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Autism Coach

Unbottling Common Neurotransmitter Bottlenecks

Posted by Susan Bennett on

Each of us contains a chemistry set that carries out complex chemical reactions throughout our body and brain.  These chemical reactions make up our metabolism (chemical changes in the body) and keep us alive.   Most of these chemical reactions are carried out with the help of enzymes.  Metabolic processes break down substances, form new substances, and transfer energy from one substance to another.

Enzymes are a type of protein that gathers building blocks such as amino acids, and then facilitates a chemical reaction that converts these building blocks into one or more new molecules.  Energy is also released from chemical reactions in the form of heat.  The heat generated by these reactions gives us a body temperature of 98.6° (37° Celsius).

Our body is constantly converting building blocks into new molecules to another as needed.  In fact there are metabolic cycles where a molecule is used to form a new molecule, the new molecule is converted to yet another molecule, and so on until eventually the cycle recreates the original molecule all over again.

Simple Metabolic Pathway.jpg

Neurotransmitters are molecules used within the brain and central nervous system to communicate, store and retrieve information. Optimal amounts and ratios of neurotransmitters are required for optimal mental health and function. 

Metabolic pathways interact with each other like gears meshing with each other to coordinate different activities and processes within the body:

Metabolic Processes Interconnecting.jpg

If one of the gears in a complex mechanism isn’t working correctly, it can throw off the function of the gear next to it. It is like throwing a monkey wrench into a complex gear-driven mechanical system:

Disrupted Pathway 1 of 3.jpg

The first disrupted metabolic pathway throws monkey wrenches into the pathways it interacts with, it can throw off the function of those pathways:

Disrupted Pathway 2 of 3.jpg

If the enzymes needed to convert the neurotransmitters into the next form in a metabolic cycle are missing or not functioning efficiently or properly, then the neurotransmitters may not be converted into the next form required by the body and nervous system.   Unconverted neurotransmitters can build up in excessively high levels and can actually cause neurological damage.  

These bottlenecks result in neurotransmitter imbalances. Individuals with neurotransmitter imbalances have too much of some neurotransmitters, not enough of others. It turns out in individuals with issues like anxiety, OCD, depression, aggression, substance abuse issues, ADD/ADHD, and autism have neurotransmitter imbalances.

Metabolic pathways that don't efficiently convert neurotransmitters into the next form required by the body and nervous systems become bottlenecks.  These bottlenecks can interfere with other metabolic processes and a cascade of metabolic disruption can occur.

Unbottling common bottlenecks can help normalize many metabolic processes on a fundamental level to get at the cause of problems and improve health as opposed to simply masking or treating symptoms.

In individuals with imbalanced neurotransmitters it is common to find:

The Phenyalanine Bottleneck

In autism, there is frequently too much phenylalanine, which is also the case in a genetic condition known as phenylketonuria, which can lead to mental impairment.  

Phenylalanine is an aromatic amino acid is used to make several other aromatic amino acids/neurotransmitters that include are also aromatic based amino acids and molecules including:    Tyrosine, Tryptophan, L-DOPA, Dopamine, Octopamine, Synephrine, Norepinephrine, and Epinephrine.  

Aromatic amino acids and neurotransmitters all have an aromatic ring incorporated into their molecule: 

It turns out that a specific enzyme is needed to convert phenylalanine into other aromaticc molecules in the metabolic pathway for making all the other neurotransmitters.  This enzyme is the Aromatic Amino Acid Hydroxylase (AAAH).  This enzyme, in turn, requires a molecule called bipoterin (also known as tetrahydrobiopterin or BH4) to work properly:

The Biopterin Bottleneck

If the Biopterin is not available for the AAAH enzyme, phenylalanine builds up.  As it turns out Biopterin is needed for several critical functions in the body:

  • Converting Phenylalanine into Tyrosine.
  • Converting Tryptophan into its active form - 5-hydroxytryptophan (5-HTP).  5-HTP in turn is used to manufacture Serotonin (for alertness and good mood) and Melatonin (promotes sleep).
  • Converts Tyrosine to L-DOPA. L-DOPA is needed to make the neurotransmitters norepinephrine and epinephrine.
  • A precursor for creating Octopamine.  Octopamine is a neurotransmitter found in the central and sympathetic nervous systems. Reduced levels of Octopamine cause social deprivation, the inability to communicate, a compromised flight or fight response, and learning disabilities. In one preliminary study, parents of autistic children trialed using Bitter Orange, which contains Octopamine, and observed improved social awareness, better socialization, and better receptive language. (4)
  • Converting Arginine to Nitric Oxide (NO).  Nitric oxide helps to dialate blood vessels, allowing oxygen and nutrients to reach cells.  Production of nitric oxide. Nitric oxide dilates the blood vessels to allow oxgyen to reach all the cells. Not enough nitric oxide results in the collapse of micro-capillaries in the brain which can result in mini-strokes that cause neurological damage, according to the late Dr. Andrew Moulden. Cells depending on oxygen and nutrients from micro-capillaries (including neurons) are in a state of oxidative stress, do not function optimally and can become damaged, and even build-up toxic by-products. Many supplements that help individuals with autism dilate (open up) blood vessels including Citrulline, Vinpocetine, and the flushing form of niacin.
  • Detoxifying ammonia. When there excessive levels of intestinal pathogens, they produce toxic by-products, such as ammonia. Candida overgrowths produce excessive levels of ammonia.  Symptoms of excessive ammonia levels are strong body odor and brain fog. BH4 is used by the body to detoxify ammonia. Excessive levels of toxic by-products use up and deplete the body of BH4.

On top of all this, when BH4 is used up, it converts to the inactive form of BH2.  When not enough BH4 is available, BH2 is plugged into a dysfunctional metabolic pathway which in turn produces the incredibly toxic free radical, Super Oxide which causes massive damage to tissues and puts a burden upon the body to repair excessive damage to genes and molecules from Super Oxide.

The figure below depicts important metabolic processes that are commonly disrupted in individuals with neurotransmitter imbalances, and shows just some of the places where BH4 plugs into critical metabolic processes:

disrupted-pathways-1-2-24-18.jpg


Why Is there a Phenylalanine/Biopterin Bottleneck?

The Phenylalanine/Biopterin bottleneck is likely to be primarily caused because of contamination of our food supply from the weedkiller, Roundup, which is now widely used to grow genetically modified (GMO) crops and is also sprayed on many other crops just prior to harvest. 

Roudup kills weeds by blocking a metabolic pathway called the shikimate pathway. This pathway is essential in plants and microbes for the synthesis of a class of amino acids called the “aromatics.”  When this pathway is blocked, the plants die.  Glyphosate's disruption of the shikimate pathway is due in part to its chelation of (binding to and making unavailable) Manganese (Mn).  Manganese is a catalyst for enolpyruvylshikimate phosphate synthase (EPSPS), a critical early enzyme in the shikimate pathway.  In studies where animals are exposed to Roundup, they are consistently deficient in Manganese and Cobalt.  Cobalt happens to be a component of Vitamin B12 (cobalamin) which  is also critical in several important metabolic pathways for methylation and detoxification.

Plants and microbes use the shikimate pathway to produce the aromatic amino acids, tryptophan and tyrosine. Because humans don’t have this pathway, we can’t produce these essential nutrients, and so we depend on plants and microbes to provide these nutrients for us. Glyphosate, by interfering with this pathway, leads to a deficiency in Tryptophan and/or Tyrosine.

Other disruptions to metabolic pathways by Roundup include the following:

  • Glyphosate activates an enzyme called phenylalanine ammonia lyase (PAL), which breaks down phenylalanine and releases ammonia as a by-product.  Excess ammonia in the blood stream can trigger a cascade leading to brain fog, encephalitis and seizures.  Excess ammonia also uses up BH4 because BH4 is needed to detoxify ammonia.
  • Roundup kills many beneficial microbes  in the intestinal tract that use the shikimate pathway.  When these microbes are killed, pathogenic microbes tend to flourish that tolerate Roundup. A characteristic feature of children with autism is an overgrowth of pathogenic bacteria in the gut, which can lead to neurological defects arising from exposure of the brain to toxins produced by these bacteria. 
  • Malnourishment occurs because beneficial microbes are not present to produce precursors to important vitamins and neurotransmitters including:  serotonin, melatonin, melanin,epinephrine, dopamine, octopamine, thyroid hormone, folate, coenzyme Q10, vitamin K, and vitamin E.  The lactobacillus family of beneficial microbes requires Manganese and the chelation of Manganese by Round-up results in lower levels of these beneficial microbes in the intestinal tract. The lactobacillus family makes the calming neurotransmitter GABA and its precursor, butyric acid. 
  • Only a few bacteria can break down Glyphosate in the intestinal tract, and these turn out to produce toxic by-products. Clostridia difficile (C.diff) and Pseudomonas Aeruginosa are two pathogens that appear to be able to break down Glyphosate.  When they break down Glyhposate, they produce formaldehyde as by-product.  Formaldehyde is a neurotoxin and carcinogen. C. Diff also produces a toxic phenol called p-Cresol, which is associated with both autism and Parkinson's Disease.  The pathogenic, Salmonella, also is resistant to glyphosate.  
  • Glyphosate when metabolized by mammals, including us, yields two neurotoxins:  Aminomethylphosphonic acid (AMPA) and glyoxylate. Glyoxylate is a highly reactive glycating agent, which will disrupt the function of
    multiple proteins in cells that are exposed.  Glycation is when glucose reacts to and binds to tissues near it causing damage to tissues.  An accurate blood test for determining if a person is autistic is based upon identifying high levels of glycation end-products (AGES).  
  • Chelates beneficial metals which means that plants and animals have reduced levels of beneficial minerals including:  magnesium, cobalt, and manganese.
  • Reduces level of the anti-oxidant Super Oxide Dismutase which can trigger mitochondrial dysfunction.
  • Reduces levels of methionine and glycine.
  • Reduces production of Cytochrome P450 (CYP) enzymes.  CYP enzymes break down toxins in food and also break down man-made chemicals. These enzymes are also needed for bile acid formation. Bile acids are secreted during digestion to break down fats and excrete toxins such as arsenic - if you have light colored stools you aren't producing enough bile and are more likely to be building up concentrations of heavy metals. Roundup also appears to block bile ducts, reducing bile flow.  A study on rats showed that both males and females exposed to Roundup® had 50% reduction in hepatic CYP enzyme levels compared with controls.
  • Porphyria, pyroluria and chemical sensitivity may be caused by Roundup because Roundup blocks bile ducts and blocked bile ducts contribute to Porphyria and multiple chemical sensitivity.
  • Manganese deficiency impairs the function of the pancreas. Rats fed a Mn-deficient diet had significantly reduced concentrations of Mn in liver, kidney, heart, and pancreas, compared with controls. Furthermore, pancreatic insulin content was only 63% of control levels, and insulin release following glucose administration was also reduced.
  • Both Mn deficiency and Mn toxicity, attributable to glyphosate, can occur simultaneously. Because of glyphosate's disruption of CYP enzymes, the liver becomes impaired in its ability to dispose of Mn via the bile acids, and instead it transports the Mn via the vagus nerve to brainstem nuclei, where excess Mn leads to Parkinson's Disease.  while the brainstem suffers from excess Mn, the rest of the brain incurs Mn
    deficiency due to the depressed serum levels of Mn. Mn is particularly important in the hippocampus, and deficiency there can lead to seizures. A high incidence of seizures is found in children with autism. Seizures are also associated with reduced serum Mn and this is consistent with the liver's inability to distribute Mn to the body via the bile acids. 
  • Oxalic acid in excess becomes a neurotoxin.  Beneficial microbes that break down oxalates, including Bacillus subtillis,  are dependent on Mn as a cofactor.
  • Mangesium deficiency leads to impaired glutamine synthase and arginase, both of which use Mn as a cofactor.  Glutamine synthase which converts Glutamate to Glutamine.  Glutamine synthase depends upon Mn as a cofactor, so depleted Mn supplies would lead to a build-up of glutamate that cannot be returned to the neurons using normal channels.
  • Ammonia is a highly diffusible gas that readily crosses the blood–brain barrier, and its detoxification depends upon the conversion of glutamate to glutamine, which is catalyzed by glutamine synthase, the enzyme in microglia that relies upon Mn as a cofactor.  Thus, impaired function of glutamine synthase leads to the accumulation of both glutamate and ammonia in the brain, both of which are established neurotoxins.
  • Excess ammonia due to impaired ability to detoxify excess nitrogen via the urea cycle can lead to impaired memory, shortened attention span, sleep–wake cycle disruption, brain edema, intracranial hypertension, seizures, ataxia, and coma.  Arginase, the final enzyme of the urea cycle, is ubiquitous in living systems, and also depends upon Mn. The excess accumulation of ammonia due to inactive glutamine synthase combined with the decreased ability to metabolize ammonia to urea constitute a double hit leading to ammonia toxicity in the brain.

