Do not take more than 100 mg per day as higher doses of B6 have been associated with peripheral neuropathy.)

• Luteolin also lowers glutamate.
• Berberine helps transport/convert glutamate and is protective; in astrocytes, berberine can decrease glutamate-induced cytotoxicity by reducing mitochondrial fragmentation and neurodegeneration.
• Coenzyme Q10 blocks the glutamate toxicity through stimulating mitochondrial biogenesis.
• Taurine: neuroprotective capabilities against glutamate-induced excitotoxicity through several identified mechanisms, including opening of the Cl (-) channel associated with GABA(A) and glycine receptors.
• Ginger compounds can affect the glutamine-glutamate-GABA metabolism, thereby reducing the glutamate level and increasing GABA synthesis.
• Curcumin (specifically BCM-95® curcumin, as most other formulations of curcumin do not cross the blood-brain barrier.
• L Theanine has been shown in multiple animal studies to stimulate the production of serotonin, dopamine and GABA, which have neuroprotective effects on the brain and enhance cognition. L-theanine also blocks the activity of glutamate, thus it is “glutamatergic.”
• Trans-Resveratrol lowers glutamate.
• Selenium is protective against glutamate.

Selenium prevents glutamate-induced cell death.  Selenium deficiency will increase susceptibility to glutamate toxicity. 

• B12 is protective against glutamate.
• Alpha Lipoic Acid (ALA) helps convert glutamate.

 
What about lifestyle modifications? 
 
When it comes to headache occurrence, there are steps you can take that may help improve your condition and symptoms. Consider these factors in your overall therapeutic approach:
 

• Follow a low glutamate diet. One contributing factor is consuming processed foods made with modified, freeform glutamate. For example, glutamate is used to make MSG (or monosodium glutamate), a synthetic chemical that is added to many modified foods to increase their savory taste. Glutamate has been used as food additive for enhancing flavor for over 1,200 years. In some countries and cultures, the process of fermenting and aging foods (i.e., soybeans) is used to enhance “umami” flavor, but this also increases glutamate concentration. Increased glutamate additives are also widely used in our food supply and subsequently mass marketed to consumers without any explanation of how these can affect our health.

 
Following a dietary approach that limits glutamate is vital to potentially reducing the incidence of headaches. Dr. Josh Axe, DC, DNM, CNS, is a certified clinical nutritionist who wrote an excellent piece that covers what glutamate-containing foods to avoid: https://draxe.com/nutrition/glutamate/
You may also want to look at the program by Sue Kira, a well-known naturopath and nutritionist: https://www.truevitality.com.au/low-glutamate-diet-by-sue-kira/

• Incorporate exercise! Through exercise, the brain can direct glutamate to be used as an energy source to dispose of excess amounts of the neurotransmitter.
• Alcohol may impact the glutamatergic system in many ways, including affecting the functions of glutamate receptors and transporters in the brain. Abstaining or significantly reducing consumption should be considered.
• Reduce stress as studies have shown repeated stress may alter glutamate function. Consider yoga, meditation, or a deep breathing practice to naturally lower your stress response and potentially reduce glutamate overproduction.

 
Intractable headaches can be just one symptom of a disorder, whether migraine or long COVID as well as another neurological or autoimmune condition. When devising a comprehensive treatment protocol, it’s important to identify the root cause of which excessive glutamate may be a significant contributing component. That’s why our clinic works with each patient to fully understand your individual needs and to make recommendations that are most appropriate for your health.
 
We invite you to please check out our extensive blog library with multiple resources and more information and don’t hesitate to reach out to our offices if we can help!
 
In hope and healing,
Dr. Suzanne Gazda
 
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