GABA dysfunction in POTS, Long COVID, Fibromyalgia and Long COVID

Dr Graham Exelby December 2024

Abstract

GABA (γ-aminobutyric acid), the primary inhibitory neurotransmitter in the central nervous system, plays a critical role in maintaining neuronal balance and regulating autonomic functions. Emerging evidence suggests that dysregulation of GABA signalling is a central feature of complex syndromes such as Postural Orthostatic Tachycardia Syndrome (POTS), Long COVID, fibromyalgia, and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). These conditions, marked by overlapping symptoms including fatigue, cognitive impairment, pain, and autonomic dysfunction, may share common mechanistic pathways involving GABA and NMDA receptor imbalances.

This paper examines the multifaceted roles of GABA in central and peripheral physiology, highlights the molecular underpinnings of its dysfunction, and explores the interplay between GABAergic and glutamatergic systems. Additionally, we review the gut-brain axis and its impact on GABA production, focusing on microbiome influences, amino acid metabolism, and neuroinflammation. Potential therapeutic approaches, including dietary interventions, microbiome modulation, and pharmacological agents targeting GABA signalling, are discussed as promising strategies to mitigate these debilitating conditions. Understanding the complex biochemistry of GABA dysfunction offers valuable insights into novel pathways for clinical intervention and recovery.

Introduction

GABA (γ-aminobutyric acid) serves as the cornerstone of inhibitory neurotransmission in the mammalian nervous system. By regulating neuronal excitability and maintaining excitation-inhibition balance, GABA plays a pivotal role in central and peripheral physiology. Dysregulation of GABAergic signaling has emerged as a critical factor in complex conditions such as POTS (Postural Orthostatic Tachycardia Syndrome), Long COVID, fibromyalgia, and ME/CFS (Myalgic Encephalomyelitis/Chronic Fatigue Syndrome). These disorders, marked by overlapping symptoms like autonomic dysfunction and cognitive impairments, may share common mechanistic pathways linked to GABA and NMDA receptor imbalances. This paper explores GABA's multifaceted roles, the molecular underpinnings of its dysfunction in these conditions, and potential therapeutic interventions.

GABA assays as part of the amino acid studies in clinic in POTS, Long COVID, Fibromyalgia and Chronic Fatigue Syndrome had revealed frequent low GABA levels, in combination with other amino acid dysfunctional levels. Our findings are discussed in- Amino Acids, Essential Vitamin and Mineral Burn Off in Post Exertional Malaise (27)

GABA is produced in various organs throughout the body, with the highest concentrations found in the central nervous system and the pancreas.    While GABA is present in many organs, its functional significance outside the central nervous system and pancreas is still an area of active research. The pancreatic islets stand out as a unique peripheral site of significant GABA production, where it plays crucial roles in regulating hormone secretion and islet cell function.

1.     Central Nervous System   The brain and spinal cord are the primary producers of GABA in the body. (2)  In the central nervous system:

• Neurons: GABAergic neurons are the main producers of GABA, using it as their primary inhibitory neurotransmitter

• Glial cells: Recent research has shown that glial cells can also synthesize GABA, though to a lesser extent than neuron (2)(19)

  
  

2.     The pancreas, particularly the islets of Langerhans, is the second-highest producer of GABA outside the central nervous system

• Beta cells: These insulin-producing cells are the primary source of GABA in the pancreas (19)

• GABA concentration: Pancreatic islets contain GABA at levels comparable to those found in the brain, with concentrations of approximately 20 μmol/g in islets compared to 40 μmol/g in brain tissue (19)

Physiology of GABA

GABA functions as an inhibitory neurotransmitter by:

1.     Binding to GABA receptors (GABA-A and GABA-B) on postsynaptic neurons (1)

2.     Decreasing the responsiveness of nerve cells to stimuli (1)

3.     Hyperpolarizing the cell membrane, making it less likely to fire an action potential (1)

GABAA, where the receptor is part of a ligand-gated ion channel complex which open to allow ions such as Na+,K+,Ca+ and/or Cl- to pass through the membrane in response to the binding of a chemical messenger (i.e. a ligand that forms a complex with a biomolecule that usually produces a signal by binding to a site on a target protein), such as a neurotransmitter (a signalling molecule secreted by a neuron to affect a signal transfer across a synapse- this is usually another neuron but can also be a gland or muscle cell.) (3)