Unbottling the Phenyalanine/Biopterin Bottleneck

Sound approaches to reducing levels of phenylalanine and increasing levels of other neurotransmitters that are made from phenylalanine include:

  • BH4 - Supplementing directly with BH4 can be therapeutic.
  • Bitter Orange - contains both BH4 and Octopamine.  Prelimnary studies show increased levels of GABA and improvement in social skills with Bitter Orange supplementation.
  • Methyl Folate - can substitute for BH4 in some reactions and helps to recycle BH2, reconverting it into BH4. These are some of the many reasons it is important for most people to supplement with Methyl Folate.
  • Biofilm Remover + Microbiome Builder Kit  - promotes beneficial microcrobes so fewer toxins are produced.
  • Intestinal Reboot - heals and normalizes function in the intestinal tract so fewer toxins are produced.  Works well with the Biofilm Remover + Microbiome Builder Kit.

In addition, dilating microcapillaries jelps to reduce oxidative stress and helps cells function optimally, with approaches including:

  • Vinpocetine - dilates blood vessels
  • Citrulline and/or watermelon (which contains Citrulline)
  • The flushing form of niacin.  A controlled niacin flush over a period of 2-3 months has been anecdotally effective in dramatic improvements in autism - starting with 50 mg  a day and working gradually up to 375-500 mg for 1-2 weeks.
  • Hyperbaric oxygen therapy also causes a rebound arterial dilation, resulting in an increased blood vessel diameter greater than when therapy began, improving blood flow.

The Glutamate/GABA/Glutamine Bottleneck

The of the two most common neurotransmitters in the brain and nervous system are Glutamate and GABA.  Glutamate excites a neuron to fire and signal the next neuron and GABA inhibits a neuron from firing.  Glutamate excites neurons and GABA inhibits neurons. Glutamate converts to GABA and Glutamine through a metabolic pathway.  Conversely GABA and Glutamine can also convert to Glutamate.

The rubella virus, which is found in the MMR vaccination can decrease the activity of glutamic acid decarboxylase (GAD)by as much as fifty percent.  This is because the immunization causes an autoimmune reaction in which the body's immune system produces antibodies to the GAD enzyme and attacks it.  The result is that Glutamate is not converted to GABA, excessive levels of Glutamate build up and there is not enough GABA. This is likely to be one of the reasons children begin to exhibit symptoms of autism immediately after receiving the MMR.   

The GAD enzyme concentrates in the frontal lobes of the brain where executive function is carried out.  Executive function includes impulse control, thinking ahead, and planning and carrying out complex tasks.  GAD is also found in the hypothalamus, the cerebellum (which controls motor function) and other brain regions.  It also turns out that a gluten or gliandin allergy causes an autoimmune response to GAD as well.  Antibodies to GAD are also found in diabetics and so diabates is also caused by a immune system reaction to immunization.  Methylation reactivates GAD, which may be one of many reasons why methylation support is frequently beneficial in autism.

Below is a diagram of a neuron.  It receives signals through it's dendrites and send signals through its axon terminals.  Note that astrocytes and oligodendrocyes, both of which are glial cells are attached to the neuron and also impact its function.

Image result for image of neuron signalling another neuron

This depicts the direction in which neurons send signals.  The first neuron on the left sends a signal through its axon to a synapse to which the second neuron is connected.  It is through the synapse that the first neuron sends a chemical signal to the second neuron.

.1: Two neurons having a synaptic connection source:internet

Here is a picture of one neuron sending a signal through its axon terminal to signal the dendrite terminal of the next neuron:  

Image result for synapse of neuron firing diagram

Note that a neuron may be killed by the release of excess Glutamate as shown below: 

Diseased Neuron

Why do some individuals become higher function when they have a fever?  Some research indicates GABA  is made in response to a number of environmental stresses in plants including high temperature stress.

