Welcome to the ISOM webpage for autism spectrum disorder. The purpose of this resource is to provide information on potential causes and promoters of autism spectrum disorder that are related to nutrition, micronutrients, and metabolism. Understanding these factors can be an important and productive part of both addressing and recovering from autism spectrum disorder.

The information provided is not intended to be a substitute for medical advice from a licensed physician or other qualified healthcare professional.

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What is autism?

Autism, or Autism Spectrum Disorder (ASD). is a complex condition involving difficulties with social communication, repetitive behavior, and limited interests.  Autism Spectrum Disorder is a lifelong developmental disorder that varies between individuals.

Symptoms of ASD may include:

  • difficulty appreciating emotions (their own and others)
  • aversion to maintaining eye contact
  • interpreting abstract ideas literally
  • inflexibility or extreme difficulty with change
  • sensory hypersensitivity
  • immense focus of niche subject(s)
  • repetitive and restrictive behaviours
  • potential selfinjurious behaviour

Early signs of autism spectrum disorder can be seen at a young age by an individual’s parents, caregivers, or pediatricians but may go undiagnosed due to a lack of symptoms. Evaluations including observation, interaction, and interviews help rule out other disorders, and confirm an ASD diagnosis.

Asperger syndrome shows overlaps with autism, but language and cognitive development are often normal, and intelligence may be above average (Gaby, 2011).

The cause of autism is unknown, but is often connected with abnormalities in biochemistry and architecture of the brain (Gaby, 2011).


American Psychiatric Association webpage



Gaby, A. R. (2011). Nutritional Medicine (VitalBook file).

The standard medical approach typically does not consider or address dietary, nutrient, and environmental contributors to autism spectrum disorder.

Conventional treatment for autism spectrum disorder works to improve an individual’s functioning, primarily at a young age. This treatment is individualized, and a structural behavioural plan is created to improve adaptive skills.

Common therapies/treatments include:

  • social skills training
  • speech and language therapy
  • occupational therapy
  • special education

The two medications approved by the FDA for children with ASD are:

  • Aripiprazole
  • Risperidone

Aripiprazole and risperidone are antipsychotic medications used to help reduce autism-related irritability. Other medications, such as antidepressants (SSRIs), stimulants, antipsychotics, and anticonvulsants, may be used in individuals with additional diagnoses.

Autism has numerous biological causes and contributors that have been identified through nutritional research and clinical practice. Each individual may experience autism symptoms for different reasons.

An orthomolecular approach:

  • identifies the drivers and causes of autism and focuses on understanding them
  • works WITH the body to restore balance and normal function, and considers the person with the autism vs. just the autism
  • addresses nutrient depletions that promote autism whereas medications do not
  • can be done SAFELY in conjunction with most medical interventions

Contributing factors for autism

Contributing factors are substances, contexts or conditions that have roles in the causation or promotion of autism spectrum disorders.

Food, food components, and food additives

Eating an unhealthy diet is known to lead to nutrient deficiencies, which, in turn, can negatively affect brain function.

Foods that promote good brain health:

  • whole, fresh foods
  • good-quality animal and plant-based protein
  • good-quality fats
  • starches (minimal amounts)
  • antioxidant-rich vegetables and fruit

Substances that are bad for brain health:

  • sugar-containing foods and snacks
  • high glycemic foods (sugars and starches)
  • processed fats (processed plant oils, hydrogenated fats)
  • artificial ingredients (colours and preservatives)
  • fast food meals

Diet and ASD

  • A balanced and diverse diet is an important factor for ensuring an adequate supply of nutrients for energy and healthy metabolism.
  • However, a common feature of ASD is food selectivity and the resulting impact on food consumption.
  • Food selectivity rates tend to be higher and more persistent in people with ASD than the general population (Rafee et al., 2019).