GABAB metabotrophic receptors which are G protein-coupled receptors that open or close ion channels via intermediaries, including in the peripheral autonomic nervous system (G proteins) (4)

GABA's inhibitory effects contribute to:

• Reducing anxiety and stress

• Promoting relaxation and calmness

• Regulating sleep

• Controlling muscle tone

• Modulating pain perception (2)

In the developing nervous system, GABA also plays important roles in:

• Regulating neural progenitor cell proliferation

• Guiding neuronal migration and differentiation

• Promoting neurite elongation and synapse formation (2)

Figure 1. GABA (gamma Aminobutyric acid, γ-Aminobutyric acid)

Source: Jynto, CC0, via Wikimedia Commons

Figure 2. Structure of a typical chemical synapse

Source: Thomas Splettstoesser (www.scistyle.com), CC BY-SA 4.0 <https://creativecommons.org/licenses/by-sa/4.0>, via Wikimedia Commons

Deficiency in GABA signalling:

• Studies have shown reduced GABAergic inhibition in the motor cortex of patients who recovered from COVID-19 with neurological complications, including fatigue and dysexecutive syndrome. (14)

• GABA deficiency may contribute to symptoms such as fatigue, cognitive impairment, and autonomic dysfunction in ME/CFS, Long COVID, and POTS (15)(16)

Gut-brain axis:

• GABA plays a lead role in the gut-brain axis, potentially influencing symptoms like anosmia, ageusia, headaches, and depression in Long COVID. (15)

• The gut microbiomes of Long COVID and ME/CFS patients are often deficient in GABA-producing bacteria, which may contribute to the overall GABA deficiency. (16)

NMDA Receptors' Role

The N-methyl-D-aspartate (NMDA) receptor is a glutamate receptor, the human brain's primary excitatory neurotransmitter. It plays an integral role in synaptic plasticity, a neuronal mechanism believed to be the basis of memory formation, as well as excitotoxicity.  Excitotoxicity refers to a key event in neurologic diseases where excessive activation of glutamate receptors leads to neuronal damage or cell death.  Excitotoxicity is thought to play a role in the pathophysiology of a variety of diseases, such as epilepsy or Alzheimer disease.(12) 

Excitatory-inhibitory imbalance

• An imbalance between excitatory glutamatergic signalling (via NMDA receptors) and inhibitory GABAergic signalling may underlie some of the neurological symptoms in these conditions. (15)

• This imbalance could contribute to cognitive dysfunction, sensory abnormalities, and autonomic dysregulation. (15)(16)

Autonomic dysfunction:

• Dysregulation of GABA and glutamate signalling in areas without a blood-brain barrier, known as circumventricular organs (CVOs), may contribute to autonomic and neuroendocrine symptoms in these conditions.  (16)

GABA relationship to glutamate.(1)

GABA is made from glutamate following a reaction with the enzyme glutamic acid decarboxylase.   GABA and glutamate act like an “on” and “off” switch. They work in opposite ways. GABA is the main inhibitory neurotransmitter in your brain, stopping the chemical messages from passing from nerve cell to nerve cell. Glutamate, on the other hand, is the main excitatory neurotransmitter in your brain, permitting the chemical messages to be carried from nerve cell to nerve cell.

Neurologic and mental health conditions are thought to be related to times when GABA messaging activity (“signalling”) is dysfunctional.

Decreased GABA activity may contribute to:

• Anxiety and mood disorders

• Schizophrenia

• Autism Spectrum Disorders

• Depression

• Epilepsy, Non-epileptiform seizures

Other medical conditions associated with GABA imbalance include:

• Pyridoxine deficiency. This is needed to make GABA. It usually causes frequent seizures during infancy. The seizures aren’t successfully treated with anticonvulsant medications, but do respond to vitamin supplementation.

• Hepatic encephalopathy

• Huntington’s Disease

• Dystonia

• Spasticity

• Hypersomnia

Amino Acids Involved in GABA Formation

The primary pathway for GABA synthesis involves the following amino acids:

• Glutamate: This is the main precursor for GABA synthesis.   Glutamate is an excitatory neurotransmitter and a non-essential amino acid.

