If you are a nutrition practicing health professional you’ve likely heard of methyl B12. If you’re a patient or this is new to you as a practitioner, you will enjoy learning about this important subject.

An exciting study indicates that supplementation with methyl B12 (the coenzyme or active form of vitamin B12 which is also known as methylcobalamin) could lead to an overall amelioration of autism symptoms by improving DNA methylation [1]. You see, not all genes are active at all times: it is the role of DNA methylation, an epigenetic mechanism, to turn a cell’s genes on and off at the appropriate time – this process appears to be impaired in many individuals with autism [2].

methyl-B12-autismWhat exactly is methylation?

It seems that methylation has become the latest buzzword in the health world and for good reason: methylation is an essential biochemical process that occurs over a billion times per second in every single cell of our body. To keep things simple (and avoid putting you to sleep), methylation occurs when a methyl group (a carbon atom linked to three hydrogen atoms) is passed to another molecule.

So why should you care about methylation?

Listing all the roles of methylation is beyond the scope of this article but, in a nutshell, methylation is a necessary process used by cells to control gene expression – this type of methylation, known as DNA methylation, is vital for healthy growth and development. DNA methylation also enables suppression of retroviral genes as well as other potentially hazardous sequences of DNA that may impair a person’s health.

Methylation is also involved in:

  • The production of vital substances such as glutathione which controls oxidative stress or melatonin, a hormone involved in sleep regulation.
  • The body’s optimal use of nutrients.
  • The body’s production of energy (ATP).
  • Immune function.
  • Natural detoxification pathways.
  • The brain’s activities and the production of neurotransmitters – defects in the methylation cycle have been linked to various cognitive behavioral issues and may contribute to the development of autism [3]. Moreover, children with autism also experience higher oxidative stress levels and have lower levels of biotin, vitamins B5 and E and total carotenoids [4]. These vitamins are involved in energy production in the body and also possess antioxidant properties. Put simply, children with autism have a decreased capacity for methylation which makes them more vulnerable to depression, infections, brain fogs, irritability and fatigue. Now that you have the basics, let’s go back to the methyl B12 study.

The study protocol

A total of 50 children with autism spectrum disorder completed this 8-week study – they were either given subcutaneous injections of methyl B12 (75μg/kg) or saline placebo (the control group) every three days. Neither the researchers nor the participants knew who was receiving the methyl B12 and who was getting the placebo until after the study. To determine the efficacy of the treatment, the researchers utilized the Clinical Global Impressions Improvement (CGI-I) scale after the 8-week study period. In this study, this scale was used to assess overall improvement of autism symptoms by evaluating the severity of the symptoms from 1 (very much improved) to 7 (very much worse). The researchers also used the Aberrant Behavior Checklist and the Social Responsiveness Scale during their assessment. Laboratory assessments were also conducted to evaluate methionine methylation and antioxidant glutathione metabolism.

Study findings

Compared to the children who received the saline injections, those who were treated with methyl B12 showed considerable improvements in overall symptoms as shown by the CGI-I scale results. However, no significant difference was found between the two groups regarding the two other measures which assessed the severity of specific autism symptoms.

Why did the researchers use methyl B12 (and not another member of the B12 family)?

Previous research indicates that individuals with autism have low levels of vitamin B12 in their brain which could explain why neurological and neuropsychiatric symptoms are common in this population [5]. To understand why methyl B12 was used in this study, it can help to understand that out of the vitamin B12 family, only methyl B12 is able to directly activate the methionine/homocysteine pathway which is involved in fueling the brain, metabolism and muscle growth. If this pathway is not activated (that is homocysteine is not re-methylated and converted back to methionine, homocysteine will build up in the blood where it can cause numerous health issues).

In a nutshell, here’s how the remethylation of homocysteine to methionine occurs: initially, methionine synthase catalyzes this remethylation reaction by using a methyl (CH3) group from 5-methyltetrahydrofolate (5-MTHF). This methyl group is then transferred to the reduced form of cobalamin to generate methylcobalamin (methyl B12) and tetrahydrofolate. Next, the methyl group is transferred from methyl B12 to homocysteine – this generates methionine. As you can see, for methylation to be effective, the body needs both folate and methyl B12.

What this means for a client/patient:

  • Keep in mind that there are many forms of vitamin B12 on the market. As a nutrition or health care professional, you want to ensure that you recommend a quality methylcobalamin supplement and not cyanocobalamin which is a cheap, dangerous synthetic form of the vitamin.
  • Note that folic acid is also the synthetic version of folate – in other words, they are totally different. Everybody should steer clear of folic acid, not only those individuals with autism or methylation issues.

I always recommend individuals work with a good integrative physician or nutrition professional.  They can test B12 status, most often with an organic acid urine test looking at MMA levels (methylmalonic acid), rather than blood levels which can be deceiving. If you are a nutrition professional you will want to  recommend the proper dose and form. Most often that will be methylcobalamin as the study highlights, but there are also adenosyl- and hydroxy- forms, as well as sublingual, injections, and other methods of administration. Other articles in the future (and our BioIndividual Nutrition Training), address these other forms; however, since the focus of this study was on methyl B12, we’ll save the others for another day.


1. Hendren, R. L., James, S. J., Widjaja, F., Lawton, B., Rosenblatt, A., & Bent, S. (2016). Randomized, placebo-controlled trial of methyl B12 for children with autism. Journal of child and adolescent psychopharmacology. [Access the original article here.]

2. Menezo, Y. J., Elder, K., & Dale, B. (2015). Link between Increased Prevalence of Autism Spectrum Disorder Syndromes and Oxidative Stress, DNA Methylation, and Imprinting: The Impact of the Environment. JAMA pediatrics169(11), 1066-1067.

3. James, S. J., Cutler, P., Melnyk, S., Jernigan, S., Janak, L., Gaylor, D. W., & Neubrander, J. A. (2004). Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism. The American journal of clinical nutrition80(6), 1611-1617.

4. Adams, J. B., Audhya, T., McDonough-Means, S., Rubin, R. A., Quig, D., Geis, E., … & Barnhouse, S. (2011). Nutritional and metabolic status of children with autism vs. neurotypical children, and the association with autism severity. Nutrition & metabolism8(1), 1.

5. Zhang, Y., Hodgson, N. W., Trivedi, M. S., Abdolmaleky, H. M., Fournier, M., Cuenod, M., … & Deth, R. C. (2015). Decreased Brain Levels of Vitamin B12 in Aging, Autism and Schizophrenia. PloS one11(1), e0146797-e0146797.

In my earlier article about oxalates, I explained how oxalates influence the biochemical progression and symptomatic expression of varied chronic diseases. Through an overarching “lens” of 18 years’ research and clinical experience with autism, I identified multiple areas for scientific inquiry and therapeutic direction for a variety of chronic health conditions and underlying symptomatology.

This article specifically investigates oxalates and autism; where the range of metabolic implications is vast – from impairment of mitochondrial function (and energy production) to disruption of mineral balance and the creation of severe oxidative stress in the body. The downstream effects of these biochemical aberrations touch dozens of systemic avenues.

I’ll explain some of the processes that can be severely affected in autism, that are likewise noted in those with high oxalate, and explore the potential role of oxalates in the body as a pathogenesis (biological mechanism or cause) of autism. These symptomatic expressions, and the findings from several key studies highlighted in this article, prompt eager investigation of the role of oxalates in autism.

Before we begin, to understand the basics: what oxalate is, where it comes from, and common symptoms read my previous article on oxalate.

Oxalates in Autism Study

In 2012, the European Journal of Paediatric Neurology published a study that investigated the role of oxalates in autism. Researchers measured a 2.5-fold greater level of oxalates in the urine, and a three-fold greater level of oxalate in the plasma, in children with autism.1

Their finding was specifically, hyperoxaluria; a condition of high oxalate. Interestingly though, high oxalate levels in urine did not necessarily correlate with high levels in the plasma. One child might have high urinary levels, but not high plasma; another might have high plasma levels, but not high urine.

A clinical challenge we face today is that only urinary levels are being used as an indicator of oxalate levels.

Plasma oxalate testing is only available in a research setting. The 2012 study tells us that not every child with oxalate impairment will present with high oxalate in their urine (they might have high oxalate in their plasma). This makes determining high oxalate, via testing (urine only), very challenging.

It’s significant to note that the study on autism and oxalate excluded the following groups from their selection criteria: those on a special diet, those with a history of seizures or antibiotic use, those with gastrointestinal disease (in addition to those with kidney stones). This is important to note, because all of these can be conditions of or cause hyperoxaluria.

Also noteworthy is a chart representing all of the controls (you can look at the study online here) on the top of page 5. You’ll notice all the controls have little blue boxes. There’s almost an invisible line at 0.05, and all of the controls fit within that 0.05 level. But the autism subjects were all over the map. Apparently, healthy controls are able to regulate the oxalate much better than other people (in this study, people with autism).

A history of antibiotic use can make oxalate issues worse, as can gastrointestinal diseases. Clinicians report that children with autism have higher rates of antibiotic use and seem less able to fight infection, and research demonstrates that gastrointestinal conditions are higher in autism than for neurotypical children.[4],[5],[6] Also, many autistic children suffer seizures, and oxalates can cause seizures.[7],[8],[9]

The study’s selection criteria (omissions) may affect an underrepresentation of the range of oxalate (plasma and urinary) that would occur in a full range of autistic patients. Even with the exclusions, significant oxalate issues were identified. This warrants further study, without excluded variables, to investigate how results may differ. If these groups had been included, rates and levels of oxalate would most likely be even higher.

Interestingly, the researchers had expert oxalate scientists review their findings, specifically the 2.5 – 3-fold increase in oxalate levels. The scientists were concerned for the children’s health. The levels were so high that they felt the children should (and may) have serious health implications based on oxalates in this elevated range; they’ve witnessed the detrimental effects of oxalate levels that high.

In summary, the study concluded that: “hyperoxalemia or hyperoxaluria may be involved in the pathology of autism spectrum disorders in children.” 1 It then continues to explain that based on the high oxalate finding, certain treatment options, such as a low oxalate diet, probiotic therapy, possibly with Oxalobacter formigenes, and a variety of supplementation may be helpful in these children.1

Oxalates are significant in autism because clinically we see a great deal of oxidative stress, considerable inflammation, mitochondrial damage or dysfunction, as well as faulty sulfation and seizures—areas where oxalates can wreck havoc. The discovery and clear indication that high oxalate may be involved in the pathology of autism is both significant and hopeful. This research and the biochemical connections we are highlighting provide further hope and direction for helping children with autism.