Some manifestations of food selectivity in ASD include:

  • slightly restricted food choices (avoid only specific foods)
  • limiting to a single food item (avoid most foods)
  • requiring foods to be prepared and/or presented in a specific way

Factors that influence food selection restrictions include (Rafee et al., 2019):

  • food packaging
  • food preparation methods
  • food presentation or arrangement
  • specific utensils provided for food consumption
  • oral and fine motor impairments
  • digestive issues
  • oral defensiveness

Food selectivity can lead to decreased intake of nutrients as well as increased uptake of toxic metals and other food contaminants. Poor nutrient status and increased toxic load are implicated in the manifestation and expression of ASD.

Healthy diets for supporting ASD

Diets that have shown benefit in the context of ASD include:

  • GFCF – gluten-free/casein-free (see GFCF diet, Orthomolecular Interventions)
  • Mediterranean
  • Paleo
  • SCD – specific carbohydrate diet
  • GAPS (Gut-and-psychology)
  • Ketogenic
  • Feingold

Mediterranean diet

  • ​​The Mediterranean diet is considered a good model for a healthy diet. It includes foods that are beneficial, and also reduces or eliminates foods that promote mental health issues.
  • General components of the Mediterranean diet include:
    • plenty of vegetables and fruit
    • healthy fats including olive oil
    • regular consumption of seafood
    • poultry, beans, and small amounts of red meat
    • small amounts of dairy as yogurt and cheeses
    • whole grains instead of refined grains

More information and menu plans:


(Mediterranean Diet 101, 2021)

Paleo diet

Foods to eat: (added space below)

  • meat, fish, eggs
  • vegetables, fruits
  • nuts, seeds
  • healthy fats and oils
  • herbs, spices 

Foods to avoid: (added space below)

  • sugar, high-fructose corn syrup
  • grains
  • legumes and beans
  • dairy products
  • vegetable oils and trans fats
  • artificial sweeteners
  • processed foods

More information and menu plans:


(The Paleo Diet — A Beginner’s Guide + Meal Plan, 2018)


Mediterranean Diet 101: Meal Plan, Foods List, and Tips. (2021, October 25). Healthline. https://www.healthline.com/nutrition/mediterranean-diet-meal-plan

Rafee, Y., Burrell, K., & Cederna-Meko, C. (2019). Lessons in early identification and treatment from a case of disabling vitamin C deficiency in a child with autism spectrum disorder. International Journal of Psychiatry in Medicine, 54(1), 64–73. https://doi.org/10.1177/0091217418791443

The Paleo Diet—A Beginner’s Guide + Meal Plan. (2018, August 1). Healthline. https://www.healthline.com/nutrition/paleo-diet-meal-plan-and-menu

What are exorphins?

  • Exorphins are short strands of amino acids, absorbed from partially digested food, that bind to opiate receptors in the brain.
  • The exorphins gliadorphin and casomorphin are generated from normal digestive breakdown of gluten and casein. Gliadorphin is derived from the gluten component of grains, and casomorphin is derived from the casein component of dairy.
  • At normal levels, exorphins have roles in food-seeking and appetite regulation. 
  • At high levels, exorphins drive addictions and alter sensory perceptions (Pruimboom and De Punder, 2015), and cause:
    • speech and hearing problems
    • spaciness and “brain fog”
    • near-constant fatigue
    • irritability, aggression and moodiness
    • anxiety and depression
    • sleep problems

Causes of increased brain exorphins:

  • Leaky gut (increased intestinal permeability) can allow large amounts of exorphins to enter the bloodstream from the digestive track and access the brain.
  • The enzyme dipeptidyl peptidase-IV (DPP-IV) breaks down gliadorphin and casomorphin into harmless amino acids. However, DPP-IV function can be inhibited by the gliadin component of gluten. When DPP-IV is inhibited, less gliadorphin and casomorphin is broken down, so more of it reaches the brain.

