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  • Writer's pictureGraham Exelby

Amino Acid, Essential Vitamin and Mineral Burn off in Post Exertional Malaise

A Preliminary Assessment

Dr Graham Exelby July 2024.


Post-exertional malaise (PEM) can be compared to the metabolic changes that a marathon runner may experience following their race.  Coat hanger pain can contribute to PEM through hypoperfusion and muscle ischaemia.   When muscles have inadequate oxygen then switch to anaerobic metabolism, with accumulation of lactic acid which causes the characteristic cramping and pain.   The relationship between the two is shown with exercise, where in POTS even minor exertion increases pain, fatigue and cognitive difficulties which characterize PEM. (7)  The interplay between reduced blood flow, lactic acid accumulation and autonomic dysfunction leads to a snowballing increase in symptoms and prolonged recovery times.  ME/CFS patients have reduced reserves of Adenosine triphosphate (ATP) vital for mitochondrial energy production, and replenishment of ATP may take days.


Post-exertional malaise in ME/CFS involves complex metabolic changes including alterations in amino acid metabolism, with breakdown (burn off) particularly of the branched amino acids leucine, isoleucine and valine, with evidence of affects 24 hours after exercise and PEM activation.   Non-essential amino acids, particularly those that can fuel the TCA cycle independently of pyruvate dehydrogenase (whose function is impaired in PEM) may become increasingly important for maintaining energy production during PEM episodes.(1)(2)(3)  

 

Hypermetabolism appears to play a significant role in PEM characterized by increased excretion of urine metabolities indicating an abnormally high rate of metabolism.   The hypermetabolism in PEM is also associated with

  • the increased excretion of 1-methylhistidine in urine during PEM indicates elevated muscle protein breakdown.  This may also contribute to amino acid depletion as muscle is a significant reservoir of amino acids in the body. (1)

  • intestinal barrier breakdown,

  • acetate excretion,

  • glycolytic abnormalities with altered glucose: lactate ratios,

  • purine metabolism dysregulation with decreased hypoxanthine,

  • hypoacetylation affecting multiple cytoplasmic enzymes and DNA histone regulation affecting cellular function and gene expression

  • metabolite loss most likely from hypermetabolic state and hypoacetylation contributing to the prolonged recovery period in CFS patients after exercise.

 

Cort Johnson (4) in his 2021 paper described the findings of a large Norwegian study (5) by Hoel et al, which looked at the metabolic changes that occur in Chronic Fatigue Syndrome.   They found 67 metabolites affected in CFS suggesting a core energy dysfunction, with widespread changes in lipids and amino acids.    This was described as the cells trying to access energy any way they can, turning to metabolism of fatty acids and amino acids instead of carbohydrates.

 

These patients had metabolic patterns similar to those found in starvation and after intensive exercise.   Hoel et al (5) found 3 subsets of patients:

  • High degree of fatty acid and amino acid breakdown with high levels of ketone derivatives suggesting a ketogenic slant in 40%.  Reduced levels of amino acid metabolites and low tryptophan was found.  With little evidence of mitochondrial dysfunction this pattern was similar to starvation and after high-energy exercise. 

  • Increased fatty acid breakdown but characterized by increased amino acid breakdown and evidence of mitochondrial dysfunction in 45%.  There were increased pyruvate levels suggesting this wasn’t being broken down properly and that the mitochondria may not be getting the acetyl-CoA and NADH they needed.   Increased tryptophan but lack of tryptophan derivatives suggested it wasn’t being broken down correctly.  This group with the most severe symptoms, had metabolomic profiles similar to those of inflammatory diseases.

  • The 3rd group, 15%, had intermediate profiles.

 

Hoel et al(5) suggested that elevated energy strain may result from exertion-triggered tissue hypoxia and lead to systemic metabolic adaptation and compensation. Through various mechanisms, such metabolic dysfunction represents a likely mediator of key symptoms in ME/CFS.