How Oxalates Cause Problems in Autism

OxalateCrystalsI’ll next explain some of the systemic processes that can be severely affected in those with autism, that are likewise noted in those with oxalate problems – then I’ll explore the link between the two, and the possibility of high oxalates as a pathogenesis of autism.

Firstly, let’s discuss how the health (or dis-ease) in the gut and certain nutrient deficiencies affect whether someone is more susceptible to a condition of high oxalate. And then let’s explore how oxalates can cause or exacerbate the conditions often found in autism:

  • Oxidative stress
  • Inflammation
  • Mitochondrial damage[10]
  • Seizures7,8,9
  • Faulty sulfation

Gastrointestinal Tract

As noted in my earlier article, the health of the gastrointestinal tract influences whether someone develops a problem with oxalates. Leaky gut, insufficient beneficial bacteria (including but not limited to a species called Oxalobacter Formigenes), poor fat digestion, and insufficient mineral intake affect whether (and how much) oxalate gets absorbed into the bloodstream from the gut. Many of these conditions, particularly leaky gut and a poor microbial balance, are common in those with autism.

Gut issues are so prevalent in autism,[11] and this condition in the gut compounds the potential problems with oxalate, and makes issues with oxalate more likely.

Compromised digestive capacity and an impaired ability to metabolize oxalate compounds may be linked to complications in autism. According to autism advocate and activist Dr. Leigh Ann Chapman, “Ordinarily, not much oxalate is absorbed from the diet, but the level of absorption has to do with the condition of the gut. There is a lot of medical literature showing that when the gut is inflamed, when there is poor fat digestion (steatorrhea), when there is a leaky gut, or when there is prolonged diarrhea or constipation, excess oxalate from foods that are eaten can be absorbed from the GI tract and become a risk to other cells in the body. Since these gastrointestinal conditions are found frequently in autism, it seems reasonable to see if lowering the dietary supply of oxalates could be beneficial.” [12]

Nutrient Deficiencies and Endogenous Production

Each person’s ability to process oxalate varies, based on the health of their gut as mentioned above, as well as nutrient deficiencies, systemic conditions, and genetic differences. Some deficiencies, including vitamin B6 and B1 deficiency can cause the body to produce oxalate (endogenously) in problematic amounts. This means that in children deficient in these important B vitamins, their body can create oxalate, rather than requiring it to come in from the diet. B6 deficiency is very common in autism, and for decades studies have shown the benefits of B6 supplementation in autism. Other deficiencies such as vitamin A deficiency can cause the body to absorb excess oxalate through the gut.

Further, because one’s body chemistry can convert a substance into oxalate; such as supplements like ascorbic acid or the amino acid glycine (a key component in bone broth) – complications can arise. Fructose, xylitol, and other sugar alcohols can also convert to oxalate. Certain supplements, as well as a diet too high in meat, can be a problem for some people.

In addition to oxalate levels increasing with nutrient deficiency, oxalates themselves can cause nutrient deficiency.  When oxalate is present from the diet, oxalate in the gut binds to minerals and inhibits absorption. This means diets high in oxalate can cause mineral deficiency including calcium and magnesium deficiency.

Oxidative Stress and Inflammation

Oxalates can lead to oxidative stress, and subsequently cause inflammation and injury.[13], [14] Because high oxalates can elevate superoxide (i.e. free radicals), they deplete glutathione and antioxidant status.[15]

Oxidative stress, inflammation, and low glutathione status are common occurrences in autism[16], [17], as well as many other chronic diseases. By understanding this relationship and recognizing a potential source of chronic inflammation and stress, practitioners can better address what may be causing the problems. And in this case, oxalate is an important factor to consider.

Mitochondrial Damage

Oxalates can also damage mitochondria. In the 2008 Veena study, researchers concluded that mitochondrial damage is an essential event in hyperoxaluria, so when you have high oxalates, you will have damage to the mitochondria. The same study indicated that oxalate impairs mitochondrial function. They found high oxalate created 30% depression of Complex I, a 54% depression of Complex II, a 35% depression of Complex III, and a 63% depression of Complex IV.12

Further, mitochondrial dysfunction has been found in autism.14, [18] Oxalates decrease mitochondrial function and increase oxidative stress, which is really important to consider for the many different conditions that can seriously affect the mitochondria, including autism.


Twenty-two to thirty percent of children with autism suffer seizures.[19], [20] It is also postulated that one cause for these seizures may be neuro-inflammation.[21] We know that oxalates can cause seizures and also create inflammation. Therefore it is quite possible that oxalates may be a cause of seizures in autism.

Carambola Starfruit

Interestingly, the fruit carambola (also known as starfruit) is popular throughout Southeast Asia and the South Pacific and contains a high amount of oxalate. One study noted that “Carambola contains a large quantity of oxalate, which can induce depression of cerebral function and seizures.” 9

Studies have shown that high oxalate levels can cause seizures in individuals. Specifically, people with high oxalate whether from poisoning from accidental ingestion or antifreeze, or in other cases due to liver or kidney transplants, what the researchers found in essence was that oxalate can cause seizures.

As noted in the Oxalates and Autism study, the researchers did not “count” people that were on a special diet or those with a history of seizures. And, as explained earlier, seizures can stem from a condition of high oxalate. Again, it would be useful to repeat this study and include people with seizures, to see if prevalence of oxalate issues in autism is even higher than initially measured – and if oxalates may play a role in the etiology of seizures or exacerbate seizures.

Sulfur and Poor Sulfation

It’s equally important to understand sufate and sulfation when investigating autism and oxalates.

The body requires sulfate for vital sulfation processes, including processing phenolic foods. If certain foods or substances are consumed (or even inhaled) when sulfate is low, it can cause phenol reactions such as red cheeks and ears, hyperactivity, irritability, aggression, sleep issues, and more. There is much literature about poor sulfation and autism; I see these noted reactions often in my nutrition practice. Therefore, some children and adults with autism that have low sulfate often also have an issue with phenols and with oxalates. Not always, but these biochemical relationships suggest that some children may find relief by avoiding both for a period of time.

In regard to oxalate, when sulfate is low, oxalate can get into the cell on the sulfate transporter and interfere with cellular function.

There is a two-way relationship with oxalate and sulfate. Not only can oxalates lead to poor sulfation (as mentioned above) oxalate can also interfere with the body’s ability to allow sulfate into the cell inhibiting sulfation. And as mentioned above, low sulfate levels can allow oxalate into the cell on the (unoccupied) sulfate transporter. When this happens, it can affect the mitochondria and subsequently virtually every system of the body.

In autism, there seems to be a vicious ATP/sulfate challenge that we see. We often find high sulfate in the urine, and this gives some practitioners the false notion that sulfate is sufficient, if not high. However, while it’s high in the urine, we often find low sulfate and poor sulfation in autism. Why is this?

My hypothesis: oxalates could be at play. If ATP is low, the kidneys need ATP to recycle sulfate and, with low ATP, it could cause sulfate to be low. If sulfate is low, it allows oxalate to get into the cell, and it can decrease ATP production. When ATP is low, it can lead to low sulfate, both because it can decrease SAMe going through that pathway, as well as low ATP in the kidneys, causing the dumping of sulfate (causing it to be high in the urine when the body desperately needs it).
Either way, regardless of the cause of low sulfate, children with autism are known to have low sulfate and poor sulfation.[22],[23],[24] Therefore addressing high oxalates and low sulfate when they are an issue can be very helpful to children with autism.


Oxalates are a promising and emerging field that far exceeds kidney stone issues. Investigating their effects on the mitochondria, inflammation, and all systems of the body, reveals that oxalates play a role in many chronic diseases. The study “A potential pathogenic role of oxalate in autism” revealed hyperoxaluria in autism, further helping define the role of oxalate in autism.

With autism, oxalates can cause oxidative stress, inflammation, and seizures; something that is corroborated by the actual prevalence of these conditions in those with autism. Moreover, the conditions under which oxalates can become most problematic: disrupted microbiome, leaky gut, poor sulfation, B6 deficiency, and diets high in oxalate, are also common in autism.

I’ve been researching the influence of oxalates and utilizing a low oxalate diet for more that a dozen years. My future articles on this subject with explain: high oxalate foods, low oxalate diets, and important supplement support. Most importantly, I’ll provide best practices for implementing a low oxalate diet; how to decrease oxalates in food, know when it’s enough, and other ways to support the body during this process. Sometimes one key clinical insight can “course correct” someone’s existing diet and lead to new breakthroughs; often, it’s oxalates.

It’s critical that, as practitioners and professionals, we look at the role of oxalates in autism, so we can encourage further research and best support our patients, clients, and families in need.

microscope and abstract molecules isolated

Scientific References:

[1] Konstantynowicz, J., Porowski, T., Zoch-Zwierz, W., Wasilewska, J., Kadziela-Olech, H., Kulak, W., Owens S.C., Piotrowska-Jastrzebska J., and Kaczmarski, M. (2012). A potential pathogenic role of oxalate in autism. European Journal of Paediatric Neurology, 16(5), 485-491.

[2] Terribile, Maurizio, Maria Capuano, Giovanni Cangiano, Vincenzo Carnovale, Pietro Ferrara, Michele Petrarulo, and Martino Marangella. “Factors increasing the risk for stone formation in adult patients with cystic fibrosis.” Nephrology Dialysis Transplantation 21, no. 7 (2006): 1870-1875.

[3] Danese, Silvio, Stefano Semeraro, Alfredo Papa, Italia Roberto, Franco Scaldaferri, Giuseppe Fedeli, Giovanni Gasbarrini, and Antonio Gasbarrini. “Extraintestinal manifestations in inflammatory bowel disease.” World Journal of Gastroenterology 11, no. 46 (2005): 7227.

[4] Molloy CA, Manning-Courtney P: Prevalence of chronic gastrointestinal symptoms in children with autism and autistic spectrum disorders. Autism 2003, 7(2):165-171.