Drivers of DPP-IV insufficiency include:

  • overconsumption of wheat and milk
  • genetic susceptibility
  • antibiotics
  • gelatin from vaccines
  • candida
  • mercury and other heavy metals
  • pesticides
  • nutritional deficiencies

Exorphins and ASD

  • Exorphins are found in urine, blood, and spinal fluid of individuals with ASD (Knivsberg et al., 2002).
  • A variety of ASD behaviours may be explained by the effects of exorphins on neurotransmitter systems (Shattock et al.,1990; Knivsberg et al., 2002), including ritualist behaviours, excessive activity, perseveration, as well as speech and language delays (Elder, 2008).
  • The effect of exorphins on the body opiate system and central nervous system may contribute to ASD-associated digestive tract symptoms of diarrhea, constipation, abdominal pain, and gastroesophageal reflux (Elder, 2008).

Recommendations for addressing exorphins:

  • support healthy nutrient status with diet and supplements
  • address leaky gut
  • follow the GFCF diet (See Orthomolecular Interventions > GFCF diet)


Bressan, P., & Kramer, P. (2016). Bread and other edible agents of mental disease. Frontiers in human neuroscience, 10, 130.

Elder, J. H., Shankar, M., Shuster, J., Theriaque, D., Burns, S., & Sherrill, L. (2006). The Gluten-Free, Casein-Free Diet In Autism: Results of A Preliminary Double Blind Clinical Trial. Journal of Autism and Developmental Disorders, 36(3), 413–420. https://doi.org/10.1007/s10803-006-0079-0

Knivsberg, A. M., Reichelt, K. L., HØien, T., & NØdland, M. (2002). A Randomised, Controlled Study of Dietary Intervention in Autistic Syndromes. Nutritional Neuroscience, 5(4), 251–261. https://doi.org/10.1080/10284150290028945

Pruimboom, L., & De Punder, K. (2015). The opioid effects of gluten exorphins: asymptomatic celiac disease. Journal of Health, Population and Nutrition, 33(1), 24.

Shattock, P., Kennedy, A., Rowell, F., & Berney, T. (1990). Role of neuropeptides in autism and their relationships with classical neurotransmitters. Brain Dysfunction, 3(5–6), 328–345.

Environmental factors

Environmental toxins are chemicals and substances with properties that make them harmful to health. They can be naturally occurring or human-made.

Some environmental toxins include:

  • heavy metals such as lead, cadmium, arsenic, and mercury
  • chemicals like benzene, formaldehyde, volatile organic compounds (VOCs) and phthalates
  • toxins from mold and metabolites from inappropriate intestinal flora

Key effects of environmental toxins:

  • free radical damage
  • DNA damage
  • interference with normal body reactions
  • mimic hormones
  • increase body inflammation
  • change the way cells function
  • cause cell mutations
  • kill cells

The ability to effectively metabolize environmental toxins is affected by:

  • amount of specific and total exposure to toxins
  • availability of detoxification-supporting nutrients
  • detoxification capacity

Environmental toxins and children

  • Based on body weight, children eat, drink, and breathe more than adults which leads to a comparably higher intake of toxins.
  • Children are also more susceptible to chemical exposures due to rapid growth and underdeveloped protective body systems.
  • Chemical exposures for children start at conception and continue through pregnancy and childhood  (Environmental Toxins, n.d.).
  • Exposures to chemicals at critical times in a child’s development can cause life-long health issues.

Environmental toxins and ASD

Exposure to environmental toxins may increase risk of autism in genetically-susceptible people (Jyonouchi, 2009).

A study of twin pairs determined that environmental factors accounted for 55% of the risk for developing ASD compared to 37% for genetic factors (Rossignol et al., 2014).

Genetics, environmental toxins and ASD

Some individuals with ASD may be more susceptible to environmental toxins due to polymorphisms in genes required for detoxification (Rossignol et al., 2014).