 

Long Covid research by Appleman et al, (6) has also shown post-exertional malaise (PEM), with associated fatigue, pain and local and systemic metabolic disturbances, severe exercise-induced myopathy and tissue infiltration of amyloid-containing deposits in skeletal muscles of patients with long COVID.   

 

Coat hanger pain

 

“Coat hanger pain” is seen frequently in patients with dysautonomia, especially POTS, as well as fibromyalgia and CFS.   Humm et al (7) describes the typical ache usually began with standing or sitting, as discomfort and pain in the neck and shoulder, and research suggests this could result from reduced blood flow and oxygen delivery to the muscles in the affected areas.  They showed that muscle membranes in patients with orthostatic hypotension become progressively depolarized during standing, which they felt was most likely the result of muscle ischaemia, related to the drop in perfusion pressure caused by orthostatic hypotension.

 

Brainstem Hypoperfusion

 

The brainstem, which consists of the midbrain, pons and medulla, has been implicated in ME/CIFS in many studies.   It regulates the respiratory, cardiovascular, gastrointestinal, and neurological processes, which can be affected by long-COVID and similar disorders eg migraine and CFS.   Griffith University showed in 2023 that the brainstem is larger in Long Covid and ME/CFS patients (is this a pre-requisite for POTS or a secondary phenomenon ?) (8)

 

Wirth et al (9) described reduced blood flow to the brainstem causing neurological symptoms including impaired cognitive function or “brain fog.”    This hypoperfusion can impact both the global and local regulation of blood flow in the brain.   They also reported an increase in intracranial pressure observed in ME/CFS patients, and later proposed by Hulens (10) and Bragee (11) also has been frequently observed compounding problems.

 

The brainstem hypoperfusion also seen in CFS Spect scans from our clinic findings, is believed to be part of the same process of hypoperfusion and mitochondrial dysfunction that underpins the coat hanger pain of FMS, although an emergent  hypothesis of glutamate/astrocyte dysfunction by Guedl (12)(13) in Long Covid provides a possible explanation for some impaired glymphatic function through impairment of the paravascular space function and potential effects on symptoms such as fatigue, brain fog and head pressure.

 

This astrocyte association becomes very relevant in FMS where glutamate dysfunction has already been recognized, and with this the impairment of glymphatic function.

 

In the severe CFS, Wirth et al (9) noted a reduction in blood flow from lying to sitting was 24.5%.  As a possible explanation for the orthostatic intolerance and the decrease in cerebral blood flow they proposed the presence of both a strong vasoconstrictor effect mediated by an elevated sympathetic tone and weakened vasodilator influences. Covid-19 seriously affects the endothelium and there is evidence of chronic endothelial dysfunction in the post-Covid-syndrome similar to that in ME/CFS.(14)

 

Similarly, Wirth et al (9) reported muscle mitochondrial dysfunction, as evidenced by higher levels of pyruvate and lower levels of ATP and phosphocreatine in muscles, suggesting an impairment in muscle energy metabolism, which is also observed in ME/CFS, indicating a likely overlap in the pathophysiological mechanisms of these conditions​​.

 

Amino Acid Metabolism


There are 20 amino acids, organic compounds composed mainly of nitrogen, carbon, hydrogen, and oxygen. Animals have seven conditionally essential amino acids that can be synthesized and are usually not required in the diet. However, they are essential components of the diet for specific populations that cannot synthesize them in adequate amounts. There are four “nonessential” amino acids can be synthesized and, thus, are not required in diet. The remaining nine “essential” amino acids are obtained from diet.(15)


Amino acid metabolism refers to the biochemical pathways that produce, break down, and use amino acids. The body uses amino acids to make proteins, enzymes, hormones, and other important molecules. Protein synthesis and degradation are both essential for maintaining homeostasis in the body.(16)


Amino acids can also generate glucose, ATP, and fatty acids, and they are metabolic precursors for numerous biomolecules, including haeme groups, nucleotide bases, and signalling molecules (catecholamines, neurotransmitters).  In addition, they are essential for epigenetic modifications.(15)


Amino acid oxidation is a process that helps the body release energy from protein molecules. This process occurs in the liver and muscles and results in the production of ketone bodies which can be used by cells to generate energy.(16)


The Essential Amino Acids (17)


  1. Phenylalanine: Your body turns this amino acid into the neurotransmitters tyrosine, dopamine, epinephrine, and norepinephrine. It plays an integral role in the structure and function of proteins and enzymes and the production of other amino acids.