[5] Nikolov Roumen N, Bearss Karen E, Jelle Lettinga, Craig Erickson,
Maria Rodowski, Aman Michael G, McCracken James T, McDougle Christopher J, Elaine Tierney, Benedetto Vitiello, Eugene Larnold, Bhavik Shah, Posey David J, Louise Ritz, Lawrence Scahill: Gastrointestinal Symptoms in a Sample of Children with Pervasive Developmental Disorders. J Autism Dev Disord 2009, 39:405-413.

[6] Adams, J. B., Johansen, L. J., Powell, L. D., Quig, D., & Rubin, R. A. (2011). Gastrointestinal flora and gastrointestinal status in children with autism–comparisons to typical children and correlation with autism severity. BMC gastroenterology, 11(1), 22.

[7] Díaz, Cándido, et al. “Long Daily Hemodialysis Sessions Correct Systemic Complications of Oxalosis Prior to Combined Liver–Kidney Transplantation: Case Report.” Therapeutic Apheresis and Dialysis 8.1 (2004): 52-55.

[9] Chen, Chien-Liang, et al. “Neurotoxic effects of carambola in rats: the role of oxalate.” Journal of the Formosan Medical Association 101.5 (2002): 337-341.

[10] Veena, C. K., Josephine, A., Preetha, S. P., Rajesh, N. G., & Varalakshmi, P. (2008). Mitochondrial dysfunction in an animal model of hyperoxaluria: a prophylactic approach with fucoidan. European journal of pharmacology, 579(1), 330-336.

[11] McElhanon, Barbara O., Courtney McCracken, Saul Karpen, and William G. Sharp. “Gastrointestinal Symptoms in Autism Spectrum Disorder: A Meta-analysis.” Pediatrics 133, no. 5 (2014): 872-883.

[12] Chapman, L. A. (2007). A Low Oxalate Diet for Autism. Retrieved December 1, 2015, from www.http://chapmannd.com

[13] Biswas, Subrata K., et al. “Which comes first: renal inflammation or oxidative stress in spontaneously hypertensive rats?.” Free radical research 41.2 (2007): 216-224.

[14] Khan, Saeed R. “Hyperoxaluria-induced oxidative stress and antioxidants for renal protection.” Urological research 33.5 (2005): 349-357.

[16] Rose, S., S. Melnyk, O. Pavliv, S. Bai, T. G. Nick, R. E. Frye, and S. J. James. “Evidence of oxidative damage and inflammation associated with low glutathione redox status in the autism brain.” Translational psychiatry 2, no. 7 (2012): e134.

[17] Rossignol, D. A., and R. E. Frye. “A review of research trends in physiological abnormalities in autism spectrum disorders: immune dysregulation, inflammation, oxidative stress, mitochondrial dysfunction and environmental toxicant exposures.” Molecular psychiatry 17.4 (2011): 389-401.

[18] Rossignol, D. A., and R. E. Frye. “Mitochondrial dysfunction in autism spectrum disorders: a systematic review and meta-analysis.” Molecular psychiatry 17, no. 3 (2011): 290-314.

[19] Volkmar FR, Nelson DS: Seizure disorders in autism. J Am Acad Child Adolesc Psychiatry 1990, 29:127-129.

[20] Tuchman R, Rapin I: Epilepsy in autism. Lancet Neurol 2002, 1:352-358.

[21] Theoharides, Theoharis C., and Bodi Zhang. “Neuro-inflammation, blood-brain barrier, seizures and autism.” J Neuroinflammation 8.1 (2011): 168.

[22] Waring, R. H., and L. V. Klovrza. “Sulphur metabolism in autism.” Journal of Nutritional and Environmental Medicine 10, no. 1 (2000): 25-32.

[23] Alberti, Antonino, Patrizia Pirrone, Maurizio Elia, Rosemary H. Waring, and Corrado Romano. “Sulphation deficit in “low-functioning” autistic children: a pilot study.” Biological psychiatry 46, no. 3 (1999): 420-424

[24] Waring, R. H., Ngong, J. M., Klovrza, L., Green, S., & Sharp, H. (1997). “Biochemical parameters in autistic children.” Developmental Brain Dysfunction, 10, 40-43.

A growing body of research is implicating mitochondrial dysfunction as a root cause of a wide spectrum of metabolic, lifestyle and degenerative diseases including: Chronic Fatigue Syndrome, Autism, Cancer, Diabetes, Alzheimer’s, Fibromyalgia and potentially many more. Essential to human survival at the most basic level we review the evidence that these specialized organelles are suffering in our modern environment.

Mitochondria and Energy Production

These minute powerhouses in every cell are responsible for regulating and storing cellular energy. They convert ingested energy, for example glucose, into a format the body can actively use, called ATP (Adenosine Tri Phosphate).

ATP carries energy within its atomic bonds which can be released for use in biochemical processes. Hydrolysis of ATP to ADP (Adenosine Di Phosphate) liberates energy: breaking the phosphate bond is exothermic (it gives off energy) due to the inherent instability of ATP which would ‘prefer’ to be in its ADP state.  After conversion of ATP to ADP, and release of the energy holding the phosphate in place, the ATP molecule (now ADP) is ‘spent’ and needs to be recycled.

Electrochemical reactions (collectively known as oxidative phosphorylation) take place inside the mitochondria along the electron transport chain to reattach a phosphate group to create ATP again. This endless recycling of ADP to ATP is needed to maintain energy production.

Even though each cell contains approximately one billion ATP molecules it is only sufficient to meet the cell’s energy requirements for a few minutes and constant activity is required to keep energy flowing  – amazingly humans manufacture and consume their own weight in ATP every day[1]. Cells needs energy to function optimally so even a minor impairment of mitochondrial function can have dramatic systemic ramifications.

The Scientific Study of Mitochondria

Mitochondria are actually bacterial in nature and they evolved with us endosymbiotically: mitochondrial DNA is inherited through the maternal line. [2] Unable to maintain themselves outside of eukaryotic cells, mitochondria have been co-opted into our energy production systems. However, they have their own genetic system distinct from the nuclear genome – they even use a different protein coding system for translation of mitochondrial DNA.[3]

Mitochondrial DNA is exquisitely sensitive to environmental challenges, specifically oxidative damage and stress, due to the high ratio of coding regions (versus non-coding regions) in the DNA; and a lack of protective histones supporting their DNA structure and environment.[4] Alarmingly, oxidative damage occurs at a rate five to ten times greater in mitochondrial DNA versus nuclear DNA and “damaged mitochondria promptly accelerate intra-cellular oxidation”.[5]

De Novo mutations have been specifically linked to both autism and schizophrenia indicating that the DNA damage leading to the disease is developed and not inherited.[6] Specific alterations in the mitochondrial DNA coding for complexes in the electron transport chain and pyruvate dehydrogenase have been identified in the frontal cortex of patients with autism which cause inadequate (anaerobic) utilization of glucose and an excess of unwanted metabolic byproducts.[7]

Mitochondria uniquely sit in two very different areas of biological research: structural (proteins, tissues, genome etc.) and bioenergetics (energy metabolism). These interfacing areas of research have until relatively recently been uncoupled and in vivo research has been difficult due to a lack of biomarkers and assays to detect mitochondrial damage. This lack of ability to diagnose problems with energy flow in and out of the mitochondria means the root cause of many diseases relating to mitochondrial function has been overlooked or ignored.[8]

Mitochondrial Function and Biogenesis

free-radicalsIn addition to their role in energy regulation, mitochondria are also involved in the maintenance of intracellular calcium levels and calcium buffering (required for cellular signaling)[9]. They also regulate cell numbers and defend against unwanted or dangerous cells by triggering programmed cell death (apoptosis).[10] Signaling between the human (nuclear) and mitochondrial genome is also controlled by the mitochondria themselves via the production of Reactive Oxygen Species (ROS).

Excessive ROS (also known as free radicals) is a metabolic byproduct and one of the triggers for apoptosis. For example, asbestos induced lung disease has been linked to elevated alveolar epithelial apoptosis  due to increased ROS caused by the asbestos damage.[11] Elevated levels of mitochondrial calcium can also trigger apoptosis and recent research indicates that apoptosis of nerve cells contributes to Alzheimer’s.[12]

While mitochondria have their own unique DNA, the majority of the proteins required to synthesize the organelle are recruited from nuclear coded proteins. This means they need to communicate effectively with nucleic DNA to produce the protein pieces required to join with existing subcomponents. Since the co-ordination required for mitochondrial biogenesis requires the expression of two different genomes, any epigenetic problems with DNA signaling due to a lack of nutrients or toxicity are amplified.[13]

Pharmacology and Mitochondrial Disease

Azidothyramidine was commercialized for the treatment of HIV/AIDs in the late 1980’s and transformed the disease from a death sentence to a chronic manageable condition. Unfortunately, prolonged treatment with the drug, and others nucleoside analogs, has severe or fatal side effects. Over 30% of patients treated experienced heart muscle damage and loss of vision with mitochondrial toxicity (via multiple routes) being the agreed cause.[14]

The association with pharmacologically active compounds and mitochondrial function is now so well recognized that pharmaceutical companies have developed high throughput screening to specifically look for mitochondrial damage during the drug development process. Other classes of compounds including antibiotic, antiepileptic, antidiabetic, antipsychotic, antidepressant, beta-blocker, and nonsteroidal anti-inflammatory drugs have also demonstrated the ability to damage mitochondria; many others may reveal the same problems with further research.[15]

Fueling the Mitochondria

Mitochondria can use different sources of fuel (glucose, protein and fat) both with and without oxygen depending on the cellular conditions. A delicate balance of regulatory mechanisms and hormones determines which of these fuel sources should be preferentially utilized. The byproducts of the different pathways also control a wide variety of downstream biological processes meaning that fuel availability (or capacity to utilize it) has wider implications.