Heavy metals and ASD

  • Autistic children are presumed to have impaired ability to detoxify or remove mercury and other heavy metals as a result of decreased methylation, sulfation, and antioxidant activity (Newmark, 2012).
  • Autistic children have been shown to have significantly higher urinary concentrations and body burden of mercury versus the general population (Newmark, 2012).
  • Hair and nail sample analysis has shown significantly higher concentrations of copper, lead, and mercury in autistic individuals, with a concurrent significant decrease in countering minerals magnesium and selenium. The concentrations correlated to degrees of ASD symptom severity (Lakshmi Priya & Geetha, 2011).
  • Copper excess has been found in 85 or more percent of people with ASD (Lakshmi Priya & Geetha, 2011).
  • Copper burden in ASD children correlates with severity symptoms (Lakshmi Priya & Geetha, 2011).

Addressing environmental toxins

  • Environmental and dietary sources of toxic metal exposures need to be removed as much as possible.
  • Many patients will improve with a basic protocol of a healthy diet, supplementation of essential nutrients, exercise and rest. Sweating from exercise or sauna can also help remove toxic metals (Sears, 2018).
  • Detoxification of toxic metals must be properly supported with a protocol tailored to an individual’s situation and toxic load, in order to minimize the risk of releasing, then depositing the metals back into tissues. The best approach for brain detoxification is conservatively, “with repeated, modest treatments, using multiple agents” (Sears, 2018).


Environmental Toxins. (n.d.). Environmental Toxins. Retrieved January 10, 2022, from https://pcs.harriscountytx.gov/Pages/EnvironmentalToxins.aspx

Jyonouchi, H. (2009). Food allergy and autism spectrum disorders: Is there a link? Current Allergy and Asthma Reports, 9(3), 194–201. https://doi.org/10.1007/s11882-009-0029-y

Lakshmi Priya, M. D., & Geetha, A. (2011). Level of Trace Elements (Copper, Zinc, Magnesium and Selenium) and Toxic Elements (Lead and Mercury) in the Hair and Nail of Children with Autism. Biological Trace Element Research, 142(2), 148–158. https://doi.org/10.1007/s12011-010-8766-2

Newmark, S. (2012). Autism Spectrum Disorder. In Integrative Medicine (Third). Elsiver.

Sears, M. E. (2013). Chelation: Harnessing and Enhancing Heavy Metal Detoxification—A Review. The Scientific World Journal, 2013. https://doi.org/10.1155/2013/219840

Rossignol, D. A., Genuis, S. J., & Frye, R. E. (2014). Environmental toxicants and autism spectrum disorders: A systematic review. Translational Psychiatry, 4(2), e360. https://doi.org/10.1038/tp.2014.4

Metabolic conditions

Autism symptoms can be caused or promoted by nutrient deficiencies or dependencies.


  • Nutrient deficiency is when the minimum amounts of nutrients needed for normal body function are not met by diet
  • A nutrient deficiency results in depletion of nutrients in body tissues, and changes to mental and physical functioning from diet, medications.


  • The metabolic need for a nutrient exceeds what can be supplied by diet and results in impaired biochemical processes and functions.
  • A nutrient dependency results from long-term environmental and genetic stressors.

Digestive tract dysfunction in ASD

  • Digestive tract abnormalities are a common component of ASD. Studies have found gastroesophageal reflux, constipation, diarrhea, abdominal pain, vomiting, and malnutrition in over 90% of ASD patients (Tomova et al., 2015).
  • Chronic inflammatory bowel disease is highly prevalent in people with ASD, affecting both the small and large intestines (Jyonouchi, 2009).
  • Chronic enterocolitis (ileal lymphoid nodular hyperplasia) has been found in about 90% of autistic children (Gaby, 2011)
  • Problems with the digestive tract can lead to nutrient deficiencies, increased systemic inflammation, increased toxin generation in the digestive tract, leaky gut, food allergies, and autoimmune conditions.
  • Inflammatory cytokines are shown to be upregulated in the intestinal lining of ASD children with digestive tract symptoms (Jyonouchi, 2009).
  • Several studies of ASD children have reported chronic inflammation and oxidative stress in the central nervous system (Jyonouchi, 2009).
  • A study of children with autism found anti-brain IgG antibodies in 27% of the children versus only 2% of the controls. As well, IgM antibodies were found in 36% of autistic children versus zero percent of the controls (Newmark, 2012).