• Glutamine: While not directly involved in GABA synthesis, glutamine serves as a precursor to glutamate in the glutamate-glutamine cycle (1)

The synthesis of GABA from glutamate occurs through a single-step reaction:

• Glutamate is decarboxylated by the enzyme glutamate decarboxylase (GAD) (2)

• This reaction requires pyridoxal phosphate (the active form of vitamin B6) as a cofactor

The chemical equation for this reaction is:

• Glutamate + GAD + Pyridoxal phosphate → GABA + CO₂

• GABA can also be synthesized from putrescine via a secondary pathway involving diamine oxidase and aldehyde dehydrogenase

Vitamin B6 Toxicity and GABA Inhibition.

Vitamin B6 is extensively used in fortified foods including breakfast cereals, energy drinks and dietary supplementation, often at doses significantly higher than the RDA. 

The active form of vitamin B6 is pyridoxal 5’-phosphate, and acts as a cofactor in many metabolic processes including synthesis of GABA.  Vitamin B6 toxicity typically occurs from excessive supplementation, not dietary intake.   The mechanism of toxicity involves the inactive form pyridoxine (PN) competitively inhibiting the active form PLP, which impairs the synthesis and function of GABA signalling in both the nervous system and the pancreas.   Symptoms of vitamin B6 toxicity are often manifest as peripheral neuropathy.(20)(21)(22)

Metabolism of GABA

After GABA has performed its signalling function, it is metabolized through the following process:

• GABA transaminase converts GABA and α-ketoglutarate into succinic semialdehyde and glutamate

• Succinic semialdehyde is then oxidized into succinic acid by succinic semialdehyde dehydrogenase

• Succinic acid enters the citric acid cycle as a usable energy source (2)

Understanding GABA's physiology and synthesis is crucial for developing treatments for various neurological and psychiatric disorders associated with GABA dysfunction, such as epilepsy, anxiety disorders, and insomnia.   DNA studies by Dr Valerio Vittone have shown mutations that may affect the physiology of the GABA pathway and its function.

Figure 3.  Release, Reuptake, and Metabolism Cycle of GABA

Source: Miresaa, CC BY-SA 4.0 <https://creativecommons.org/licenses/by-sa/4.0>, via Wikimedia Commons

GABA Function in the Amygdala

GABA (gamma-aminobutyric acid) plays a crucial role in the amygdala:

1. Inhibitory control: GABA is the primary inhibitory neurotransmitter in the central nervous system, including the amygdala. It helps regulate neuronal excitability and prevents overactivation of the amygdala (5)(6)

2. Anxiety regulation: The amygdala is a key structure in processing fear and anxiety. GABA's inhibitory action helps modulate anxiety-related behaviours by suppressing excessive neuronal firing (5)(6)

3. Emotional processing: GABAergic neurons in the amygdala are involved in defining the valence (positive or negative) of incoming sensory stimuli, which is crucial for appropriate emotional responses (6)

4. Balancing excitation and inhibition: GABA works in opposition to glutamate (the main excitatory neurotransmitter) to maintain a delicate balance in amygdala function. This balance is essential for proper information processing and emotional regulation (1)(5)

5. Circuit modulation: Inhibitory interneurons in the amygdala, which use GABA as their neurotransmitter, play a key role in shaping the flow of information through the amygdala circuit (6)

6. Stress response: GABA signalling in the amygdala helps regulate the stress response, with chronic stress potentially leading to reduced GABAergic inhibition and subsequent amygdala hyperactivity (5)(7)

7. Therapeutic target: The importance of GABA in the amygdala makes it a significant target for anxiety treatments. Many anxiolytic medications, such as benzodiazepines, work by enhancing GABA signalling (5)(6)

Understanding GABA's role in the amygdala is crucial for developing new treatments for anxiety disorders and other conditions involving emotional dysregulation.

