Brain Research in Autism

Dr Martha Herbert MD PhD, a pediatric neurologist at the Center of Morphometric Analysis, Massachusetts General Hospital, wrote a piece that summed up one of the underlying schisms in the research community that explains a lot of the chaos in the brain research community regarding autism as well as why making sense of this research is the source of many disagreements:

"The positions in the parallel sets of debates tend to cluster into two provisional models, each of which links clinical and research data into a different gestalt.  One model sees autism as a strongly genetic brain-based disorder, with a constant prevalence but a recent increase in awareness that has led to the appearance—but not the reality—of an epidemic. The other model sees autism as a genetically influenced but environmentally modulated condition involving multiple systems of the body, with increased numbers being real and related to changes in environmental factors."

Basically, the disagreement is whether autism is the RESULT of abnormalities in the brain, or whether abnormalities found in the brain are CLUES to a deeper underlying cause that was probably triggered by environmental factors.  If you believe that abnormalities in the brain cause autism, then it makes sense to fish around until you find the abnormalities and then simply identify the genes responsible.  As Dr Herbert so eloquently points out in the above article, this approach has not really lead anywhere.  If you view abnormalities in the brain as the result of deeper, underlying causes- if you view autism as a disorder that affects the brain, as Dr Herbert says, rather than one that is of the brain, finding abnormalities in the brain leads to the conclusion that autism is a whole-body, multi-system disorder.  While there is a component of genetic involvement, it is not in a deterministic way- a saying that you hear over and over in the biomedical world is that "genes load the gun, the environment pulls the trigger".  The above article by Dr Herbert is a good introduction to the basics of the biology of autism, including increased oxidative stress, widespread inflammation (including neuroinflammation), impaired mitochondrial function, impaired detoxification ability, and impaired cellular metabolism.

Autism: a Brain Disorder, or a Disorder that Affects the Brain?  by Martha Herbert
Clinical Neuropsychiatry (2005) 2, 6, 354-379
In this paper, Dr Herbert discusses the ideas presented in the article linked to above in much greater detail.  Additionally, she discusses some of the brain research more specifically and flushes out the implications of the different models in regards to interpretation of the results.

So, keeping in mind that brain research in autism is most useful as one piece of a much larger puzzle, here are some studies that provide some insight.  Studies that find involvement of one or more particular brain region:

Stanford Scientists Successfully Reverse Autism Symptoms in Mice
"Overactivity in the reticular thalamic nucleus was shown to cause autism-like behaviors in mice. Drugs that reduce this activity reversed the symptoms."

Left-hemispheric atypicalities in the primary auditory cortex are associated with language comprehension and social skills in children with Autism Spectrum Disorder
"First, the results revealed a reduction of M200 and altered M200 sensory gating effect in the left auditory cortex in children with ASD. Second, these alterations were related to lower language comprehension skills and higher autistic symptom severity. Finally, altered MEG responses were associated with gray matter thickness reduction as well as abnormal gyrification in the primary auditory cortex in ASD. The study revealed low-level functional and structural atypicalities in children with ASD and their relation to clinical phenotype."

Studies suggesting abnormalities in cortical development:

Low-Dose Naltrexone (LDN)

Low-Dose Naltrexone, usually abbreviated LDN, is used fairly often in treating some of the diseases that co-occur with MCAS and even MCAS itself.  It is considered to be quite safe.  In this capacity it is usually used to treat chronic pain, particularly in cases of Fibromylagia and Ehlers-Danlos Syndrome.  The drug was originally used to treat heroin addiction (and sometimes alcohol addiction) by reducing the symptoms of withdrawl.  Later it was discovered that very low doses could stop an HIV infection from becoming AIDS.  LDN has been found to have anti-inflammatory properties, anti-depressive properties, and anti-anxiety properties.  Doctors began using it in this low dose form to treat other things including Crohn's Disease, Fibromyalgia, MS, some skin disorders, and lately even in treating some cancers.  While the ways that LDN helps in many diseases is not well understood, it is clear that it is very safe and able to help many people suffering a wide range of diseases/disorders.