  2. Valine: This is one of three branched-chain amino acids (BCAAs) on this list. helps stimulate muscle growth and regeneration and is involved in energy production.

  3. Threonine: This is a principal part of structural proteins such as collagen and elastin, which are important components of your skin and connective tissue. It also plays a role in fat metabolism and immune function.

  4. Tryptophan: Often associated with drowsiness, tryptophan is a precursor to serotonin, a neurotransmitter that regulates your appetite, sleep, and mood.

  5. Methionine: This amino acid plays an important role in metabolism and detoxification. It’s also necessary for tissue growth and the absorption of zinc and selenium, minerals that are vital to your health.

  6. Leucine: Like valine, leucine is a BCAA that is critical for protein synthesis and muscle repair. It also helps regulate blood sugar levels, stimulates wound healing, and produces growth hormones.

  7. Isoleucine: The last of the three BCAAs, isoleucine is involved in muscle metabolism and is heavily concentrated in muscle tissue. It’s also important for immune function, haemoglobin production, and energy regulation.

  8. Lysine: Lysine plays major roles in protein synthesis, calcium absorption, and the production of hormones and enzymes. It’s also important for energy production, immune function, and collagen and elastin production.

  9. Histidine: Your body uses this amino acid to produce histamine, a neurotransmitter that is vital to immune response, digestion, sexual function, and sleep-wake cycles. It’s critical for maintaining the myelin sheath, a protective barrier that surrounds your nerve cells. (17) The metabolism of histidine, glutamine and glutamate are closely related, so imbalances could disrupt normal metabolic processes.  Histidine can be degraded to glutamate via urocanic acid.(32)  It has a role in carnosine synthesis which may play a part in PEM. (34)


Non-essential amino acids include (18)(19):


1.     Alanine clears toxins released during muscle protein breakdown, aids in regulating blood glucose and cholesterol, serves as an energy source for muscles and the CNS and assist in lymphocyte production

2.     Arginine is a precursor for nitric oxide, accelerated wound healing, renal detoxification, hormone homeostasis, supports immune system function

3.     Asparagine is important for neuron development and CNS homeostasis, helps build connective tissue and aids generation of digestion with generation of secretions and mucus in the GI tract.

4.     Aspartic acid is an excitatory neurotransmitter and is involved in synthesis of other amino acids including methionine, threonine, isoleucine and lysine.  It plays a role in the citric acid cycle for energy production and the urea cycle.  It acts as an excitatory neurotransmitter in the ventral spinal cord similar to glycine (which is inhibitory).(20)  Aspartate and glutamate can excite virtually every neuron in the CNS at low concentrations.(21)  Aspartate is found in large quantities in neuroendocrine tissues eg hypothalamus. (22)  Aspartate and glycine form an excitatory/inhibitory pain in the spinal cord, similar to glutamate/GABA in the brain.(20)

5.     Cysteine stimulates collagen production and is involved in the synthesis of glutathione, and plays a role in protein folding and stability

6.     Glutamic acid (the anionic form is known as glutamate) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can synthesize enough for its use.  It is found in high concentrations throughout the brain and compartmentalized in synaptic vesicles for Ca2+-dependent release.   It is the primary excitatory neurotransmitter in the brain, responsible for fast excitatory transmission, synaptic plasticity, learning and memory processes and sensory perception.(23)   Under certain conditions excessive activation of excitatory amino acid receptors can lead to neurotoxicity, or “excitotoxicity.”(23)    Excitotoxicity can occur:

  • Excessive release, overwhelming the normal mechanisms for clearance and reuptake, where the exacerbated or prolonged activation of glutamate receptors starts a cascade of neurotoxicity that ultimately leads to the loss of neuronal function and cell death. The molecular mechanism that triggers excitotoxicity involves alterations in glutamate and calcium metabolism, dysfunction of glutamate transporters, and malfunction of glutamate receptors, particularly N-methyl-D-aspartic acid receptors (NMDAR).  