Mitochondrial fuel selection, and metabolite production, is interlinked with responses in vital systems such as immune function[16]. For example an excessive production of ROS stimulates the inflammatory response[17] and can trigger chronic diseases.[18]

Energy Preferences

Organs have different metabolic requirements: the brain relies on glucose and a derivative of fatty acids called ketone bodies while muscle uses glucose for short bursts of energy but uses fatty acids for 85% of its needs. The heart relies exclusively on anaerobic metabolism of fatty acids and has a high density of mitochondria to meets its energy requirements. [19]

Aerobic glycolysis of glucose (in the presence of oxygen) is 5 times more efficient than anaerobic glycolysis as it fully breaks down the glucose. The buildup of lactic acid, as a result of anaerobic glycolysis, can be used to indicate a drop in mitochondrial performance as it no longer metabolizes the pyruvate to release the remaining energy – elevated lactate to pyruvate ratios are often seen in patients with autism.[20] When mitochondria are utilizing fuel less efficiently they produce more ROS (like a sooty fire) and this causes further damage to the delicate organelle.

Dietary modifications to reduce glucose have been found to improve some behavioral traits commonly associated with autism in mice models. Changes in plasma metabolites reduce the neuroinflammation and impaired neurogenesis seen in both animal and human models. [21]

The excess ROS production (due to inefficient fuel usage), combined with low levels of intrinsic antioxidants and lack of precursors needed for fatty acid metabolism (specifically carnitine) often associated with autism explains why some patients experience improved symptoms with a ketogenic (fat based) diet especially when combined with carnitine supplementation. [22]

Mitochondrial Diseases and Dysfunctions

There are an increasing number of diseases which have been attributed to mitochondrial function and many share general symptoms of fatigue and muscle pain due to impaired energy provision to organs with high energy demands.

At the other end of the disease spectrum, the fatal condition MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke like episodes) causes extreme seizures, migraines and brain damage. Mutations in mitochondrial DNA mean the body is not able to meet its own energy needs, specifically during physical exertion.

While some mitochondrial diseases have a strong genetic element many are suspected to be as a result of environmental conditions which do not support efficient energy utilization. Mitochondrial dysfunction as a result of increased ROS production, lack of antioxidants and environmental pollutants has been coming under closer scrutiny as a trigger or even for conditions as diverse as autism and Gulf War Syndrome.[23] Another metabolic waste product, oxalates cause oxidative stress too and further damage the mitochondria leading to chronic disease.

The high energy demands of the brain make it more susceptible to a buildup of ROS if mitochondria are not functioning optimally. Additionally, the ROS directly damage the polyunsaturated fats which make up the majority of the brain tissue and mitochondrial damage has been implicated in a variety of neurodegenerative diseases including Alzheimer’s.[24]

Chronic stress has also been shown to inhibit mitochondrial function and induces reversible mitochondrial damage causing symptoms resembling Irritable Bowel Syndrome (IBS).[25] Sleep apnea is another condition which reduces mitochondrial function by causing frequent periods of hypoxia.[26] Glutamate has also been found to contribute to mitochondrial disease because it interferes with calcium homeostasis.[27]

Autistic Spectrum Disorder

The spectrum of symptoms, and wide variety in the severity of autism spectrum disorder, supports the notion that varying energy demands and fuel utilization throughout the body determine the degree of the impact from poorly functioning mitochondria. The huge degree of divergence points to multiple genetic susceptibilities which have been found to cluster around genes responsible for calcium and metabolic (MAPK) signaling. These foundational errors also indicate widespread “vulnerability to other chronic and systemic problems potentially including cancer, metabolic conditions and heart diseases” for both autistic patients and the public at large.[28]

Neurological symptoms are virtually always present and this is the organ with the highest energy usage and very stringent requirements about fuel sources (other high energy systems such as the bowels and muscles are also typically symptomatic).

Some patients also experience idiopathic symptoms including cardiovascular symptoms, growth retardation and fatigue which align with the known outcomes of poor mitochondrial function. [29] According to one study, defects in oxidative phosphorylation (the process by which ADP is remade into ATP) are identified in nearly 50% of patients with autism highlighting the need for metabolic evaluation to support individualized therapy.[30] Glutamate levels are also often elevated in ASD patients, further exacerbating mitochondrial toxicity.[31]

Cardiovascular Health

The heart is another organ which has high energy demands and 35% of the volume of cardiac muscles cells is taken up by mitochondria. Diabetic patients often experience cardiac problems higher than predicted levels (adjusting for hypertension and coronary artery disease) due to deficiencies in cardiac energy metabolism.[32] Various mechanisms have been identified which contribute to the multifactorial cardiac challenges, including: increased ROS production; impaired calcium regulation and incomplete biogenesis of new mitochondria.

The root cause of cardiovascular diseases, including atherosclerosis, is increasingly being linked to the mitochondria responsible for energy production and regulation. The vicious feedback loop of oxidative stress causing inflammatory responses and apoptosis further exacerbates a system under pressure leading to a variety of disease states.[33]

Cancer and Oncogenesis

Since the beginning of the 20th century, scientists knew that cancer cells had differences in their metabolism: preferentially utilizing glucose anaerobically and producing a lot of lactic acid (known as the Warburg effect) even when sufficient oxygen is available for aerobic metabolism. It is postulated that anaerobic glycolysis actually produces more of the biosynthetic intermediates needed for cellular growth and proliferation.[34]

Abnormal mitochondrial function has been found in multiple human cancer variants. In vitro replication of mitochondrial mutations, knocking out specific parts of the electron transport chain, has demonstrated cells with increased ROS (as a result of anaerobic glycolysis) have higher invasive behaviors and greater migration rates comparable to cancer cells.[35]

Additionally, some metabolic enzymes typically involved in the Krebs cycle usually actually act as oncosuppressors – this means that imbalances in fuel selection due to mitochondrial dysfunction also impacts genes promoting cell proliferation. [36]

The regulatory role of mitochondria in apoptosis is also under scrutiny for its role in cancer progression as compromised apoptotic function removes the usual protection the body has for removing dangerous cells.  Cancerous cells actually manage to deregulate the pathway which would typically save the rest of the body from tumor development.

Elevated ROS, from poorly functioning mitochondria, also increases cancer risk by damaging the DNA and stimulating pro-growth responses (tumor genesis). In an attempt to slow down the tumorigenic signaling, the body will typically respond by up-regulating the production of intrinsic anti-oxidants to reduce ROS levels.

The relationship between ROS, antioxidants and tumor genesis explains why research has repeatedly substantiated claims that fresh fruits and vegetables, packed with anti-oxidants, can prevent and even cure cancers and nutritional therapies reduce ROS while providing the nutrients needed for the body to heal itself.[37]

Evidence for other Mitochondrial Conditions

Metabolic Syndrome: Many of the risk factors for metabolic syndrome (obesity, elevated cholesterol, hypertension and diabetes) are linked with abnormal mitochondrial function. [38] Over nutrition is specifically linked with oxidative stress especially when combined with a lack of exercise.[39]

Asthma: Animal models have demonstrated the role of oxidative stress in the inflammatory response triggered during asthma. [40] Additionally, there is an increased likelihood of severe asthma attacks in obese individuals, pointing to mitochondria as the root cause of the disease.[41] The use of targeted antioxidant therapy in animal asthma models has already demonstrated a reduction in the fibrotic airway remodeling which is linked to disease progression.[42]

Chronic Fatigue Syndrome: The severity of symptoms presented by sufferers of CFS has been directly linked to the degree of mitochondrial disease. [43]

Fibromyalgia: The chronic pain of this condition has been linked to suboptimal mitochondrial function in the nervous system and patients are often low in enzymes required for complete energy metabolism, namely CoQ10.[44]

Irritable bowel syndrome: Mitochondrial DNA mutations have been found to be higher in patients with IBS and oxidative stress triggers damaging chronic inflammatory responses.[45]

Diabetes: Excessive production of ROS contribute to the pathophysiology of diabetes, specifically damaging nerves and the eyes.[46]

There is increasing evidence that mitochondrial dysfunction is responsible for, or strongly contributes to, many more chronic degenerative disorders, including: Alzheimer’s, Parkinson’s disease, Huntington Disease, Amyotrophic Lateral Sclerosis (ALS) oobesity and autoimmune diseases (lupus, Sjogren’s syndrome and rheumatoid arthritis).[47]

The New Paradigm

Science tends to put things in little, separate, boxes. Taking a step back and looking at the wider picture we can see that the various epidemics of modern disease present very different symptoms but the root cause could be remarkably simple.

Putting together the pieces of the puzzle, we can see that our ancient mitochondria can simply not cope with the insult of environmental toxins, from the food we eat; medicines we take; air we breathe; and chemicals we apply on our body. Most likely the lack of quality nutrients in the modern processed diet is also responsible for the reduced function and increasing mitochondrial damage.

Unless some drastic action is taken to improve the working conditions of these vital organelles, the progression and severity of lifestyle diseases is set to continue at an alarming rate. Figures for diabetes, cancers, cardiovascular disease and more are soaring and the abuse of our mitochondria seems to be the elephant in the room that has finally been noticed.


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[20] J Jay Gargus Department of Physiology and Biophysics and Department of Pediatrics, Section of Human Genetics/School of Medicine & Faiqa Imtiaz, Arabian Diagnostics Laboratory, King Faisal Specialist Hospital and Research Centre, “Mitochondrial Energy-Deficient Endophenotype in Autism”, American Journal of Biochemistry and Biotechnology 4(2):198-207 2008, http://thescipub.com/PDF/ajbbsp.2008.198.207.pdf

[21] A Currais, C Farrokhi, R Dargusch, M Goujon-Svrzic, and P Maher, “Dietary Glycemic Index Modulates The Behavioral and Biochemical Abnormalities Associated with Autism Spectrum Disorder”, Molecular Psychiatry 21; 426-436, Published online June 9, 2015, http://www.nature.com/mp/journal/v21/n3/abs/mp201564a.html

[22] Eleonora Napoli, Nadia Duenas, Cecilia Giulivi, “Potential Therapeutic Use of Ketogenic Diet in Autism Spectrum Disorders”, Frontiers in Pediatrics, 2014 June 30; 2:69, http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4074854/

[23] Beatrice Golomb MD, PhD, “Oxidative Stress and Mitochondrial Injury in Chronic Multisymptom Conditions: From Gulf War Illness to Autism Spectrum Disorder”, Nature Proceedings : hdl:1010/npre.2012.6847.1: January 30, 2012, http://drmyhill.co.uk/drmyhill/images/d/df/Oxidative_Stress_and_Mitochondrial_Injury_in_CMC.pdf