LDN is an immune-modulator rather than an immune-suppressant.  Drugs that are immune-suppressors treat the symptoms of some diseases by suppressing the body's production of inflammatory molecules, suppressing the body's ability to fight infection.  This may put a disease into a less active state but it does not actually treat the disease by addressing the underlying cause, and it can leave the person dangerously susceptible to infection.  By up-regulating the expression of certain cellular receptors, LDN actually changes the immune system itself, making it more able to respond appropriately to a challenge.  It can be said to "modulate" the immune system because it reduces inflammation while supporting a person to be more healthy in an overall sense.  

LDN works by blocking the opiate receptors on cells for about 3 hours at a time, which tricks the body into thinking that there aren't enough receptors, causing it to produce more.  The body also responds by producing more endorphins, which are the body's own chemicals to reduce pain and cause a state of well-being.  It reduces inflammation in the brain and CNS by acting on the TLR-4 receptors on immune cells called glial cells, causing them to reduce their production of pro-inflammatory molecules including IL-6.  This provides an anti-inflammatory effect on the brain but this benefit can include other parts of the body because the brain controls so much of the body.

The only two side effects that seem to be reported much are that it can cause people to have vivid dreams,and that when a person begins taking it, during the first few weeks it can cause insomnia.  However, there are also some people who report that it causes there sleep to improve.  Some patients experience benefits from LDN very soon after starting it, while it can take longer in others.  It should be tried for at least 2 to 3 months before deciding that it isn't working for a patient.  

Low dose Naltrexone for induction of remission in inflammatory bowel disease patients

Low-dose naltrexone for the treatment of fibromyalgia: Findings of a small, randomized, double-blind, placebo-controlled, counterbalanced, crossover trial assessing daily pain levels

The effect of low-dose naltrexone on quality of life of patients with multiple sclerosis: a randomized placebo-controlled trial

Naltrexone a potential therapeutic candidate for COVID-19

Low-dose naltrexone in the treatment of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)
"The high frequency of treatment response and good safety profile observed in this retrospective open label study could prompt prospective controlled studies to confirm the feasibility of LDN in alleviating ME/CFS symptoms."

Potential pathophysiological role of the ion channel TRPM3 in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and the therapeutic effect of low-dose naltrexone
"The Transient receptor potential melastatin 3 (TRPM3) channel, involved in pain transduction, thermosensation, transmitter and neuropeptide release, mechanoregulation, vasorelaxation, and immune defense, shows altered function in ME/CFS. Dysfunction of TRPM3 in natural killer (NK) cells, characterized by reduced calcium flux, has been observed in ME/CFS and PCS patients, suggesting a role in ineffective pathogen clearance and potential virus persistence and autoimmunity development. TRPM3 dysfunction in NK cells can be improved by naltrexone in vitro and ex vivo, which may explain the moderate clinical efficacy of low-dose naltrexone (LDN) treatment."

Naltrexone at low doses (LDN) and its relevance to cancer therapy
"Considering the increase in the number of anecdotal reports of activity, there will likely be a bigger drive toward using LDN in the oncological setting. These reports support clinical trials of LDN in cancer, especially when given in combination with certain chemotherapy."

"We review three mechanisms through which LDN can influence cancer progression; namely, (a) antagonism of receptors to which LDN binds, which include toll-like receptors 7–9 that lead to IL-6 suppression b) modulation of immune function in patients; and c) direct inhibition of signaling pathways involved in cancer cell control, including the priming of pro-apoptotic pathways."

Supplement Notes (Vitamins)

LETTER VITAMINS:

Bioavailability is the fraction of an administered compound that reaches the systemic circulation and is transported to site of action (target tissue).  From Linus Pauling Institute (LPI) 

B vitamins -  (B vitamins should be taken together to maintain the correct ratios of each)

B Vitamins and the Brain: Mechanisms, Dose and Efficacy—A Review

B vitamins are essential cofactors for the functioning of the electron transport chain in the mitochondria.  They are also helpful to minimize the damage to organs and cells from diabetes.