  • Impaired glutamate-glutamine cycle, when the astrocytes fail to effectively recycle glutamate leads to its accumulation in the extracellular space.   On the other hand, excitotoxicity can be regarded as a consequence of other cellular phenomena, such as mitochondrial dysfunction, physical neuronal damage, and oxidative stress.(24)

7.     Glutamine is the most abundant free amino acid in the body, providing nitrogen for synthesis of other amino acids, improves exercise endurance, supports lymphocyte/ immune function, is involved in glutathione synthesis, and is essential for intestinal cell metabolism

8.     Glycine is involved in the production of DNA, phospholipids and collagen.  It helps in the production of bile acids and supports glutathione synthesis.   It acts as an inhibitory neurotransmitter in the CNS.  Aspartate and glycine form an excitatory/inhibitory pain in the spinal cord, similar to glutamate/GABA in the brain.(20)

9.     Proline is a major component of collagen, crucial for wound healing and tissue repair.  It supports collagen function and structure and helps maintain skin elasticity.

10.  Serine is involved in phospholipid formation, is a precursor of several amino acids including glycine and cysteine.  It plays a role in DNA and RNA synthesis, and is important for proper functioning of the CNS.

11.  Tyrosine is a precursor for neurotransmitters dopamine, noradrenalin and adrenalin.  It is involved in melanin production, helps in synthesis of thyroid hormones, and supports functioning of the adrenal, thyroid and pituitary glands.


Amino Acid Dysfunction in “Burn Off”


Examination of amino acid profiles using plasma and urinary assay demonstrates a number of response patterns.    Accuracy can depend on collection techniques and avoidance of amino acid supplements before testing.    Elevated Taurine for example may be seen after consumption of energy drinks.


Glutamate: The assay for Glutamate / Glutamic acid is often not reliable as glutamine decomposes to glutamate quickly and this can produce elevated levels dependent on collection technique.  Glutamate pathways comprise the major excitatory system in the brain and linked to many other neurotransmitter pathways, including GABA, the main inhibitory neurotransmitter.


Low levels of urinary ethanolamine, lysine, tyrosine, histidine, aspartic acid and have been observed in our studies, often seen collectively.  These reflect the increased metabolic utilization in the PEM state.   Ethanolamine in particular may have more relevance in the thromboinflammatory processes seen in Long COVID with its association with PEMT mutations.   Elevated glutamic acid and 1-methylhistidine have also been seen in the urine assays.  


Plasma assays have shown low threonine, tyrosine, arginine and aspartic acid.  These are likely to reflect prolonged PEM activity and overall reduced levels.   High levels of glutamic acid also seen but these may be at least in part collection errors. High plasma histidine may be an important component of PEM and the excitotoxicity.


High plasma branched-chain amino acids (BCAAs) eg isoleucine, leucine and valine appear indicative of several metabolic disturbances.   Possible scenarios include this may reflect mitochondrial dysfunction, a response to the inflammatory processes occurring as these amino acids can modulate immune function,, and they also compete with other amino acides eg tryptophan and tyrosine for transport across the blood-brain barrier potentially affecting serotonin and dopamine synthesis.  BCAAs play a role in muscle protein synthesis and energy production.  Elevated levels could reflect the deconditioning that occurs in POTS.


As data levels progress, the convoluted implications of the altered amino acids are becoming apparent, in particular in excitatory neurotransmission, and collagen formation and integrity.


  • Ethanolamine is a component of cell membranes and involved in lipid metabolism.    It is a precursor for phosphatidylethanolamine synthesis to phosphatidylcholine.  

