Low Glutamate Diet

December 2023 Dr Graham Exelby, Dr Valerio Vittone, Ms Kelley Bright

Diet change can be extremely important managing the inflammatory pathways if POTS, Fibromyalgia, dysautonomia and similar conditions. When you eat food the body sees as a threat it releases an inflammatory response with the same pro-inflammatory cytokines being released, as causes the “cytokine storm” in the first place.

This diet seldom addresses all parts of the very complex metabolic processes that are part of these conditions, with the many variations including low histamine, ketogenic etc often needed. Many diets do help, whether FODMAPS, low gluten, elimination, but they seldom provide all the answers.

The emergent theories of astrocyte/glutamate dysfunction in POTS, can sometimes be seen in the clear association of this in autism spectrum, fibromyalgia, ADHD and migraine. Restricting glutamate to already restricted foods may provide extra benefits.

Exorphins

Exorphins are “exogenous opioid peptides” which include gluten exorphin, and can be isolated from various sources eg dairy, and vegetables eg spinach and soy. Research in areas such as autism and schizophrenia have found that genetic mutations can lead to increased absorption in these groups.

Brain opioid peptide systems are known to play an important role in motivation, emotion, attachment behaviour, and responses to stress and pain, the control of food intake and the “rewarding” effects of alcohol and nicotine.

Molecular biologist Dr Valerio Vittone describes: “Soy-derived exorphins may influence brain function and metabolic processes. Similarly, spinach contains opioid peptides that can interact with opioid receptors, affecting both gastrointestinal and neurological functions. The impact of these exorphins can be quite profound, particularly in individuals with certain metabolic or genetic predispositions as we often observe in our problematic patients.”

“Furthermore, nightshades are also very problematic. the potential presence and impact of opioid peptides in nightshade vegetables, such as tomatoes, potatoes, and peppers, are less well-documented however, may represent an intriguing area for further research. These foods contain alkaloids and other compounds that may interact with metabolism and immune function in genotype-specific ways. From my perspective, The interplay between an individual's genotype and their response to food exorphins is a critical factor."

"Nutrigenomic approaches, which examine the interaction between diet and genes, are particularly relevant here. Variations in genes related to opioid receptors or metabolic enzymes could significantly alter an individual's response to these dietary peptides.”

Many of the diets available on the internet are simply not validated. The attached diet is from a fact sheet from the Agency for Clinical Innovation, NSW Government. It has been scientifically researched. However, in practical use, I seldom see glutamate as a “stand-alone” problem.

When starting diet change, think about foods that you know you react to- eg dairy, or bread, or gluten, and remove these. If you have migraine, autism, ADHD, fibromyalgia, a 2 week trial of low glutamate, while continuing to avoid the known reactive foods is worth trialling to gauge any response, followed by a formal consultation with dietician Kelley Bright to progress beyond this diet trial.

There will still be some which are simply not obvious, and these may be answered using DNA profiling with Dr Vittone. This is particularly so when mutations such as PEMT (with its neurodegenerative associations) are present, where there are no biomarkers, only DNA to detect its presence. See DNA Mutations in POTS and Long Covid.

Why trial a Low Glutamate Diet?

The astrocytes form the paravascular spaces so important in pressure control in the glymphatic system, and the theories might easily explain fatigue as one of the major components of POTS and CFS by impaired glymphatic function. Griffith University continues its research into CFS, and more recently into Low Dose Naltrexone (LDN) it the management of these, and at this point it’s benefits may be through improved astrocyte/glymphatic functioning. The work by Hulens (1) and others puts POTS and CFS in the same basic pathology.

In CNS pathology, astrocytes become reactive and proliferate at affected sites, exerting both beneficial and detrimental functions, contributing to the cause of neurodegenerative diseases, inflammatory CNS disorders, neuropathic pain, as well as neuroprotection.(6) The research into astrocyte/glutamate in Gulf War Veterans, autism and other neurodivergent disease (2)(3)(4) demonstrates the potential usefulness of low glutamate diets when applied to POTS patients with these co-morbidities.