[24] Barry Halliwell, “Reactive Oxygen Species and the Central Nervous System” , Journal of Neurochemistry, Volume 59;(5) 1609-1623, November 1992, http://www.ncbi.nlm.nih.gov/pubmed/1402908

[25] Vicario M, Alonso C, Guilarte M, Serra J, Martinez C, Gonzalez-Castro AM, Lobo B, Antolin M, Andreu AL, Garcia-Arumi E, Casellas M, Saperas E, Malagelada JR, Azpiroz F, Santos J. “Chronic Psychosocial Stress Induces Reversible Mitochondrial Damage and Corticotropin-Releasing Factor Receptor Type-1 Upregulation In The Rat Intestine and IBS-Like Gut Dysfunction”, Psychoneuroendocrinology 2012 January;37(1):65-77, http://www.ncbi.nlm.nih.gov/pubmed/21641728

[26] Yan Deng, Xue-Ling Guo, Xiao Yuan, Jin Shang, Die Zhu, and Hui-Guo Liu, “P2X7 Receptor Antagonism Attenuates The Intermittent Hypoxia-Induced Spatial Deficits In A Murine Model Of Sleep Apnea Via Inhibiting Neuroinflammation and Oxidative Stress”, Chinese Medical Journal (English) 2015 August 20; 128(16): 2168-2175, http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4717977/

[27] Cláudia F Pereira , Catarina Resende de Oliveira, “Oxidative glutamate toxicity involves mitochondrial dysfunction and perturbation of intracellular Ca2+ homeostasis”, Neuroscience Research, Volume 37, Issue 3, July 2000, Pages 227–236, http://www.sciencedirect.com/science/article/pii/S0168010200001243

[28] Wen Y, Alshikho MJ, Herbert MR,  “Pathway Network Analyses for Autism Reveal Multisystem Involvement, Major Overlaps with Other Diseases and Convergence upon MAPK and Calcium Signaling.”, PLoS One. 2016 Apr 7;11(4):e0153329, http://www.ncbi.nlm.nih.gov/pubmed/27055244.

[29] Jacqueline R Weissman, Richard I Kelley, Margaret L Bauman, Bruce H Cohen, Katherine F Murray, Rebecca L Mitchell, Rebecca L Kern, and Marvin R Natowicz, “Mitochondrial Disease In Autism Spectrum Disorder Patients: A Cohort Analysis”, PLos ONE 3(11): e3815 November 26, 2008, http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0003815.

[30] Poling JS, Frye RE, Shoffner J, Zimmerman AW, “Developmental Regression and Mitochondrial Dysfunction in a Child With Autism” J Child Neurol.2006; 21(2):170-172. http://www.ncbi.nlm.nih.gov/pubmed/16566887

[31] Atsuko Shinohea, Kenji Hashimotob, , , Kazuhiko Nakamuraa, Masatsugu Tsujiic, Yasuhide Iwataa et al, “Increased serum levels of glutamate in adult patients with autism”, Progress in Neuro-Psychopharmacology and Biological Psychiatry, Volume 30, Issue 8, 30 December 2006, Pages 1472–1477, http://www.sciencedirect.com/science/article/pii/S0278584606002697.

[32] Bugger H and Abel ED, “Mitochondria In The Diabetic Heart”, Cardiovascular Research, 2010 Nov 1;88(2): 229-240, http://www.ncbi.nlm.nih.gov/pubmed/20639213

[33] Ballinger SW, “Mitochondrial Dysfunction in Cardiovascular Disease”, Fee Radical Biol Med. 2005 May 15;38(10):1278-95, http://www.ncbi.nlm.nih.gov/pubmed/15855047

[34] Fogg VC, Lanning NJ, and Mackeigan JP, “Mitochondria in Cancer: At The Crossroads of Life and Death”, Chinese Journal of Cancer, 2011 Aug;30(8):526-539, http://www.ncbi.nlm.nih.gov/pubmed/21801601

[35] Jia Ma, Qing Zhang, Sulian Chen, Binbin Fang, Qingling Yang, Changje Chen, Lucio Miele, Fazlul H Sarkar, Jun Xia, and Zhiwei Wang, “Mitochondrial Dysfunction Promotes Breast Cancer Cell Migration and Invasion through HIF1a Accumulation via Increased Production of Reactive Oxygen Species”, Plos ONE, July 29, 2013, http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0069485

[36] Scatena R, “Mitochondria and Cancer: A Growing Role In Apoptosis, Cancer Cell, Metabolism, and Dedifferentiation”, Advances in Experimental Medicine and Biology, 2011 December 22, Ch. Advances in Mitochondrial Medicine, Volume 942; 287-308, http://www.ncbi.nlm.nih.gov/pubmed/22399428

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Methylation-diet (1)I’m thrilled to announce the launch of Kara Fitzgerald and Romilly Hodges’ new book the “Methylation Diet and Lifestyle.” Methylation is a topic we cover extensively in our Advanced Practitioner training program at the BioIndividual Nutrition Institute. I’ve admired Kara Fitzgerald’s work for over 8 years. She’s brilliant at understanding the biochemistry of the body and the importance of nutrients and food. When I learned that she came out with a new book recently on the Methylation Diet, I knew this topic was PERFECT for our BioIndividual Nutrition members. Here’s the article Kara and Romilly wrote for us, as well as more on their book and an online webinar session we will be doing in August…

The Methylation Diet: MTHFR and Methylation Support—an Expanded Approach 
by Kara Fitzgerald and Romilly Hodges

This is a must-read for anyone who knows they have an MTHFR, or other methylation-related, gene polymorphism or is at risk for hypomethylation-related conditions including autism.

The Importance of Methylation

Defects in the body’s methylation process have been of interest to many health communities since MTHFR genetic testing, as well as functional testing for markers such as homocysteine, have become more widely-available and since the connection to different disease states—ADD, autism, cancer, diabetes, heart disease, Alzheimer’s disease, Parkinson’s disease, immune hypersensitivity, inflammation and more—is increasingly recognized. Even before that, the connection between maternal folate deficiency (one of the key methylation nutrients) and neural tube defects in children was observed and validated, leading to broad-based folic acid food fortification initiatives.

Methylation is such a fundamental process that each of our cells is continually using for many, many activities, ranging from cell division, immune cell formation, creating neurotransmitters, detoxification, and hormone metabolism, to regulating even how our genes get expressed.

There has just been this remarkable boom in methylation research, and as Functional Medicine practitioners we obviously want to fold that in to how we work with patients. This is what has led to the use of supplemental nutrient cofactors, such as folate, B12, B6, and so on, to support methylation pathways (Figure 1). The intention has been to overcome methylation deficits by pushing those reactions on to a greater level of activity, or bypassing blockages in the folate cycle completely, such as with methylated folates (5-methyltetrahydrofolate, the product of the MTHFR reaction). This is, no doubt, an important goal.

Figure 1: Core Methylation Pathways and Nutrient Cofactors

methylation pathwayThe problem with using this approach alone is that we just don’t know what the end outcome on overall methylation status, especially epigenetic methylation, is. Methylation in the body exists in a state of fluctuation but also, importantly, balance. There is research to show that too much methylation can be problematic too—excessive methylation on the epigenome is associated with cancer, autoimmunity, and allergies in particular. Epigenetic methylation is typically associated with gene repression, which can be beneficial in some circumstances, but not if we are repressing an important anti-cancer gene, or a gene that is important for immune balance.

So, of course we want to support proper methylation activity in the body, and yes we can use targeted supplemental methyl donors and cofactors where needed. However, there is so much more we can be doing to support healthy methylation beyond supplements. In our practice we have expanded our approach to incorporate evidence-based diet and lifestyle factors that not only are effective, but are extremely safe. This allows us to be more judicious and conservative in our use of supplementation, provides useful tools for those who actually don’t tolerate methylation supplementation (yes, this happens), and gives us a long-term support framework that can help patients over a lifetime.

We have so many more tools to support healthy methylation beyond supplementation.

Tools to Support Methylation

Food Choices

What does this look like? To start with, we look at sources of nutrients. Of course nutrients have a key role to play, but we can also get nutrients from food based sources, not just supplements (Figure 1). We specifically designed our Food Plans, Menu Plans and recipes to be rich in methylation nutrients, and compatible with other commonly-used dietary programs such as gluten-free and dairy-free.

Figure 1: Examples of Foods Rich in Methylation Nutrients

Methylation ‘Superfood’ Rich in these nutrients
Daikon radish
Dark leafy greens
Magnesium, potassium, B2, B6, folate
Potassium, folate, betaine
Methionine, cysteine, taurine, B2, B12, choline, sulfur compounds
Magnesium, potassium, folate, sulfur compounds
Cysteine, B2, B3, B6, folate, B12, betaine, choline

Support the Microbiome

We can also support nutrient status through the microbiome. Those little guys in our gut actually have a really important role to play in synthesizing nutrients for us, including B vitamins such as folate (Figure 2). In fact, many of them even synthesize the methylated forms of folate, and data has shown that supplementing specific bacterial species can even raise folate status, and lower homocysteine independently of any other changes. Prebiotic foods can support this activity even more.

Figure 2: Example Microbial Producers of Folate

Lactobacillus plantarum
Bifidobacterium bifidum
Bifidobacterium infantis
Bifidobacterium breve
Bifidobacterium longum
Bifidobacterium adolescentis
Bifidobacterium pseudocatenulatum

Avoid Nutrient and Methyl Depletors

Another way to support nutrient and methylation status is to minimize factors that actually deplete nutrients and methyl donors. This is a really important concept, termed ‘methyl donor drain’. One example of this at work relates to stress—when we are in a chronic state of fight-or-flight, we are using methyl donors both to produce, and also to break down, adrenaline. Those methyl donors are ‘spent’, so that they are no longer available for use in other methylation activity. And there are many other potential methyl donor drainers.

Methylation Balance

Beyond nutrients, it is really important to identify and implement those techniques that help promote methylation balance in the body. Again we can look to food here, among other factors, since there are specific food-based components—such as found in berries, rosemary, and more—that demonstrate adaptogenic effects on epigenetic methylation, providing those ‘checks-and-balances’ that will prevent inappropriate excessive methylation on our genome.