The Effects of COVID on GABA functioning

One of the characteristics of COVID infection has been the dysregulation of glucose metabolism, that can persist after apparent recovery from the virus.(23)  The pathogenesis of this is complex involving several mechanisms, including:

1. Direct viral effects as the SARS-Cov-2 virus binds to ACE2 receptors in pancreatic islet cells, potentially damaging insulin-producing cells, and also altering ACE2 function affecting glucose homeostasis.(24)

2. Exaggerated inflammatory responses through cytokines  leading to insulin resistance and damaging pancreatic islet cells (25)

3. Triggering stress hormones eg cortisol and catecholamines (25)

4. Impaired GABA (gamma-aminobutyric acid) levels and signalling.  Masoodi et al (26) found distinct alterations in lipid and amino acid metabolism in COVID patients, and identified sphingolipid, tryptophan, tyrosine, glutamine, arginine, and arachidonic acid metabolism as mostly impacted pathways. Notably, gamma-aminobutyric acid (GABA) was significantly reduced in COVID-19 patients, revealing large metabolic disturbances. (26)

The net result on GABA in COVID-19 could be a significant reduction due to several interacting factors:

1. Astrocyte dysfunction, as astrocytes are targeted by SARS-CoV-2, leading to increased glutamate release.

   1. This could disrupt the glutamate-glutamine cycle, which is crucial for GABA synthesis.(8)

2. Mitochondrial dysfunction and PDH impairment:  When there is pyruvate dehydrogenase (PDH) dysfunction, it could lead to:

   1. Reduced acetyl-CoA production, which is needed for the citric acid cycle

   2. Altered amino acid metabolism as alternative pathways are activated (9)

3. Altered amino acid metabolism:

   1. Increased catabolism of amino acids to form acetyl-CoA as a compensatory mechanism

   2. This could potentially reduce the availability of glutamate and glutamine for GABA synthesis (9)

4. Direct effects on GABA levels:

   1. Studies have shown reduced GABA levels in COVID-19 patients (8)(9)

   2. Lower plasma GABA levels have been associated with COVID-19 pathogenesis

5. Neuroinflammation:

   1. COVID-19 can cause neuroinflammation, which may downregulate GABAergic function (8)

6.  Cellular senescence. SARS-CoV-2 proteins can induce premature cellular senescence, which is characterized by low GABA levels (8)(11)

7.  Disruption of protective mechanisms:

   • ACE-2, which is targeted by the virus, is protective for GABAergic signalling (11)

   • The virus alters tryptophan catabolism and GABA-producing gut flora, potentially affecting GABA production

The net result of these factors would likely be a significant reduction in GABA levels and GABAergic function. This could contribute to various neurological and psychiatric symptoms observed in COVID-19, including anxiety, depression, and cognitive impairments.

The reduced GABA levels could also exacerbate inflammatory responses and contribute to the severity of COVID-19 symptoms. (9)(10)(12)   These effects might persist even after recovery from the acute infection, potentially contributing to long COVID symptoms.

Interplay between GABA and NMDA Systems

The interaction between GABA and NMDA receptor systems is crucial for maintaining proper neuronal function and may be disrupted in ME/CFS, Long COVID, and POTS.  Understanding the roles of GABA and NMDA receptors in these conditions may lead to new therapeutic approaches.  Modulating GABA signalling through dietary interventions, probiotics, or medications that enhance GABAergic function may help alleviate symptoms.  

Improving GABA Functioning

There are several potential ways to improve GABA functioning:

1. Addressing gut microbiome imbalances to improve GABA production and overall neurotransmitter balance may be a promising approach

2.     Dietary sources

• fermented food such as kimchi, miso and tempah

• Tea-green, black

• Wholegrains

• Legumes

• Cruciferous vegetables-spinach, broccoli, cabbage, kale

• Mushrooms, tomatoes and sweet potatoes.

3.     Supplements, although absorption is questionable- eg L-theanine or glutamine.

4.     Lifestyle factors:

• Regular exercise boosts GABA

• Meditation and mindfulness

• Adequate sleep is important for maintaining GABA balance

• The calcium to magnesium ratio (Ca:Mg) is critical for the glutamate/GABA balance. 