The dietary interventions employed in these veterans involved how to read food labels and identify hidden sources of dietary excitotoxins. The diet emphasizes consumption of nutrient-dense whole foods containing foods known to be protective against glutamate excitotoxicity, and included foods high in omega-3 fatty acids, vitamins C,D,E, B2 (riboflavin), B6, Zinc and magnesium.

While the POTS/ Long COVID comorbidities may find some improvements with a low glutamate diet, the complexity of conditions associated with glutamate excitotoxicity extends beyond just the dietary glutamate content. Other dietary components can influence inflammatory processes, such as histamine, arachidonic acid, lectins, casein, and oxalates as well as infections, etc.

These elements can also contribute to glutamate dysregulation and excitotoxicity. For instance, the indoleamine 2,3-dioxygenase (IDO) pathway leading to quinolinic acid production and subsequent NMDA receptor activation is a crucial aspect of glutamate dysregulation that may need to be addressed in a comprehensive treatment approach.

A controlled supply of nutrients is extremely important in the immune system, which is tightly regulated by many pathways, including metabolic processes. Uncontrolled immune activation can have severe long term complications, including autoimmune and allergic syndromes, cancer and transplantation rejections.

The Indoleamine 2,3 dioxygenase (IDO) pathway is one of the vital immunoregulatory pathways and which is responsive to signalling molecules which either induce or are associated with inflammation. IDO has a diverse range of functions within innate and adaptive immune systems. During chronic inflammation, IDO activity becomes elevated in the CNS. This correlates with heightened pain and neurological depression experienced in the presence of chronic inflammatory syndromes. This suggests that suppression of IDO in chronic inflammatory syndromes could rescue neurological complications.(8)

Miller and Raison (7) described the mechanisms by which the innate and adaptive immune systems interact with neurotransmitters and neurocircuits to influence the risk for depression, describing metabolic and inflammatory interactions so important in POTS with the aforementioned comorbidities.

Inflammation impacts on several neurotransmitter systems in the brain, including serotonin, dopamine and glutamate pathways, as well as the kynurenine pathway, which generates the neurotoxic metabolite quinolinic acid. Neuroimaging studies have demonstrated that disruption of neurotransmitter pathways is associated with inflammation-induced alterations in brain circuits that mediate motivation and motor activity as well as anxiety, arousal and alarm.

The cascade here involves:

1. Cytokines activate circuits regulating anxiety, alarm and fear including the amygdala, hippocampus and insula

2. Pro-inflammatory cytokines including type I and II Interferons Interleukin 1ß and TNF can reduce the availability of serotonin (5-HT)

3. Many cytokines activate the enzyme Indoleamine 2,3-dioxygenase (IDO) which breaks down tryptophan, the primary precursor into kynurenine

4. Activated microglia convert kynurenine into quinolinic acid which binds to NMDA receptors (glutamate receptor), stimulates glutamate release and blocks glutamate reuptake by astrocytes all of which converge on excitotoxicity

5. Cytokines reduce astrocytic glutamate reuptake and stimulate Glu release resulting in excessive glutamate. Glu is an excitatory amino acid neurotransmitter that in excess causes excitotoxicity and reduces brain-derived neurotrophic factor which particularly in the hippocampus can have a fundamental effect on neurogenesis and thus affect learning and memory.(7)

Low Glutamate Diet:

Aim: To provide a diet that excludes foods naturally high in free glutamate, and food additives containing glutamate.

Characteristics: Avoids the flavour enhancers 620-625 and natural glutamates such as strong cheeses (Parmesan, Camembert, Brie and Gruyere), soy sauce, oyster sauce, black bean sauce, tomato sauce, miso, yeast spread, mushrooms, plums and spinach.

Precautions: It is not possible to provide a full list of all permitted commercial products; the following are general guidelines only. Care should be taken to read all product ingredient lists to look for ingredients containing the following flavour enhancers: monosodium glutamate (MSG, 621) and related flavour compounds (620, 622, 623, 624, 625, 627, 631, 635, 636, 637, 640, 641), hydrolysed vegetable protein (HVP), textured vegetable protein (TVP). If a product lists an ingredient as flavour, without a detailed additive description or code, the product should not be used in this diet.