B1 (thiamine) -  supports sugar metabolism.  Has a relaxing and calming effect.  Can reduce symptoms caused by high blood sugar, including tinnitus.

Folinic acid improves verbal communication in children with autism and language impairment: a randomized double-blind placebo-controlled trial

B6 (P5P is the active form) - important for connective tissue production and is an important cofactor in the regulation of neurotransmitters.

Biotin - is sometimes considered to be a B vitamin.  It is made by microbes in our gut and inhibits the yeast in our bodies from turning into it's invasive form (hyphae).  It can also help reduce or stop hair loss.  

B12 - deficiency can be caused by the drug Metformin, eating a vegan diet, and surgery that removes part of the bowel.  It can easily be mistaken for a folate deficiency.  A severe form of B12 deficiency can lead to a type of anemia called Pernicious Anemia because B12 is important for the production of red blood cells and DNA and for the nervous system to function. 

Vitamin C - supports immune function, is a potent antioxidant and important component in the formation of connective tissue.   Very high doses given intravenously have been used to successfully treat sepsis and skin cancer (and possibly other cancers).

Supplemental forms of vitamin C (from the Linus Pauling Institute)

Vitamin D - significantly improves the absorption of calcium from the gut and helps our bodies to put that calcium where it is supposed to be and not where it isn't (calcification is a significant cause of many symptoms/conditions including cataracts, atherosclerosis, vertigo, and arthritis).  The preferred form is vitamin D3 and should be taken along with vitamin K2 (K2 is important for putting calcium into bones).

Vitamin E - supports immune function and reduces inflammation.  It is important for healthy blood and circulation as a blood thinner; it dissolves fresh blood clots, reduces the need for oxygen in body tissues (deficiency of vitamin E increases tissue needs for oxygen, which is why it is connected with chest pain and angina), reduces muscle cramping, helps heal burns, and reduces scarring.  Good food sources include wheat germ oil (if not allergic), sunflower seeds, almonds, raw seeds and nuts, leafy greens, and avocado.

Vitamin K2 (D3/K2)

 OTHER VITAMINS AND SUPPLEMENTS:

Melatonin is an antioxidant that can enter the mitochondria and protect them from oxidative stress, apoptosis, and impaired function (energy production).  Also supports glutathione production, has anticonvulsant properties, reduces the effect of autoimmune diseases, and helps support immune function.  It is best known for inducing sleep at night.

Mito Cocktail (Treatment for mitochondrial disease and dysfunction)

There have been very few options available for treating and managing mitochondrial disease and dysfunction (both of which are referred to as "mito").  As a result, this is one area of conventional medicine in which the value of nutritional supplements has been accepted and embraced.  People with mito usually take a custom blend of supplements every day that is refereed to as a "mito cocktail".   Many people try various combinations of these vitamins and supplements on themselves to see what helps, especially those with mito dysfunction (which is generally acquired from toxic injury, is generally much more mild, and much harder to find a doctor willing or able to treat).  There are some general guidelines and some basic components that are safe, so it is possible to go about it this way, but the doses of the components may need to be very high and it can be very hard for individuals to get the doses and combination right for their needs.  However, since so few people have access to doctors to treat mito, this is the best that many people can do.   Once a good "cocktail" is developed for a patient they may choose to have it compounded, which can make the cocktail much easier to take (especially if 
it includes many different components).

The Mito cocktail explained from Mito Action 

Diagnosis and management of patients with mitochondrial disease  (specifically table 2) 

Letter explaining importance and cost benefit of mito cocktail

Results from survey about mito cocktail on MitoAction

The Effect of Mitochondrial Supplements on Mitochondrial Activity in Children with Autism Spectrum Disorder

The Basic Components:

Many people include Alpha Lipoic Acid (ALA) in the mito cocktail, and while it is supportive of mito function it is also a powerful chelator of mercury, lead, and other toxic metals and can cross the blood-brain-barrier so if there is a body burden of toxic metals it can push those metals into the brain.  Use this with caution if metal toxicity is known or suspected.