    • PEMT mutations- Phosphatidylethanolamine N-methyltransferase (PEMT) catalyses phosphatidylcholine synthesis.   PEMT and similar mutations are involved in vascular complications, neurodegeneration and thrombo-inflammation.   It is thought that PEMT gene polymorphisms are associated with non-alcoholic fatty liver disease (NAFLD).  Fatigue is a common symptom of PEMT mutations and its associated mitochondrial dysfunction, and is thought to be involved in neurodegenerative disease.   PEMT is involved in the biosynthesis of phosphatidylcholine (PC) from phosphatidylethanolamine (PE), and likely to be the underlying culprit in persistent D-Dimer tests in Long Covid.   A mutation in PEMT could potentially lead to an accumulation of phosphatidylethanolamine, and by extension affect ethanolamine levels.    PEMT is a critical DNA mutation in POTS and Long COVID. (29)

    • The association between PEMT mutations and thromboinflammatory processes, especially as seen in COVID may explain some of the POTS and Long COVID symptoms.  Ramya Dwivedi (30) describes that “vascular complications in COVID-patients links phosphatidylserine (PS) to thrombo-inflammation.   Thrombo-inflammation plays a critical role through complement activation and cytokine release, platelet overactivity, apoptosis (thrombocytopathy), as well as coagulation abnormalities (coagulopathy).”(30) 

    • Rauchet al (31) found phosphatidylserine was associated with increased thrombo-inflammation and vascular complications.  The DNA mutations found by Dr Valerio Vittone (29) have contributed significantly to understanding the involved pathways, particularly in patients with DNA mutations eg PEMT   There are no known biomarkers for this mutation, so abnormalities in this amino acid metabolism may provide a valuable link and a way to monitor metabolism and abnormalities in this pathway.

    • PEMT mutations could contribute to oxidative stress by altering membrane composition and function.  This could affect cellular signalling, ion channel function and vascular integrity

    • Abnormalities in amino acid metabolism involving ethanolamine could be both a cause and a consequence of the metabolic disturbances associated with PEMT mutations

  • Threonine -low levels may suggest inadequate dietary intake or increased utilization.  It is important for production of glycine and serine. This is a principal part of structural proteins such as collagen and elastin, which are important components of your skin and connective tissue.

  • Lysine is vital for protein synthesis, hormone production and immune function.  Low lysine levels may be caused by prolonged stress, too much arginine or histidine supplementation competing for absorption, or carnitine deficiency.

    • Symptoms may include muscle weakness, fatigue, or high serum triglycerides due to decreased fatty acid transport from low levels of carnitine and lysine. 

    • Low utilization of lysine can lead to decreased hydroxylation, affecting the overall structure of collagen molecules, and making them more susceptible to degradation from mast cell-derived proteases, reducing

    • Insufficient lysine modification can interfere with normal assembly of collagen fibrils, affecting the mechanical properties of tissues

    • As collagen is a major component of the extracellular matrix, this may lead to broader issues in tissue integrity. (36)(37)

    • Lysine is a building block for collagen synthesis, and low utilization may decrease overall collagen production

    • Nicotinamide (Vitamin B3) can influence lysine’s role in collagen synthesis, especially in the context of diabetes and wound healing.   Lysine’s role in collagen synthesis is through hydroxylation which is facilitated by the conversion of NAD+ to NADH, which involves nicotinamide as a component of NAD+.(38)

  • Tyrosine is a precursor for neurotransmitters and thyroid hormones.  The catecholamines affected include dopamine, noradrenalin and adrenalin.  Tyrosine dysfunction particularly due to tyrosine hydroxylase, affects the conversion of tyrosine to L-Dopa, the direct precursor of dopamine.   Dysfunction in tyrosine hydroxylase can result in neurological symptoms eg dystonia, tremor and Parkinson’s disease.(32)(33))

  • Histidine is essential in protein synthesis, tissue repair and production of red and white blood cells.

    • It is synthesized in the tissue by carnosine synthase from histidine and β-alanine, at the expense of ATP hydrolysis.

    • It plays an important role in enzymes eg serine proteases (such as trypsin.) 