Inflammation and Additional Factors

These are some, but by no means all, of the concepts that we’ve incorporated into our program; we also work on inflammation, oxidative stress, mitochondrial fitness, sleep, exercise, environmental toxins (Figure 3), medication effects, dietary patterns and macronutrient ratios, meal timing and more. These factors address both the availability of methyl donors in the body, as well as that homeodynamic methylation balance.

Figure 3: Environmental Toxins That are Known to Alter DNA Methylation

Automobile fumes
Bisphenol A (BPA)
Persistent Organic Pollutants (POPs)
Jet fuel
Mold toxins (e.g. aflatoxin)

To find out exactly how these factors influence methylation and how to apply them for a holistic approach to methylation support, we have published our program in an eBook, which is available at www.drkarafitzgerald.com/practitioners/eBook. We encourage you to read it, apply it, and tell others about it. Methylation may be just one piece of the puzzle for autism and other conditions, but it is such a fundamental one. This approach is a much-needed evolution of how we need to be thinking about supporting healthy methylation.

Use the following code for a 10% discount on Methylation Diet and Lifestyle: BNI10

Sign up for our free webinar on August 16 at:  http://bioindividualnutrition.com/the-methylation-diet-webinar/

About the Authors:

Kara FitzgeraldDr. Kara Fitzgerald received her doctorate of naturopathic medicine from National College of Natural Medicine in Portland, Oregon. She completed the first CNME-accredited post-doctorate position in nutritional biochemistry and laboratory science at Metametrix (now Genova) Clinical Laboratory under the direction of Richard Lord, Ph.D. Her residency was completed at Progressive Medical Center, a large, integrative medical practice in Atlanta, Georgia. Dr. Fitzgerald is lead author and editor of Case Studies in Integrative and Functional Medicine, a contributing author to Laboratory Evaluations for Integrative and Functional Medicine and the Institute for Functional Medicine’s updated Textbook for Functional Medicine. She has been published in numerous peer-reviewed journals. Dr. Fitzgerald is on faculty at the Institute for Functional Medicine, and is an Institute for Functional Medicine Certified Practitioner. She is a clinician researcher for The Institute for Therapeutic Discovery. Dr. Fitzgerald regularly lectures internationally for several organizations and is in private practice in Sandy Hook, Connecticut.

Romily HodgesRomilly Hodges completed her Master’s degree in Human Nutrition at the University of Bridgeport, CT. She is a Certified Nutrition Specialist through the Board for the Certification of Nutrition Specialists, and completed her practice hours under the supervision of Dr. Deanna Minich, PhD and Dr. Kara Fitzgerald, ND. She has published in the Journal of Nutrition and Metabolism on food-based modulators of detoxification enzymes, and has been a contributing author to Sinatra & Houston, Nutritional and Integrative Strategies for Cardiovascular Medicine. She has been teaching assistant to Dr. Minich for the Certified Food and Spirit Practitioner Program and the Food and Spirit Advanced Detoxification Module. She is the staff nutritionist at the office of Dr. Kara Fitzgerald where she advises and supports patients in the implementation of complex, multi-layered dietary and nutritional protocols that are uniquely personalized to each individual’s needs.

New science and clinical experience reveal concerns about oxalates that far exceed traditional kidney stone pathology. In order to best support their patients and clients, integrative practitioners, and especially diet and nutrition specialists would benefit from greater understanding of their influence.

Oxalates are highly reactive molecules; they present in our body as sharp crystals or crystalline structures with jagged edges that cause pain, irritation, and distress. They can bind with certain minerals; particularly calcium and magnesium, as well as iron and copper. Having high oxalate in the body can be problematic; and not giving proper consideration to one’s oxalate intake can impede the effectiveness of even the best healing diet protocol.

High oxalate in the body (hyperoxaluria) can be a factor in many chronic conditions; including digestive issues, autoimmune disorders, and neurological conditions. Oxalates affect mitochondrial function and can create inflammation; thus influencing every system in the body.

OxalatesDefinedThis article explores the repercussions of the oxalate cascade in a variety of chronic diseases; and my follow-up article will specifically investigate oxalates and autism – and how you, the knowledgeable practitioner, can help.

Understanding Oxalates

OxalateCrystalsAlthough most commonly identified with the formation of calcium oxalate kidney stones (oxalate bound to calcium), when unbound, free oxalate can interfere with cellular functions; affecting health on a broader, systemic level. Clinical studies and anecdotal experience indicate that oxidative stress, mitochondrial disruption and damage, and nutrient depletions, trigger widely varied symptoms including fatigue and inflammatory cascades, joint pain or pain anywhere in the body. Chronic low energy is very common because of a reduction in ATP in the mitochondria. Oxalates could be a hidden source of headaches, urinary pain, genital irritation, joint, muscle, intestinal or eye pain.

Other common oxalate-caused symptoms may include mood conditions, anxiety, sleep problems, weakness, or burning feet. Indicators can be digestive, respiratory, or even bedwetting for children.

It’s important to note that oxalates can inhibit the absorption of calcium, magnesium, and other minerals; which actually makes oxalates an “anti-nutrient.” Minerals in food become bound by oxalate – for instance calcium (thereby forming insoluble calcium oxalate) – and cannot then be absorbed properly by the intestinal tract. This can lead to mineral deficiencies, such as calcium and/or magnesium deficiency.

In the gut of a healthy person, oxalates typically bind together with these minerals (are not absorbed through the gut), then eliminated in the stool. While this inhibits absorption of nutrients, beneficially this ensures they are excreted rather than crossing the gut into the blood stream and causing cellular distress and damage.

High Oxalate

Once oxalate gets into cells where it can disrupt mitochondrial function; it can cause all sorts of systemic disturbances. Here are some of the varied effects of high oxalate in the cells and tissues – that we’ll explore through the course of this article:

  • Disrupt mineral absorption and usage
  • Impair cellular energy
  • Deplete nutrients like glutathione and interfering with biotin
  • Create oxidative stress[1]
  • Activate the immune system to trigger inflammatory cascades
  • Interfere with and damage mitochondrial function[2]
  • Damage cells and tissues
  • Cause seizures during toxic exposure to oxalate[3],[4],[5]
  • Cause faulty sulfation
  • Cause histamine release

Types & Sources of Oxalates

Exogenous and Endogenous

Oxalates stem from two main sources: exogenous (outside the body; from dietary intake) and endogenous (produced within the body, cell or tissue).

Exogenous oxalate can accumulate from a diet that is high in spinach, nuts, beans, or other high oxalate foods. This is why individualizing therapeutic diets is essential; because “by the book” some well-known special diets strongly rely on higher-oxalate foods (especially almonds/almond flour). Diets often heavy on these nut flours include: SCD, GAPS, and Paleo. And vegetarian diets are often high in oxalate; since they usually include many beans, grains, nuts and seeds, as well as high oxalate greens or starchy vegetables, like spinach or sweet potatoes.

High Oxalate Foods

  • Spinach
  • Swiss chard
  • Almonds and almond flour
  • All nuts
  • Chia seeds
  • Sesame seeds
  • Buckwheat
  • Quinoa
  • Most legumes
  • Potatoes
  • Sweet potatoes
  • Chocolate
  • Beets

Practitioners should be aware that diets high in oxalate could create a wide variety of problems for some people. Making informed choices or modifying a diet for oxalate can make a dramatic difference in lowering the oxalate load (note: it is important to reduce oxalates in the diet very slowly).

However, most of our body’s total oxalate content is created during normal body metabolism. “It is increasingly accepted that 80-90% of urinary oxalate is produced endogenously,” [6]  within the cell, and this can directly wreak havoc in the body.

The Origin of Oxalate Issues

Deficiencies and Endogenous Production

Each person’s ability to process oxalate varies, based on certain deficiencies, pathways or genetic differences. Some deficiencies, including vitamin B6 and B1 deficiency can cause the body to produce oxalate (endogenously) in problematic amounts. Other deficiencies such as vitamin A deficiency can cause the body to absorb excess oxalate through the gut.

Further, because one’s body chemistry can convert a substance into oxalate; such as supplements like ascorbic acid or the amino acid glycine (a key component in bone broth) – complications can arise. Fructose, xylitol, and other sugar alcohols can also convert to oxalate. Certain supplements, as well as a diet too high in meat, can be a problem for some people.

When the Gut is Unhealthy

The health of the gut and one’s microbiome influence whether or not a person has an issue with oxalate.

Oxalates can be a problem when: the gut is inflamed and hyper-permeable (i.e. leaky gut), fat is not digested and there is fat malabsorption, or when there is not enough good bacteria (especially particular forms) to break the oxalate down. Developing problems with oxalates is more likely if there aren’t enough minerals in the gut to bind the oxalate.

Oxalobacter Formigenes

Leaky gut and low beneficial bacteria can contribute to oxalate problems. Oxalobacter formigenes is a strain of beneficial bacteria that degrade oxalate. Unfortunately, even one, or a few courses of antibiotics can wipe out oxalobacter formigenes for months, if not indefinitely. Certain probiotics break down oxalate, not just the oxalobacter. If there’s a history of antibiotic use, dysbiosis or other conditions that negatively affect the microbiome, one should work on correcting the flora balance, as well as be suspicious of any concerns with oxalates.

Fat malabsorption

Excess undigested fat compound matters. The extra fat floating around in the gut can bind to calcium, which makes the calcium unavailable for oxalate binding, causing free oxalate to absorb into the body.

With optimal health, good digestion, and mineral intake, calcium would be available for binding to that oxalate; however, when there is excess fat the calcium binds to the fat, allowing the oxalate to be free to get into the bloodstream and into the cells. For people with oxalate issues, it is important to know whether fat malabsorption is at play.  A stool analysis can help you determine if fat malabsorption is at play. Some clients/patients may also present with symptoms of fat digestion issues such as floating or greasy stools. For those who have had a GI scope, gastroenterologists can often see signs of fat malabsorption. Once it is determined that fat is not digesting and absorbing, an individual may need to restrict fat intake in their diet to avoid further complication of oxalate issues, particularly in the short run, as they work on digestion whether with digestive enzyme, supporting bile production, or other means.

Sulfate, Poor Sulfation, and Mitochondrial Dysfunction

In addition to gut issues, sulfate and sulfation can be underlying factors in oxalate issues. When sulfate is low, and sulfation biochemistry is poor, oxalate problems can arise.