Dysbiosis and ASD

  • Dysbiosis is an imbalance of bacteria in the digestive tract, typically manifesting as decreased beneficial bacteria, combined with an increase in pathogenic bacteria.
  • Studies show the composition of digestive tract flora in ASD children is different from that of normal children (Finegold et al., 2002).
  • In a study of 80 children with ASD and digestive tract symptoms, 61% had growth of endotoxin-producing bacteria associated with ongoing bowel damage (Newmark, 2012).
  • When children with regressive autism were treated with the antibiotic vancomycin, they experienced short-term improvement in behavioural symptoms. The improvement was attributed to a decrease in neurotoxins generated by inappropriate bacteria (Sandler et al., 2000).

Leaky gut and ASD

  • The term leaky gut refers to a condition of increased intestinal permeability.
  • Increased permeability of the digestive tract allows inappropriate entry of food particles, bacterial toxins and other molecules into the bloodstream where they can directly access the brain.
  • Once in the bloodstream these particles can promote:
    • systemic inflammation
    • autoimmune activity
    • opioid-like responses in the brain
  • A study of 21 autistic children, without known intestinal issues, found increased intestinal permeability in 43% of autistic children verses none of the non-autistic children (D’Eufemia et al., 1996).
  • Another study of 25 autistic children, with digestive tract symptoms, found intestinal permeability in 76% of the children (Newmark, 2012).

Addressing digestive tract issues

Basic steps for addressing digestive tract issues:

  • Diet:
    • low sugar/starch
    • low dairy
    • identify and avoid food allergens
    • anti-inflammatory diet
  • Basic supplements for digestive tract healing:
    • vitamins A, C, D, and E
    • zinc
    • omega 3 fatty acids
    • L-glutamine
    • probiotics (to normalize gut bacteria)
    • bacteria/yeast killing (caution due to potential die-off symptoms)


D’Eufemia, P., Celli, M., Finocchiaro, R., Pacifico, L., Viozzi, L., Zaccagnini, M., Cardi, E., & Giardini, O. (1996). Abnormal intestinal permeability in children with autism. Acta Paediatrica (Oslo, Norway: 1992), 85(9), 1076–1079. https://doi.org/10.1111/j.1651-2227.1996.tb14220.x

Finegold, S. M., Molitoris, D., Song, Y., Liu, C., Vaisanen, M.-L., Bolte, E., McTeague, M., Sandler, R., Wexler, H., Marlowe, E. M., Collins, M. D., Lawson, P. A., Summanen, P., Baysallar, M., Tomzynski, T. J., Read, E., Johnson, E., Rolfe, R., Nasir, P., … Kaul, A. (2002). Gastrointestinal microflora studies in late-onset autism. Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America, 35(Suppl 1), S6–S16. https://doi.org/10.1086/341914

Gaby, A. R. (2011). Nutritional Medicine (VitalBook file).

Jyonouchi, H. (2009). Food allergy and autism spectrum disorders: Is there a link? Current Allergy and Asthma Reports, 9(3), 194–201. https://doi.org/10.1007/s11882-009-0029-y

Newmark, S. (2012). Autism Spectrum Disorder. In Integrative Medicine (Third). Elsiver.