    • Histidine is required as a precursor of carnosine in human muscle and parts of the brain where carnosine appears to play an important role as a buffer and antioxidant. Carnosine is synthesized from histidine and β-alanine, at the expense of ATP hydrolysis. (33)

    •  Carnosine plays an important role in exercise performance and skeletal muscle homeostasis. It is widely used among athletes in the form of supplements. It may play a significant role in PEM, but at present this is merely speculative. (34)

    • Histidine can be decarboxylated to histamine by histidine decarboxylase. This reaction occurs in the enterochromaffin-like cells of the stomach, in the mast cells of the immune system, and in various regions of the brain where histamine may serve as a neurotransmitter.

    • Inborn errors have been recognized in all of the catabolic enzymes of histidine. Histidine is required as a precursor of carnosine in human muscle and parts of the brain where carnosine appears to play an important role as a buffer and antioxidant. It can also be degraded to glutamate.(33)

    • Low levels of Pl histidine have been identified in PEM in our amino acid studies, which suggests, when Pl glutamate levels are elevated, increased catabolism of histidine to glutamate.

    • Histidine supplementation can be inappropriate in liver disease, with increases in ammonia and glutamine. o   The increasing glutamate levels may increase the glutamate excitotoxicity.(35)

  • Aspartic acid is an excitatory neurotransmitter and is involved in synthesis of other amino acids including methionine, threonine, isoleucine and lysine.  It plays a role in the citric acid cycle for energy production and the urea cycle.  It acts as an excitatory neurotransmitter in the ventral spinal cord similar to glycine (which is inhibitory).(20)  Aspartate and glutamate can excite virtually every neuron in the CNS at low concentrations.(21)  Aspartate is found in large quantities in neuroendocrine tissues eg hypothalamus. (22)  Aspartate and glycine form an excitatory/inhibitory pain in the spinal cord, similar to glutamate/GABA in the brain.(20)


The amino acids needed for ATP production and utilization include:

 

  • Glutamine which can be converted into glucose through gluconeogenesis, then used to produce ATP

  • Alanine serves as a substrate for gluconeogenesis, especially when fasting or intense exercise

  • Arginine plays a role in the urea cycle and can be converted into nitric oxide that is involved in various signalling pathways influencing energy metabolism, as well as contributing to the synthesis of creatine which helps in ATL production

  • Methionine is involved in the synthesis of S-adenosylmethionine (SAMe), a critical donor in biochemical reactions, including those affecting ATP production and energy metabolism.   DNA mutations in this have consistently been seen by DNA studies by Dr Valerio Vittone.(29)

  • Leucine activates the mTOR pathway that promotes protein synthesis and cellular growth, indirectly supporting ATP production by enhancing muscle recovery and energy utilization

  • Cysteine is important for synthesizing glutathione, an anti-oxidant that protects cells from oxidative stress which can impair ATP synthesis

  • Glycine is involved in the synthesis of creatine, which is crucial for ATP regeneration in muscle cells.(39)


Other amino acids potentially involving the thromboinflammatory pathway:


  • Arginine, a precursor for nitric oxide, which plays a role in vascular function and inflammation

  • Glutamine, with its role in immune function and inflammatory responses

  • Cysteine important for glutathione synthesis, which is crucial for antioxidant defence

  • Tryptophan involved in kynurenine pathway -linked to inflammation and oxidative stress

  • Glycine has anti-inflammatory properties and is involved in haeme synthesis

  • Methionine is important for methylation reactions and can affect homocysteine levels, linked to cardiovascular risk


Brief Guide to Amino Acids (15)


  • The citric acid cycle or Kreb’s cycle or TCA cycle is a series of biochemical reactions to release the energy stored in nutrients through oxidation of acetyl-CoA derived from carbohydrates, fats and proteins.  This energy released is in the form of ATP or Adenosine triphosphate, the “molecular unit of currency.” Glycolytic and TCA cycle intermediates generate the nonessential and conditionally essential amino acids.