5.     Magnesium can bind to both NMDA and GABA receptor sites, influencing their function. the glutamate/GABA balance by addressing magnesium deficiencies (15) or using medications that affect NMDA receptor function could be beneficial

7.     Medications that enhance GABAergic function in the brain, primarily by acting as GABA receptor agonists or positive allosteric modulators include:

• Benzodiazepines which modulate GABAA receptors, eg diazepam, alprazolam, lorazepam, which unfortunately also carry the real risk of dependence and abuse (5)(6)

• Gabapentin and pregabalin increase GABA synthesis and release. (17)

• Baclofen is a GABA-B receptor agonist used to treat muscle spasticity. (18)

• Valproic acid increases GABA levels and is used for epilepsy and bipolar disorder. (17)

Conclusion

In summary, GABA dysfunction represents a significant biochemical intersection for conditions like POTS, Long COVID, fibromyalgia, and ME/CFS, characterized by shared features of autonomic and neurological dysregulation. The intricate interplay between GABA and NMDA receptor systems underscores the critical need for targeted therapeutic strategies.

Emerging evidence linking GABA signalling to gut microbiome composition and metabolic pathways offers novel avenues for intervention. Future research should aim to unravel the molecular intricacies of GABAergic dysfunction and its interplay with systemic physiology, paving the way for personalized treatments to mitigate these debilitating conditions.

References:

1.     Gamma-aminobutyric acid (GABA). Cleveland Clinic. https://my.clevelandclinic.org/health/articles/22857-gamma-aminobutyric-acid-gaba

2.     GABA. Wikipedia. https://en.wikipedia.org/wiki/GABA

3.     Sato S, Yin C, Teramoto A, Sakuma Y, Kato M. Sexually dimorphic modulation of GABA(A) receptor currents by melatonin in rat gonadotropin-releasing hormone neurons. J Physiol Sci. 2008 Oct;58(5):317-22. doi: 10.2170/physiolsci.RP006208. Epub 2008 Oct 7. PMID: 18834560.

4.     Generalized non-convulsive epilepsy: focus on GABA-B receptors. J Neural Transm Suppl. 1992;35:1-198. PMID: 1324976.

5.     Jie F, Yin G, Yang W, Yang M, Gao S, Lv J, Li B. Stress in Regulation of GABA Amygdala System and Relevance to Neuropsychiatric Diseases. Front Neurosci. 2018 Aug 14;12:562. doi: 10.3389/fnins.2018.00562. PMID: 30154693; PMCID: PMC6103381.

6.     Babaev, O., Piletti Chatain, C. & Krueger-Burg, D. Inhibition in the amygdala anxiety circuitry. Exp Mol Med 50, 1–16 (2018). https://doi.org/10.1038/s12276-018-0063-8

7.     Liu, ZP., Song, C., Wang, M. et al. Chronic stress impairs GABAergic control of amygdala through suppressing the tonic GABAA receptor currents. Mol Brain 7, 32 (2014). https://doi.org/10.1186/1756-6606-7-32

8.     Marinkovic K, White DR, Alderson Myers A, Parker KS, Arienzo D, Mason GF. Cortical GABA Levels Are Reduced in Post-Acute COVID-19 Syndrome. Brain Sci. 2023 Dec 1;13(12):1666. doi: 10.3390/brainsci13121666. PMID: 38137114; PMCID: PMC10741691.

9.     Tian J, Dillion BJ, Henley J, Comai L, Kaufman DL. A GABA-receptor agonist reduces pneumonitis severity, viral load, and death rate in SARS-CoV-2-infected mice. Front Immunol. 2022 Oct 25;13:1007955. doi: 10.3389/fimmu.2022.1007955. PMID: 36389819; PMCID: PMC9640739.

10.  Masoodi, M., Peschka, M., Schmiedel, S. et al. Disturbed lipid and amino acid metabolisms in COVID-19 patients. J Mol Med 100, 555–568 (2022). https://doi.org/10.1007/s00109-022-02177-4

11.  Sfera, A.; Thomas, K.G.; Sasannia, S.; Anton, J.J.; Andronescu, C.V.; Garcia, M.; Sfera, D.O.; Cummings, M.A.; Kozlakidis, Z. Neuronal and Non-Neuronal GABA in COVID-19: Relevance for Psychiatry. Reports 2022, 5, 22. https://doi.org/10.3390/reports5020022

12.  Tian J, Kaufman DL. The GABA and GABA-Receptor System in Inflammation, Anti-Tumor Immune Responses, and COVID-19. Biomedicines. 2023 Jan 18;11(2):254. doi: 10.3390/biomedicines11020254. PMID: 36830790; PMCID: PMC9953446.