Sulfate is very important in the body; it’s needed for processing phenolic foods, and dozens of processes in the body including digestion, gut integrity, and neurodevelopment.

There is a two-way relationship between oxalate and sulfate/sulfation. Said another way: oxalates can cause low sulfate and low sulfate can cause oxalate problems. As noted, excess oxalates can lead to poor sulfation by oxalate interfering with the body’s ability to allow sulfate into the cell, inhibiting sulfation. On the other hand, with poor sulfation from low sulfate levels, oxalate more readily gets into a cell on the (unoccupied) sulfate transporter.

Another way that low sulfate can cause problems with oxalates, involves the role of the kidneys. Susan Owens, who heads the Autism Oxalate Project, said that insufficient sulfate inside the kidney tubule cells would interfere with the ability of the kidneys to remove oxalate from the blood and to deliver the oxalate to the urine. Therefore, inadequate sulfate could cause higher levels of oxalate in the system.

It’s a double-edged sword if you’ve got low sulfate. If there isn’t enough sulfate, you might not be regulating your oxalate very well. Depleted sulfate can allow for higher oxalate absorption, and the more oxalate you absorb, the less sulfate your body is likely to have.

Because there are so many conditions that have poor sulfation underlying them, it’s sensible to consider a low oxalate diet and other support for a variety of chronic health matters. We need to step well outside the mainstream thinking of just kidney stones.

Faulty sulfation is of influence to these chronic health conditions:

  • Autism[7],[8]
  • Food sensitivity[9]
  • Parkinson’s disease
  • Alzheimer’s disease
  • Migraine
  • Chronic fatigue syndrome[10]
  • Rheumatoid arthritis[10]
  • Lupus[10]
  • Inflammatory bowel disease[10]
  • Asthma[10]
  • Depression[10]
  • Hyperactivity[10]

Furthermore, when sulfate is low, it can cause phenol reactions to various foods. Therefore, those who have low sulfate may also have an issue with phenols and with oxalates in food. It’s not across the board, but these are some of the key relationships. People with depleted sulfate frequently do well on a low phenol and low oxalate diet. Of course, that cannot be true for everyone – which is why BioIndividual Nutrition is essential. Routinely though, when I’m supporting clients to lower oxalate, I will consider the potential benefit of a low phenol regime as well.

Effects of High Oxalate in the Body

Mitochondrial Dysfunction

Oxalates, inside the cell, can damage the mitochondria.[11]

Once oxalate impedes mitochondria function, it can affect every cell, organ, and system of the body. This is a primary reason that oxalates can become so problematic. But it’s also why the full scope of oxalate’s effect on chronic disease can be wide reaching and difficult to study through association.

But how does oxalate get into the cell and damage the mitochondria?

I earlier noted that when sulfate is low, oxalate can be “transported” into the cell on the sulfate transporter, and disrupt or damage the mitochondria. Additionally, oxalate can get into the cell by endogenous production, which happens in the cell and, therefore, doesn’t require being transported in. While high oxalate may or may not be the initial impetus of mitochondrial conditions, because of their tendency to get into the mitochondria and cause damage, it’s reasonable to assume that oxalate is an important factor to consider for those with mitochondrial issues.

Here are some of the conditions involving mitochondrial dysfunction:

  • Autism
  • Alzheimer’s
  • Neurodevelopmental disorders
  • Seizures
  • Parkinson’s
  • Hypertension
  • Retinopathy
  • Multiple sclerosis
  • Obesity
  • Cancer

Oxidative Stress, Inflammation, and Glutathione

Medical illustration about pain located in the head area. Digital illustration.

There are even more pieces to this puzzle. High oxalate can lead to oxidative stress, and subsequently inflammation and injury,[12],[13]  which can cause oxalate stone formation in the kidney, and damage to any soft tissue or area of the body where they interfere with cellular function.

High oxalates can elevate superoxide and deplete glutathione and antioxidant status.[14]  Conversely, antioxidants and free radical scavengers can decrease oxalate stone formation in the kidney, as well as reducing the inflammation caused by oxalate.

Oxidative stress, inflammation, and low glutathione status are common manifestations in many chronic diseases. Understanding this relationship and the potential sources of chronic inflammation and stress can help practitioners appropriately address the triggers that can be causing the problems, and in this case, oxalate is an important factor to consider.

Conditions linked to oxidative stress and inflammation:

  • Autism [15], [16], [17]
  • Asthma
  • Allergies
  • ADHD [18]
  • Autoimmune conditions
  • Depression [19], [20]
  • Anxiety [21], [22]
  • Inflammatory bowel disorders
  • Eczema
  • Schizophrenia [23], [24]
  • Obesity, heart disease, and diabetes

For people or practitioners addressing issues with oxidative stress, inflammation, and the aforementioned conditions, it’s important to consider oxalate’s potential systemic implications when devising therapeutic intervention.

Conclusion – Through The Lens of Autism

Oxalate can affect many systems of the body. Extensive research indicates a multitude of chronic health conditions where systems are impaired and oxalate is implicated.

Chronic Conditions Associated with High Oxalate:

  • Asthma
  • Autism[25]
  • Autoimmune thyroid or other autoimmunity
  • Chronic fatigue syndrome
  • Cystic Fibrosis[26]
  • Fibromyalgia
  • Hypothyroid[27]
  • IBD (inflammatory bowel disease)[28]
  • Interstitial Cystitis
  • Kidney Stones in family
  • Low muscle tone
  • Migraine and Headaches
  • Mitochondrial damage and dysfunction
  • Rett Syndrome[29]
  • Seizures
  • Vulvodynia

Julie_Speaking_Autism_Summit_2015For fifteen years I’ve researched and educated parents and clinicians about therapeutic diet and nutrition for autism. It’s a very complex chronic disorder, and studying its intricacies provides great insight into addressing a wide variety of health conditions.

From the list of conditions in this article alone, you can see the similarities of implicating factors are great. Autism and many other disorders share underlying mechanisms of inflammation, mitochondrial dysfunction, and faulty methylation and sulfation, as well as digestive disorders, leaky gut, and dysbiosis as we’ve discussed today.

As we continue to survey the underlying factors and consider how oxalate may play a role, it’s easy to appreciate, and not particularly surprising, that there are so many chronic disorders that may be affected by oxalate. The degree of overlap in those conditions is significant and worth exploring more deeply.

In my next article, I’ll dive into this topic even further – looking specifically at oxalate and autism. Through that overarching “lens” I’ll share what I’ve researched, learned, and experienced over the years and share what you can do – as a clinician or parent, to help your patient/client or child – when you suspect that oxalates may be an issue.

Julie Matthews
Certified Nutrition Consultant

Scientific References

[1] Lee, Hyo-Jung, et al. (2012). “Gallotannin suppresses calcium oxalate crystal binding and oxalate-induced oxidative stress in renal epithelial cells.” Biological & Pharmaceutical Bulletin 35(4): 539–544.

[2] Veena, C. K., Josephine, A., Preetha, S. P., Rajesh, N. G., & Varalakshmi, P. (2008). Mitochondrial dysfunction in an animal model of hyperoxaluria: a prophylactic approach with fucoidan. European Journal of Pharmacology 579(1), 330-336.

[3] Díaz, Cándido, et al. (2004). “Long daily hemodialysis sessions correct systemic complications of oxalosis prior to combined liver–kidney transplantation: case report.” Therapeutic Apheresis and Dialysis 8.1, 52-55

[4] Pfeiffer, H., et al. (2004). “Fatal cerebro-renal oxalosis after appendectomy.” International Journal of Legal Medicine 118.2, 98-100.

[5] Chen, Chien-Liang, et al. (2002). “Neurotoxic effects of carambola in rats: the role of oxalate.” Journal of the Formosan Medical Association 101.5, 337-341.

[6] Conyers, R. A., R. Bais, and A. M. Rofe. (1990). “The relation of clinical catastrophes, endogenous oxalate production, and urolithiasis.” Clinical chemistry 36, no. 10, 1717-1730.

[7] Waring, R. H., and L. V. Klovrza. (2000). “Sulphur metabolism in autism.” Journal of Nutritional and Environmental Medicine 10, no. 1, 25-32.

[8] Alberti, Antonino, Patrizia Pirrone, Maurizio Elia, Rosemary H. Waring, and Corrado Romano. (1999). “Sulphation deficit in “low-functioning” autistic children: a pilot study.” Biological Psychiatry 46, no. 3, 420-424.

[9] Scadding, G. K., R. Ayesh, J. Brostoff, S. C. Mitchell, R. H. Waring, and R. L. Smith. (1988). “Poor sulphoxidation ability in patients with food sensitivity.” BMJ: British Medical Journal 297, no. 6641, 105.

[10] Moss, Margaret, and Rosemary H. Waring. (2003). “The plasma cysteine/sulphate ratio: A possible clinical biomarker.” Journal of Nutritional and Environmental Medicine 13, no. 4. 215-229.

[11] Veena, C. K., Josephine, A., Preetha, S. P., Rajesh, N. G., & Varalakshmi, P. (2008). Mitochondrial dysfunction in an animal model of hyperoxaluria: a prophylactic approach with fucoidan. European Journal of Pharmacology 579(1), 330-336.

[12] Biswas, Subrata K., et al. (2007). “Which comes first: renal inflammation or oxidative stress in spontaneously hypertensive rats?” Free Radical Research 41.2, 216-224.

[13] Khan, Saeed R. (2005). “Hyperoxaluria-induced oxidative stress and antioxidants for renal protection.” Urological Research 33.5, 349-357.

[14] Khand, F. D., et al. (2002). “Mitochondrial superoxide production during oxalate-mediated oxidative stress in renal epithelial cells.” Free Radical Biology and Medicine 32.12, 1339-1350.

[15] Vargas, Diana L., et al. “Neuroglial activation and neuroinflammation in the brain of patients with autism.” Annals of neurology 57.1 (2005): 67-81.

[16] Li, Xiaohong, et al. “Elevated immune response in the brain of autistic patients.” Journal of neuroimmunology 207.1 (2009): 111-116.

[17] Rossignol, D. A., and R. E. Frye. “A review of research trends in physiological abnormalities in autism spectrum disorders: immune dysregulation, inflammation, oxidative stress, mitochondrial dysfunction and environmental toxicant exposures.” Molecular psychiatry 17.4 (2011): 389-401. 4 Donev, Rossen, and Johannes Thome. “Inflammation: good or bad for ADHD?.” ADHD Attention Deficit and Hyperactivity Disorders 2.4 (2010): 257-266.