  • Free amino acids produced from degradation of either cellular proteins or dietary proteins are deaminated to yield NH4+ and a carbon skeleton. NH4+ enters the urea cycle and the carbon skeleton can enter metabolic pathways to generate ATP, glucose, and fatty acids.

  • Glutamate acts as both a nitrogen donor and acceptor and is the central amino acid for the movement of nitrogen among amino acids.

  • Tyrosine is the precursor to generation of noradrenalin, adrenalin, dopamine, and melanins.

  • Methionine provides the methyl group for many DNA and histone methyltransferases to regulate epigenetics.

  • Cysteine, glutamate, and glycine generate the antioxidant glutathione.

  • Nitric oxide synthases use arginine to generate nitric oxide (NO).

  • Glycine and glutamate can serve as neurotransmitters.

  • Glutamate can generate another amino acid neurotransmitter, γ-aminobutyric acid (GABA), which does not participate in protein synthesis.

  • Tryptophan is a precursor for serotonin.

  • Serotonin is used to generate melatonin.

  • L dopa is converted to dopamine, by enzyme amino acid decarboxylase.   This can occur in both dopaminergic and serotonergic neurons (25)

  • Tryptophan is converted to serotonin also involving enzyme amino acid decarboxylase.(25)

  • Histidine is converted to histamine, involving histidine decarboxylase

  • Phenylalanine is converted to phenylethylamine (PEA) by enzyme amino acid decarboxylase.   This conversion is dependent on Vitamin B6 as a cofactor.  This conversion can occur in various tissues including the brain, and is regulated by monoamine oxidase (MAO).(25)(26)   Phenylethylamine (PEA) is a neurotransmitter and neuromodulator.  It rapidly crosses the blood brain barrier but has a very short half-life in the brain, rapidly metabolized by monoamine oxidase M. (27)

  • It increases the release and inhibits the reuptake of dopamine and noradrenalin in the brain, leading to higher levels which can improve mood, focus and concentration.(28) 

  • PEA activates  trace amine-associated receptors further enhancing dopamine and serotonin release.(27)

  • By increasing dopamine PEA may improve working memory, executive function and attention, potentially helping ADHD

  • Increased dopamine and serotonin may improve mood and reduce anxiety and depression

  • L dopa and tryptophan are dietary derived.   Amino acid decarboxylase is also B6 dependant.

  • Serotonin/ dopamine have an effect on glutamate through the DARPP-32 pathways.  This is a complicated pathway involving multiple steps. 

  • DARPP-32 is involved in the modulation of glutamatergic signalling by dopamine and serotonin, and is an integrator of various different enzymes and regulatory mechanisms.

Associated Vitamin Deficiencies


When amino acids are low, a number of vitamins may be low or in increased demand.

Vitamin B6 (pyridoxine) is important for neurotransmitter synthesis and immune function may be depleted by increased metabolic demands.  It is a required cofactor for amino acid metabolism. 

  • L dopa and tryptophan are dietary derived.   Amino acid decarboxylase is also B6 dependant.

  • Symptoms of B6 deficiency:

  • Skin rashes, especially seborrhoeic dermatitis

  • Cracked sore lips and angle of mouth

  • Anaemia and fatigue

  • Depression and confusion

  • Immune dysfunction

  • Neurological symptoms eg neuropathic pain and numbness

  • Symptoms of B6 toxicity: this is almost never caused by dietary intake, but usually by high-dose supplements.

  • Peripheral neuropathy

  • Painful skin lesions

  • Photosensitivity

  • Nausea

  • Impaired body movements

Vitamin B12 (cobalamin) works closely with folate in amino acid metabolism and protein synthesis.  The impact of PEM on B12 is not fully understood but potential impacts include:

·       Increased oxidative stress with breakdown of amino acids, indirectly affecting B12 metabolism and methylation reactions

·       Mitochondrial dysfunction.  PEM involves mitochondrial dysfunction and b12 is crucial for cellular energy production, this dysfunction interfering with B12 utilization at a cellular level

·       Altered methylation. B12 is essential for methylation processes, and the metabolic stress in PEM may increase the demand for methylation reactions, affecting B12 utilization and availability

·       Impaired B12 absorption with the association with gut dysfunction in CFS

·       Altered energy metabolism and potential for B12 deficiency

Folate (vitamin B9) essential for metabolism of several amino acids including histidine, glycine and serine

Vitamin C (ascorbic acid) Vitamin C, a powerful antioxidant may be affected by PEM as the body attempts to deal with the increased oxidative stress, and a higher utilization.  