13.  Jewett BE, Thapa B. Physiology, NMDA Receptor. [Updated 2022 Dec 11]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK519495/

14.  Versace V, Sebastianelli L, Ferrazzoli D, Romanello R, Ortelli P, Saltuari L, D'Acunto A, Porrazzini F, Ajello V, Oliviero A, Kofler M, Koch G. Intracortical GABAergic dysfunction in patients with fatigue and dysexecutive syndrome after COVID-19. Clin Neurophysiol. 2021 May;132(5):1138-1143. doi: 10.1016/j.clinph.2021.03.001. Epub 2021 Mar 13. PMID: 33774378; PMCID: PMC7954785.

15.  Chambers, P. Antioxidants and Long COVID. Open Access Library Journal. 2022. https://www.scirp.org/journal/paperinformation?paperid=120821

16.  Chambers, P. Long COVID, POTS, and ME/CFS: Lifting the Fog. Journal of Neurology and Neurophysiology. 2023. https://www.iomcworld.org/open-access/long-covid-pots-and-mecfs-lifting-the-fog-98646.html#ai

17.  Nail,R. What to Know about GABA. Medical News Today. 2024. https://www.medicalnewstoday.com/articles/326847

18.  GABA Agents. Drugbank Online. https://go.drugbank.com/categories/DBCAT000428

19.  Hagan DW, Ferreira SM, Santos GJ, Phelps EA. The role of GABA in islet function. Front Endocrinol (Lausanne). 2022 Sep 29;13:972115. doi: 10.3389/fendo.2022.972115. Erratum in: Front Endocrinol (Lausanne). 2023 Oct 02;14:1301830. doi: 10.3389/fendo.2023.1301830. PMID: 36246925; PMCID: PMC9558271.

20.  Wilson MP, Plecko B, Mills PB, Clayton PT. Disorders affecting vitamin B6 metabolism. J Inherit Metab Dis. 2019 Jul;42(4):629-646. doi: 10.1002/jimd.12060. Epub 2019 Mar 20. PMID: 30671974.

21.  Hemminger A, Wills BK. Vitamin B6 Toxicity. [Updated 2023 Feb 7]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK554500/

22.  Paluszny A, Qiu S. Vitamin B6 Toxicity Secondary to Daily Multivitamin Use: A Case Report. Cureus. 2023 Nov 14;15(11):e48792. doi: 10.7759/cureus.48792. PMID: 38098895; PMCID: PMC10720370.

23.  Montefusco, L., Ben Nasr, M., D’Addio, F. et al. Acute and long-term disruption of glycometabolic control after SARS-CoV-2 infection. Nat Metab 3, 774–785 (2021). https://doi.org/10.1038/s42255-021-00407-6

24.  Alshammari S, AlMasoudi AS, AlBuhayri AH, AlAtwi HM, AlHwiti SS, Alaidi HM, Alshehri AM, Alanazi NA, Aljabri A, Al-Gayyar MM. Effect of COVID-19 on Glycemic Control, Insulin Resistance, and pH in Elderly Patients With Type 2 Diabetes. Cureus. 2023 Feb 23;15(2):e35390. doi: 10.7759/cureus.35390. PMID: 36846644; PMCID: PMC9954760.

25.  Zahedi M, Kordrostami S, Kalantarhormozi M, Bagheri M. A Review of Hyperglycemia in COVID-19. Cureus. 2023 Apr 12;15(4):e37487. doi: 10.7759/cureus.37487. PMID: 37187644; PMCID: PMC10181889.

26.  Masoodi M, Peschka M, Schmiedel S, Haddad M, Frye M, Maas C, Lohse A, Huber S, Kirchhof P, Nofer JR, Renné T. Disturbed lipid and amino acid metabolisms in COVID-19 patients. J Mol Med (Berl). 2022 Apr;100(4):555-568. doi: 10.1007/s00109-022-02177-4. Epub 2022 Jan 22. PMID: 35064792; PMCID: PMC8783191.

27.  Exelby, G. Amino Acid, Essential Vitamin and Mineral Burn off in Post Exertional Malaise 2024. https://www.mcmc-research.com/post/amino-acid-essential-vitamin-and-mineral-burn-off-in-post-exertional-malaise