[18] Donev, Rossen, and Johannes Thome. “Inflammation: good or bad for ADHD?.” ADHD Attention Deficit and Hyperactivity Disorders 2.4 (2010): 257-266.

[19] Miller, Gregory E., and Ekin Blackwell. “Turning Up the Heat Inflammation as a Mechanism Linking Chronic Stress, Depression, and Heart Disease.” Current Directions in Psychological Science 15.6 (2006): 269-272.

[20] Raison, Charles L., Lucile Capuron, and Andrew H. Miller. “Cytokines sing the blues: inflammation and the pathogenesis of depression.” Trends in immunology 27.1 (2006): 24-31.

[21] O’Donovan, Aoife, et al. “Clinical anxiety, cortisol and interleukin-6: Evidence for specificity in emotion–biology relationships.” Brain, behavior, and immunity 24.7 (2010): 1074-1077.

[22] Pitsavos, Christos, et al. “Anxiety in re- lation to inflammation and coagulation markers, among healthy adults: the AT- TICA study.” Atherosclerosis 185.2 (2006): 320-326.

[23] Saetre, Peter, et al. “Inflammation-relat- ed genes up-regulated in schizophrenia brains.” Bmc Psychiatry 7.1 (2007): 46.

[24] Leonard, Brian E., Markus Schwarz, and Aye Mu Myint. “The metabolic syndrome in schizophrenia: is inflammation a contributing cause?.” Journal of Psychopharmacology 26.5 suppl (2012): 33-41.

[25] Konstantynowicz, J., Porowski, T., Zoch-Zwierz, W., Wasilewska, J., Kadziela-Olech, H., Kulak, W., Owens S.C., Piotrowska-Jastrzebska J.,  and Kaczmarski, M. (2012). A potential pathogenic role of oxalate in autism. European Journal of Paediatric Neurology 16(5), 485-491.

[26] Terribile, Maurizio, Maria Capuano, Giovanni Cangiano, Vincenzo Carnovale, Pietro Ferrara, Michele Petrarulo, and Martino Marangella.(2006).  “Factors increasing the risk for stone formation in adult patients with cystic fibrosis.” Nephrology Dialysis Transplantation 21, no. 7, 1870-1875.

[27] Goldman, Max, and Gregory J. Doering. (1979). “The effect of dietary ingestion of oxalic acid on thyroïd function in male and female Long-Evans rats.” Toxicology and Applied Pharmacology 48, no. 3, 409-414.

[28] Danese, Silvio, Stefano Semeraro, Alfredo Papa, Italia Roberto, Franco Scaldaferri, Giuseppe Fedeli, Giovanni Gasbarrini, and Antonio Gasbarrini. (2005). “Extraintestinal manifestations in inflammatory bowel disease.” World Journal of Gastroenterology 11, no. 46, 7227.

[29] Motil, Kathleen J., Rebecca J. Schultz, Steven Abrams, Kenneth J. Ellis, and Daniel G. Glaze. (2006). “Fractional calcium absorption is increased in girls with Rett syndrome.” Journal of Pediatric Gastroenterology and Nutrition 42, no. 4, 419-426

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nutrients_elementsRecently, there has been quite a lot of controversy in the media (and even in the nutrition field) on whether diet and nutritional supplements can help autism. I’ve been focused on the science and application of nutrition and special diets for autism for 14 years. The scientific rationale for giving strategic attention to the food and nutrition children with autism receive is strong.

This recent “controversy” was in response to a new study that came out last week, that I feel is quite flawed. I’ll be addressing these “findings” in the coming days and look forward to sharing my broader thoughts with you.

However, before I do, I wanted to share a very important study published by Dr. James Adams, a prolific autism researcher, who has published dozens of studies on autism, and has conducted many specifically on nutritional status and supplementation in children with autism, with more to come.

Today I want to share the results from, “Effect of a vitamin/mineral supplement on children and adults with autism.”

This study is actually a follow up to another study he did.  So before I get to the study on the effects of supplementation in autism, I wanted to summarize the findings in the first study, Nutritional and metabolic status of children with autism vs. neurotypical children, and the association with autism severity, described in detail here.

Researchers found deficiencies and metabolic abnormalities in children with autism, including: low levels of biotin, plasma glutathione, SAM, plasma uridine, plasma ATP, NADH, NADPH, plasma sulfate, and plasma tryptophan. The children with autism had high oxidative stress markers and plasma glutamate. Biotin was the only vitamin with a significant difference in the children – it was 20% lower in the children with autism. Interestingly, their mean levels of vitamins, minerals, and most amino acids commonly measured in clinical care were within published reference ranges.”   However, while most nutrients were within “reference range,” the study found – along with the deficiencies and metabolic abnormalities above – many additional differences and deficiencies that are noteworthy:

  • B5, vitamin E and total carotenoids levels showed “possibly significant” lower levels in children with autism.
  • Folate and Niacin – possibly significant in autism (Functional needs assessed using FIGLU and n-methyl-nicotinamide)
  • Low lithium in autism
  • Twenty-five percent of the autism group was below the reference range for iodine and calcium.
  • Tryptophan, a precursor to serotonin was significantly lower in the autism group. (Low tryptophan plays a role in depression and poor sleep)
  • Glutamate, an excitatory neurotransmitter, was significantly higher (Glutamate is a factor in hyperactivity)
  • Other differences were possibly significant such as slightly decreased tyrosine and phenylalanine and slightly higher serine.

So while most of the vitamins and mineral levels fell within “published reference ranges,” the study found many metabolic differences and a number of markers indicating deficiency and concluded that “The autism group had many statistically significant differences in their nutritional and metabolic status, including biomarkers indicative of vitamin insufficiency, increased oxidative stress, reduced capacity for energy transport, sulfation and detoxification. Several of the biomarker groups were significantly associated with variations in the severity of autism.”

The next study published by Dr. Adams, and the one I want to highlight today, looked at the “Effect of a vitamin/mineral supplement on children and adults with autism” in this same group of individuals. This study was a randomized, double-blind, placebo-controlled treatment study on the use of a vitamin/mineral formula for three months. The study used a previous version of this multivitamin/mineral formula  – ANRC Essentials is now available as a slightly reformulated supplement to account for some of the findings in these studies.

The study results were impressing. In this study they found improvements in nutrient status, biomarkers, and autism symptoms. The study showed:


  • 3 months of supplementation increased the level of most vitamins, including vitamins B1, B3, B5, B6, folate, B12, C, E, and biotin.
  • The supplement also improved two functional biomarkers in urine, FIGLU and methylmalonic acid, indicating the supplement improve functional vitamin status of folate and vitamin B12.

So while vitamins were theoretically “in range” in the previous study, levels increased and improved to a more optimal level (not excess) with supplementation.

In the case of the functional biomarkers for folate and B12, this brings up an important biochemical point. For some individuals, laboratory values “appear” in normal range in the blood. However, this can be misleading as these nutrients may not be able to be utilized properly, so an actual deficiency is present. For example, with folic acid, it’s difficult for many people (such as those with methylation issues) to convert folic acid to the usable active folate form, so while levels of “folic acid” appear sufficient and “in range,” the active usable form of folate is actually insufficient and the individual is really deficient. With B12, many experts feel the standard reference range (for “normal” blood levels) is too low and some people need more, or a different form. Therefore, testing blood levels only may miss many people that are deficient. Therefore MMA which is an indicator of functional B12 status, is preferred by many clinicians and researchers to assess B12 status.

This study’s results may be illustrating these points – while levels of folic acid and vitamin B12 were in range, supplementation improved these biomarkers and likely vitamin status.


  • The supplement increased the levels of many essential minerals including: calcium, iodine, lithium, manganese, molybdenum, and selenium.
  • The increase in lithium levels was large (this form of lithium was very well absorbed), so researchers felt less lithium may be better in future studies.

Biomarkers – Sulfation, Methylation, Glutathione and Oxidative Stress

The wonderful thing about this study is that it assessed biomarkers of important biochemical processes such as sulfation, methylation, and low glutathione (transsulfuration), all of which which researchers have found to be low in autism. They also measured oxidative stress, a process found to be high in autism. By studying these metabolic biomarkers and well as nutrient status, they were able to not only see what supplementation did for nutrient lab values, but what supplementation did for system and biochemical functioning. In this study they found:

  • After treatment, there was a significant increase in total sulfate, and a large and marginally significant increase in free sulfate. Adequate sulfate levels are important for sulfation, for which there are hundreds of functions in the body including proper gut barrier function and detoxification.
  • The level of SAM increased significantly, and there was a marginally significant decrease (improvement) in uridine, a marker of impaired methylation, indicating that supplementation may have improved methylation.  Methylation is important for adequate neurotransmitter levels and gene expression.
  • Reduced glutathione improved significantly and nearly normalized. Glutathione is a major antioxidant (important to neutralize oxidative stress), and has many functions including detoxification.

This means that in addition to having better levels of nutrients in the body, these nutrients helped to boost and improve functioning of many systems including biochemical processes that handle immune function, proper inflammatory response, detoxification, gastrointestinal health, and hundreds of other functions.

Symptom Improvement

Furthermore, this study also measured parents impressions from the supplementation and found improvements in every area assessed, and some were quite significant. Notice the improvements in language, hyperactive, tantruming and more.


Dr. Adams, et al. concluded in this study, “The vitamin/mineral supplement was found to be generally well-absorbed and metabolically active, resulting in improvements in biotin, glutathione, methylation, oxidative stress, ATP, NADPH, NADPH, and sulfate. The data from this study strongly suggests that oral vitamin/mineral supplementation is beneficial in improving the nutritional and metabolic status of children with autism, and in reducing their symptoms.”

This study greatly supports the use of vitamin and mineral supplementation in autism.

Study Citation:

Adams, James B., Tapan Audhya, Sharon McDonough-Means, Robert A. Rubin, David Quig, Elizabeth Geis, Eva Gehn et al. “Effect of a vitamin/mineral supplement on children and adults with autism.” BMC pediatrics 11, no. 1 (2011): 111.