	Allowed	Not allowed
Hot main dishes	All plain cooked meats, poultry, fish, eggs, legumes	Casseroles made with commercial stocks and flavour enhancers, or tomato paste
Sauces, gravies	Plain white sauce	Soy sauce, fish sauce, oyster sauce, tomato sauces Cheese sauces and black bean sauce Gravies made with stock cubes
Starchy vegetables, pasta, rice	All potato, pasta, plain rice, noodles, couscous, quinoa, semolina	Commercially flavoured noodles and savoury rice
Vegetables	All others	Spinach, tomato, mushrooms or peas Pickled vegetables
Soups	All others-check labels	Commercial condensed soups Soups with mushroom, tomato or peas
Sandwiches	All others	Tomatoes
Salads, dressings	Most salad ingredients Plain salad dressing (oil and vinegar)	Tomatoes, mushrooms, parmesan cheese Commercial salad dressings
Breads, cereals	All others	Breads and cereals containing dried fruit
Spreads	Jam, honey, peanut butter	Yeast spread, pickles and chutneys
Hor breakfast choices	All others	Mushrooms, tomatoes, canned spaghetti, baked beans Any dish made with tomato or peas eg savoury mince
Fruit	All others	Plums, grapes and dried fruit
Yoghurt	All
Desserts	Cakes and desserts containing allowed ingredients	Cakes and desserts containing dried fruit
Milk and cheese	All milks Most mild cheese	Hard aged cheese eg parmesan Camembert, blue vein, Brie and Gruyere
Beverages	All others	Vegetable juice
Biscuits	All containing allowed ingredients	Biscuits and crackers containing dried fruit or parmesan
Miscellaneous	Salt, pepper, sweetener, sugar, cream, nuts	Miso

References:

1. Hulens M, Dankaerts W, Rasschaert R, Bruyninckx F, De Mulder P, Bervoets C. The Link Between Empty Sella Syndrome, Fibromyalgia, and Chronic Fatigue Syndrome: The Role of Increased Cerebrospinal Fluid Pressure. J Pain Res. 2023;16:205-219 https://doi.org/10.2147/JPR.S394321

2. Zhang,P et al. Enhanced Glial Reaction and Altered Neuronal Nitric Oxide Synthase are Implicated in Attention Deficit Hyperactivity Disorder. Front. Cell Dev. Biol, 2022. https://doi.org/10.3389/fcell.2022.901093

3. Langan, M.T., Kirkland, A.E., Rice, L.C. et al. Low glutamate diet improves working memory and contributes to altering BOLD response and functional connectivity within working memory networks in Gulf War Illness. Sci Rep 12, 18004 (2022). https://doi.org/10.1038/s41598-022-21837-6

4. Brandley,E, Kirkland, A, Baron,M, Baraniuk, J, Holton,K. The Effect of the Low Glutamate Diet on the Reduction of Psychaitric Symptoms in Veterans with Gulf War Illness: A Pilot Randomized-Controlled Trial. Front. Psychiatry. 2022. https://www.frontiersin.org/articles/10.3389/fpsyt.2022.926688/full

5. Allergy Diet- Glutamate Low. Agency for Clinical Innovation. NSW Government. https://aci.health.nsw.gov.au/projects/diet-specifications/adult/allergy/glutamate-lowLi L, Acioglu C, Heary RF, Elkabes S. Role of astroglial toll-like receptors (TLRs) in central nervous system infections, injury and neurodegenerative diseases. Brain Behav Immun. 2021 doi: 10.1016/j.bbi.2020.10.007.

6. Miller AH, Raison CL. The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nat Rev Immunol. 2016 Jan;16(1):22-34. doi: 10.1038/nri.2015.5. PMID: 26711676; PMCID: PMC5542678.

7. Knight,M. The IDO Pathway. News Medical Life Sciences. https://www.news-medical.net/life-sciences/The-IDO-Pathway.aspx

8. Opioid Peptide.  Wikipedia. https://en.wikipedia.org/wiki/Opioid_peptide