Antioxidants - these are plant chemicals that protect the mitochondria from damage caused by oxidative stress.  Oxidative stress produces "free radicals" as a byproduct of energy production which can harm cells.  More on what free radicals are from the NIH site Office of Dietary Supplements:

"An atom or molecule made in the body that can damage cells. A free radical has at least one unpaired electron, which makes it unstable. To become stable, the free radical takes an electron away from another atom, which makes that atom unstable, and starts a chain reaction that can injure cells. Free radicals are made during chemical changes that take place in a cell or an organism to produce energy and basic materials needed for important life processes (metabolism). They also come from tobacco smoke, pollution, radiation from the sun and x-rays, and other sources outside the body. Free radicals damage cells, cause genetic alterations (mutations), and may play a role in cancer, heart disease, and age-related diseases (such as Alzheimer's, Parkinson's, and Lou Gehrig's diseases). Free radicals are also beneficial; they are involved in killing germs (microorganisms) and they help hormones and chemical messengers communicate with cells. Proteins (enzymes) made by the body, and vitamin C, vitamin E, and beta carotene in the diet help prevent free radical damage."

Arginine - is another amino acid that can be very helpful for some people with mito, especially the form called MELAS which involves stroke-like episodes.   Arginine usually needs to be taken in very high doses.  Arginine and another amino acid Lysine need to be consumed in balance for those who have chronic problems with herpes viruses (this includes cold sores, genital herpes, chicken pox/shingles, Epstein-Barr, Cytomegalovirus, and HHV6). 

B vitamins - the B vitamins, especially thiamine (B1) and Riboflavin (B2) are cofactors needed for the electron transport chain to function.  Riboflavin (B2) has shown to be particularly helpful for people with headaches and migraines.

Folic Acid and Folate -  (often considered to be a B vitamin) is also important. 

L-Carnitine - is an amino acid that helps to transport fat into the mitochondria so that it can be burned for fuel.  This amino acid is very common in the diet so there is rarely a deficiency, however high doses can be quite therapeutic for people with mito.  If buying this as a supplement, acetyl-l-carnitine is usually the preferred form, however the levocarnitine form is often considered best and is available by prescription. 

CoQ10 - this is an antioxidant found in almost all cells in the body.  It plays an important role in transporting one of the important pieces of the electron transport chain, which is the machinery in the mitochondria that converts food and oxygen into energy that our bodies can use (ATP).  It is much better absorbed if taken with an oil or fat-containing food.  More on CoQ10 can be found here at the University of Maryland Medical Center site, although this information is more general and not about mito specifically. 

D-Ribose - is a sugar that feeds the mitochondria.
Enhancing Mitochondrial Function With D-Ribose

D-Ribose Helps People with Fibromyalgia and Chronic Fatigue Syndrome (CFS)
"D-Ribose is a naturally occurring simple sugar found in all living cells. It is the fuel that mitochondria use to produce adenosine tri-phosphate (ATP), which provides the body’s cellular energy. Studies show that patients with fibromyalgia, chronic fatigue syndrome (CFS) and congestive heart failure are low in D-Ribose."

 

Melatonin - is an antioxidant that can enter the mitochondria and protect them from oxidative stress, apoptosis, and impaired function (energy production).  

 

melatonin to reverse mito dysfunction
"These Alzheimer's mice have extensive mitochondrial dysfunction, which likely contributes to their cognitive decline. To further explore the mechanism through which caffeine and melatonin protect cognitive function in these mice, we monitored the function of isolated mitochondria from APP(sw) mice treated with caffeine, melatonin, or both in their drinking water for one month. Melatonin treatment yielded a near complete restoration of mitochondrial function in assays of respiratory rate, membrane potential, reactive oxygen species production, and ATP levels. Caffeine treatment by itself yielded a small increase in mitochondrial function. However, caffeine largely blocked the large enhancement of mitochondrial function provided by melatonin."

Melatonin role in the mitochondrial function.