There are also factors in making GABA, including the microbes in the intestinal tract.  Chronic infections reduce levels of beneficial microbes that make butyric acid which not only protects the intestinal tract but is also a precursor for making GABA.  

GAD deficiency is associated with several autoimmune disorders, including autism,Hashimoto’s, Celiac Disease, gluten intolerance, type 1 diabetes, and other neurological disorders with cognitive decline such as Parkinson's Disease and Alzheimers. GAD is found in your pancreas, where it’s needed for the release of insulin.

Symptoms of an imbalance of Glutamate and GABA neurotransmitters includes aggression, OCD, and anxiety.

When there are chronic infections in the intestinal tract, excessive amounts of ammonia are produced by pathogens that also impact neurological function. 

Unbottling the Glutamate/GABA Bottleneck

The following supplements can help reduce levels glutamate and ammonia and increase levels of GABA:

  • Yucca root - helps detoxify ammonia.
  • Bitter Orange - contains BH4 which helps to detoxify ammonia, and increases levels of GABA.
  • Carnitine - reduces levels of glutamate
  • Zinc - reduces levels of glutamate
  • Lithium - reduces levels of glutamate
  • Neural Balance - contains oassionflower - inhibits overfiring of neurons and increases levels of GABA.
  • CBD oil - inhibits overfiring of neurons
  • Glycine - Magnesium Glycinate, Trimethylglycine, or Dimethylglycine can all help.  They also help prevent glyphosate from binding to molecules in the body and disrupting metabolic processes.
  • Taurine - inhibitory amino acid, helps make the GAD enzyme that converts glutamate into gaba, increases levels of GAD
  • Green tea and Theanine - Theanine is found in green tea, helps inhibit over-firing of neurons

Excreting Roundup

In studies the following supplements, herbs and foods have been found to help the body to excrete Roundup and/or protect from damage from Roundup:  Berberine, Burdock, Dandelion, Greater Celandine, Milk Thistle, Activated Charcoal, Fulvic Acid, Humic Acid, Bentonite, Manganese, Sauerkraut Juice.  Our Herbal Detoxifier has several ingredients which promote detoxification and removal of Roundup.

References

  1. Alternation of Plasma Glutamate and Glutamine Levels in Children with High Functioning Autism http://journals.plos.org/plosone/article?id=10.137...
  2. Alterations in Dopamine and Glutamate Neurotransmittion in Tetrahydrobiopterin Deficient Mice https://pdfs.semanticscholar.org/392b/30d0cfdc52b...
  3. Increased Glutamate and Homocystene and Decreased Glutamine Levels in Autism
  4. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC37875...
  5.  https://www.scribd.com/presentation/17484845/Reversing-Autism-Connecting-the-pieces-with-the-latest-research-on-BT-Hg-Octopamine-Succinic-acid-B12-Leptu-and-BIRM
  6. https://neuroendoimmune.wordpress.com/2013/07/09/g...
  7. https://www.reddit.com/r/Nootropics/comments/3xiq6...
  8. https://www.wellnessresources.com/news/gaba-managi...
  9. https://www.sciencedirect.com/topics/neuroscience/...
  10. Heat increases GAD levels; https://link.springer.com/chapter/10.1007/978-94-0...
  11. Enzymes and polymorphisms  -
  12. https://academic.oup.com/ajcn/article/75/4/616/468...
  13. GAD reactivated by methylation. 
  14. https://www.ncbi.nlm.nih.gov/gene/2571
  15. https://www.ninds.nih.gov/Disorders/Patient-Caregi...
  16. https://aasldpubs.onlinelibrary.wiley.com/doi/pdf/...
  17. https://biofoundations.org/how-to-detoxify-your-bo...
  18. https://myersdetox.com/166-glyphosate-herbicide-an...
  19. https://www.alexfergus.com/blog/how-to-protect-you...


  • Neurotransmitter Imbalances
  • Glutamate Toxicity
  • Phenylalanine toxicity
  • Ammonia toxicity
  • Glyphosate poisoning
  • Glyphosate toxicity
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