·       The “burn off” or catabolism of amino acids in PEM could indirectly affect Vitamin C dependent pathways, eg metabolism of Tyrosine.

·       Collagen synthesis may be affected by the PEM’s demand for vitamin C

·       The immune stress in PEM may increase the demand for Vitamin C to maintain immune defences

Vitamin B3 (niacin) is involved in the synthesis of tryptophan.  Low niacin can affect tryptophan breakdown and serotonin production.

Vitamin B1 (thiamine) plays a role in metabolism of branched chain acids leucine, isoleucine and valine.   

Vitamin D which is important for calcium absorption, immune function and neuromuscular health may be affected by altered absorption and increased utilization

Vitamin E an antioxidant protecting cell membranes may be depleted in oxidative stress

Associated Mineral Deficiencies

Zinc is essential  for immune function, wound healing, DNA synthesis and is a cofactor for numerous enzymes.  In a “burn off” potential mechanisms include increased demand from chronic inflammation, altered absorption or increased excretion and utilization in antioxidant processes.

Magnesium is critical for energy production, nerve function and muscle contraction. With depletion from increased metabolic demands

Selenium an antioxidant supporting immune function nand thyroid hormone metabolism may be depleted by increased oxidative stress

Copper is necessary for iron metabolism and antioxidant function, and may be altered by altered absorption and increased utilization

Manganese plays an important role in collagen formation and function and is required for the activation of prolidase an enzyme crucial for collagen synthesis


Major Neurotransmitter Pathways  (detailed in “Neurotransmitter Functioning”)

 

The balance and interplay between these different neurotransmitter pathways are crucial for normal brain function, and disruptions can lead to neurological and psychiatric disorders.


  • Dopamine pathways- involved in reward, motivation and motor control.  Dopamine is the primary neurotransmitter in the mesolimbic (reward) pathway, involved in motivation, pleasure and reinforcement of behaviours.  Dopamine pathways are critical for motor function, with disruptions leading to Parkinson’s Disease.

  • Serotonin pathways- projections to various parts of the nervous system influencing functions such as sleep, memory, appetite and mood.  It is involved in regulating sleep-wake cycles.

  • Glutamate pathways- the major excitatory system in the brain and linked to many other neurotransmitter pathways, including GABA, the main inhibitory neurotransmitter. Glutamate is involved in numerous pathways related to learning, memory and cognitive function.(18)

  • GABA (Gamma-aminobutyric acid) is the main inhibitory neurotransmitter in the CNS, helping to regulate and balance neural activity.  GABA pathways are involved in managing anxiety and stress responses.

  • Acetylcholine (Ach) pathways are crucial for maintaining cognitive function, with disruptions linked to Alzheimer’s disease.   In the peripheral nervous system Ach is essential for muscle activation.

  • Noradrenaline pathways are involved in regulating arousal, attention and fight-or flight responses.   It plays a key role in the sympathetic nervous system influencing heart rate, blood pressure and other autonomic functions

  • Histamine pathways are involved in regulating the sleep-wake cycle and promoting wakefulness.   Histamine pathways are also involved in immune responses and brain inflammation.


References:


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2.     Germain A, Giloteaux L, Moore GE, Levine SM, Chia JK, Keller BA, Stevens J, Franconi CJ, Mao X, Shungu DC, Grimson A, Hanson MR. Plasma metabolomics reveals disrupted response and recovery following maximal exercise in myalgic encephalomyelitis/chronic fatigue syndrome. JCI Insight. 2022 May 9;7(9):e157621. doi: 10.1172/jci.insight.157621. PMID: 35358096; PMCID: PMC9090259.

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