"The best-known actions of melatonin, currently supported by experimental and clinical data, include antioxidant and anti-inflammatory abilities, some of them involving genomic regulation of a series of enzymes. Besides, melatonin displays anticonvulsant and antiexcitotoxic properties. Most of the beneficial consequences resulting from melatonin administration may depend on its effects on mitochondrial physiology. The physiological effects of melatonin on normal mitochondria, its role to prevent mitochondrial impairment, energy failure, and apoptosis in oxidatively-damaged mitochondria, and the beneficial effects of the administration of melatonin in experimental and clinical diseases involving mitochondrial dysfunction and cell death, are revised."

PQQ (Pyrroloquinoline quinone) - is an anti-oxidant and actually leads to growth of new mitochondria.  It supports metabolism and stress tolerance in bacteria, generally believed to be the ancestors of mitochondria.

Grow New Mitochondria with PQQ (BioPQQ). 
Generate Fresh Mitochondria with PQQ

 

Selenium - is a potent antioxidant

Zinc - 

Additional Nutrients That Support Mito Function -

Manganese -  is an essential element needed for healthy bones, wound-healing, and the metabolism of proteins, cholesterol and carbohydrates. Manganese levels affect the levels of iron, magnesium and calcium in the body.  Manganese is an essential part of the primary anti-oxidant in the mitochondria.  

 

Molybdenum -  Molybdenum is a cofactor for the mitochondrial enzyme mitochondrial amidoxime reducing component (mARC).  This enzyme has only been discovered fairly recently and it's functions are not well understood yet.  It is thought to play an important role in prodrug metabolism, the detoxification of certain mutagenic bases, and the reduction of nitrite to nitric oxide.

Vitamin K - can increase availability of energy to mitochondria during exercise.

 

Resveratrol -
Low dose resveratrol ameliorates mitochondrial respiratory dysfunction and enhances cellular reprogramming

I will say that others at the conference (including posters) uniformly suggested 200 mgs/kg/day on the arginine. That is a HUGE amount.

The optimum dosage is approximately 300-350 mg calcium as calcium citrate for a total of 1000 mg (one gram) of calcium a day. If you’re taking this you don’t need additional sources of calcium. An even better approach would be to use magnesium citrate. The adult dosage is about 300-400 mg a day. Some practitioners recommend up to 1000 mg but many people report problems with diarrhea if they exceed 400 mg. Again, a divided dose would be best, taking the magnesium citrate with each meal.

As an example, this formulation was made for a 3yo child:
CoQ10 180 mg,
Vit. E 450 iu,
Vit C 720 mg,
Carnitine 900 mg,
ALA 180 mg,
Biotin 2 mg,
Pantothenate 135 mg.

 

 

General Supplement Notes

Favorite resources for information:
Linus Pauling Institute Micronutrient Information Center
NIH office of dietary supplements
Examine.com
Dictionary of Dietary Supplement Terms (from NIH site)
Nourishing Hope (Site for Julie Matthews, a nutritionist who specializes in using nutrition to heal health conditions, particularly neurological ones such as autism, ADHD, anxiety, OCD, etc).

Favorite Sites for Ordering: 
PureBulk Supplements
Mountain Rose Herbs
VitaCost (frequent sales, Cheap "house" brand, very large selection)
Frontier supplements and nutritional foods
Medicine of the People (native american made)
Oregon's Wild Harvest
Nootropics Depot  
Thrive Market

Additional Favorite Brands:
North American Herb and Spice
Oregon's Wild Harvest
Pure Encapsulations
Nutiva 
Enzymedica
Eidon liquid minerals in low-dose but highly absorbed ionic form.
Trace Minerals

SUPPLEMENTS FOR SPECIFIC NEEDS AND DISORDERS:
My post about supplements for mitochondrial support

Blood sugar, Diabetes, and Insulin - chromium picolinate, cinnamon, vitamin B1

Cardiovascular health - CoQ10 supports energy production in heart muscle, lowers blood pressure,it reduces the side effects from statins (meds given to lower cholesterol that have a side effect of damaging muscles by lowering levels of CoQ10), potassium (and other electrolytes)

Connective Tissue Support see this post

Supplements to Treat Pyrroluria - vitamin B6 (majority in P5P activated form), zinc, manganese.

Digestion, G.I. Disease: betaine HCl, zinc, and ACV (apple cider vinegar) to increase low stomach acid.  Glutamine heals leaky gut.  Rutin reduces intestinal inflammation. 

Mast Cell Support - NeuroProtek (combo of rutin, luteolin, ), vitamin C,
Aller-Aid™ with Quercetin Capsules

Neurological and Cognitive Support - NeuroProtek, GABA, l-theanine, magnesium threonate, zinc
New Creatine & Brain Performance Study Results Released! 
In this video Dr Brad Stanfeld presents research suggesting that creatine supplementation, already widely used for supporting muscle performance and recovery, can also enhance cognitive performance. Creatine is stored in our cells as phosphocreatine which can then be used to produce ATP to power our cells.  The hypothesis is that because brain cells require high amounts of energy to function, increasing creatine stores in the brain can increase brain function.  While creatine does cross the BBB, there is less uptake by the brain of creatine then other tissues such as skeletal muscle.  This may be because the brain is able to synthesize creatine itself whereas skeletal muscle is not.  In a well-conducted meta-analysis of studies looking into creatine and brain function, there were mixed results.  It seems probable from the research that creatine supplementation might improve memory for older adults or for people during times of increased demand on the brain, such as certain brain disorders. 

Treating yeast overgrowth - methyl B12, GSE (grapefruit seed extract), biotin.  Yeast thrives in an alkaline environment so acids such as ACV (apple cider vinegar) help, as well as the probiotic acidophilis, which are acid-producing bacteria. 

PMDD - Pre-Menstrual Dysphoric Disorder  (supplement recommendations from this video)
Calcium                 1200mg/day
Vitamin B6             50-100mg/day
Magnesium             200-360mg/day
Vitamin E                400 I.U/day
Also, the herbs Agnus Castus Fruit Extract (aka Chasteberry) and Ginko Biloba

Specific Supplements

Melatonin -
Melatonin: Buffering the Immune System

Combination Supplements:
Aller-Aid™ with Quercetin Capsules

NeuroProtek FAQs

Coromega 

BrainChild Nutritionals

SPEAK

Potential Future Supplements:
Charlotte's Web Hemp Oil 

Parasym Plus 

Agmatine (a metabolite of arginine)
"It shows promise for alleviating neuropathic pain and drug addiction and shows some potential in protecting against strokes and benefiting cognitive health."

Supplement Notes (Minerals)

What are minerals?  From The Linus Pauling Institute Micronutrient Information Center:
"Minerals are elements that originate in the Earth and cannot be made by living organisms. Plants obtain minerals from the soil, and most of the minerals in our diets come directly from plants or indirectly from animal sources. Minerals may also be present in the water we drink, but this varies with geographic locale. Minerals from plant sources may also vary from place to place, because soil mineral content varies geographically."

Calcium - necessary for maintaining healthy bones and teeth.  Also an important signaling molecule regulating cell responses to signals from other cells or in the blood, such as the constriction of muscle tissue, the firing of neurons, and the release of insulin.  Calcium is also important for controlling the dilation and constriction of blood vessels.  Calcium levels are carefully regulated in the body because too much or too little can both cause serious problems, including cardiac arrhythmias and palpitations. 

Copper - is an important anti-oxidant and a necessary component in many enzymes.  It is important for energy production (mitochondrial function), iron metabolism, immune function, connective tissue formation and maintenance (including bone), neurological function, and cardiovascular function.  Copper and zinc compete for absorption and should be taken in a ratio of 15:1 zinc to copper. 

Iodine - is antimicrobial, with action against viruses, bacteria, fungi, and parasites.  Also protects against cancer and supports thyroid function.  Necessary for proper bone and brain development in infants.  Deficiency can be caused or worsened by eating a lot of baked goods such as bread that can be high in bromide (bromide can displace iodine). 
Is Potassium Iodide a "Magic Bullet" for Radiation Exposure?

Iron - necessary for the production of heme, which is itself necessary for the production of hemoglobin to carry oxygen in the blood and for the cytochrome enzymes, which are central to the liver's ability to detoxify the blood.  Also important for DNA synthesis and energy production.  Iron levels in the body are careful controlled because both a deficiency and an excess can be very harmful. 

Lithium - low dose protects against glutamate toxicity.

Magnesium - is important for a large amount of processes in the body, including maintaining healthy blood pressure and cardiac function, metabolism, DNA synthesis, proper movement of the GI tract so that contents keep moving through at the right pace (excess magnesium causes diarrhea), calmness and other neurological functions, it helps to regulate levels of other minerals including calcium and potassium, it is a structural component of bones and muscles, 

Thiamine and magnesium deficiencies: keys to disease

Manganese -  is an essential element needed for healthy bones, wound-healing, and the metabolism of proteins, cholesterol and carbohydrates. Manganese levels affect the levels of iron, magnesium and calcium in the body.  Manganese is an essential part of the primary anti-oxidant in the mitochondria.  It is also necessary for detoxifying ammonia that builds up during amino acid metabolism via the urea cycle.  In the brain a manganese-containing enzyme converts glutamate, which is an excitatory neurotransmitter and toxic in elevated levels, into glutamine.  It is also important in the formation of bone and cartilage and wound healing.

Molybdenum - important cofactor for the enzyme sulfite oxidase that breaks down sulfites.  If the enzyme is not functioning adequately, sulfite levels go up, which can cause headaches, irritability, nose bleeds, and allergies. 

Potassium - potassium levels in the blood are carefully regulated because it is so important for so many body functions, including maintaining healthy blood pressure and cardiovascular health.  Deficiency of potassium can result in paralysis, dangerous heart arrhythmia, partly because it is an important electrolyte (is in ionic form in the blood and can conduct electricity.  The movement of potassium ions into and out of the cell is part of the process of regulating cell responses such as the firing of neurons and heart cells.  It is also important for carbohydrate metabolism.   

Selenium - is an anti-oxidant, is an important component of many enzymes, especially in the intestines and lungs.

Silica - High levels are found in the aorta, trachea, bones, and skin.  As people age their soft tissues can lose elasticity.  Silica helps by stimulating collagen type 1 which helps loose skin and stimulates fibroblasts to make new skin.  It also improves bone mineralization and density, it increases calcification of bone similar to vitamin D.  Vitamin K2 is an important cofactor for silica.  Silica also decreases blood pressure by increasing elasticity of arteries, chelates aluminum, helps hair and nails. Best form is Orthosilicic Acid.  Silica can be found in grains, polished rice, beer, mineral water, and veggies. 

Vanadium - may help control blood sugar, may be important for bone growth.

Zinc - supports healthy immune function, fighting viruses in particular, and low-grade infections can deplete the body of zinc. Zinc is also important for vision, growth and development in children, neuron-transmission, and reproduction.  Zinc helps keep testosterone at normal levels and is necessary for producing adequate stomach acid.  Phytates are anti-nutrients in some foods and block the absorption of zinc in the intestines.  Zinc is mostly found in animal foods such as shellfish (especially oysters) and meat.  Good plant sources include pumpkin seeds and brazil nuts.  Zinc and copper compete for absorption so excess copper exposure can lead to a zinc deficiency.  Some of the symptoms of elevated copper levels include anxiety, depression, and elevated cortisol levels that can put your body into fight/flight mode.  Zinc lowers cortisol and contributes to the production of GABA which is the brain's primary inhibitory neurotransmitter, thus reducing stress levels.  

The blood disorder Pyrroluria causes significant zinc deficiency and requires regular supplementation that can be quite high. A deficiency of zinc can cause loss of taste and smell.  Other signs of a zinc deficiency can include low testosterone levels and hypogonadism (shrinking testicles), and upper respiratory infections such as pneumonia.  Diabetes can be a factor because high blood sugar will deplete zinc, as can high stress levels and high cortisol.