Sandler, R. H., Finegold, S. M., Bolte, E. R., Buchanan, C. P., Maxwell, A. P., Väisänen, M.-L., Nelson, M. N., & Wexler, H. M. (2000). Short-Term Benefit From Oral Vancomycin Treatment of Regressive-Onset Autism. Journal of Child Neurology, 15(7), 429–435. https://doi.org/10.1177/088307380001500701

Tomova, A., Husarova, V., Lakatosova, S., Bakos, J., Vlkova, B., Babinska, K., & Ostatnikova, D. (2015). Gastrointestinal microbiota in children with autism in Slovakia. Physiology & Behavior, 138, 179–187. https://doi.org/10.1016/j.physbeh.2014.10.033

[BOX] Food allergies and sensitivities

Food allergies and sensitivities and mental health

  • Food sensitivities can cause imbalances in key brain chemicals and can cause anxiety, phobias, depression, irritability, mood swings (Pfeiffer 1987; Rippere & Phil, 1984).
  • “Adults and children suffering from food allergy show impaired quality of life and a higher level of stress and anxiety” (Teufel et al., 2007).
  • Food allergies and sensitivities that affect the brain can be referred to as “cerbral allergies”. Cerebral allergies encompass more than antibody-antigen reactions. Cerebral allergies are mediated by:
    1. direct biochemical effects of substances found in food or drink, for example caffeine, alcohol, and sugar
    2. hidden or delayed allergic reactions to food or drink, for example wheat, milk, corn, and egg

Foods commonly associated with allergies (Prousky, 2015):

  • dairy products
  • wheat, rye, barley
  • eggs
  • pork, beef, seafood
  • soy
  • corn
  • tomato
  • citrus fruits
  • nuts, peanuts
  • chocolate
  • coffee, tea
  • sugar
  • yeast

Food allergies and sensitivities and autism

  • Food sensitivities are considered to be a contributing factor to ASD.
  • Prevalence of food allergies in ASD children is shown to be about 14% versus about 3% in children without autism (Wang et al., 2021).
  • Adverse reactions to foods in ASD individuals can be both true allergic reactions and non-allergy mediated reactions. Non-allergy mediated allergens do not test positive on common allergy tests (Gaby, 2011). 
  • Food sensitivities in autistic children may be in part driven by leaky gut and chronic intestinal inflammation diseases.
  • A study of 36 autistic children showed significantly higher amounts of IgA, IgG, IgM, and antibodies for specific food proteins, compared to controls (Newmark, 2012).
  • The most common substances in ASD food sensitivities are gluten and casein, but other foods or other substances in certain foods (e.g. phenolics) can be involved as well (Gaby, 2011).


Gaby, A. R. (2011). Nutritional Medicine (VitalBook file).

Newmark, S. (2012). Autism Spectrum Disorder. In Integrative Medicine (Third). Elsiver.

Pfeiffer C. (1987) Nutrition and Mental Illness. Rochester, VT: Healing Arts Press.

Prousky J, (2015) Anxiety: Orthomolecular diagnosis and treatment, Kindle Edition. CCNM Press.

Rippere V & Phil M. (1984) Some varieties of food intolerance in psychiatric patients: An overview. Nutrition and Health. https://agris.fao.org/agris-search/search.do?recordID=US201301437620

Wang, L., Shen, W., Yao, H., Zheng, R., Chen, W., & Zhang, W. (2021). Association between Autism Spectrum Disorder and Food Allergy: A Systematic Review and Meta-analysis. Autism Research, 14(1), 220–230. https://doi.org/10.1002/aur.2454

Oxidative stress is the condition in the body where the protective capacity of antioxidant molecules is exceeded by reactive oxygen species (free radicals).

Oxidative stress is a result of (Moghadas et al, 2019):

  • excessive production of oxidants in the body
  • decreased levels of antioxidants in the body
  • a combination of both conditions

Oxidative stress and autism

Increased oxidative stress in the brain can result in:

  • damage to brain lipids and protein molecules
  • decreased availability of protective antioxidants (especially glutathione)
  • increased production of glutamate (which can contribute to autism symptoms)

Chronic oxidative stress has been repeatedly reported in children with ASD (Jyonouchi, 2009).

Documented markers of oxidative stress found in children with autism include (Newmark, 2012):

  • decreased protective:
    • endogenous antioxidant enzymes
    • glutathione
    • antioxidant nutrients
  • increased damaging:
    • organic toxins and heavy metals
    • xanthine oxidase (can generate reactive oxidants)
    • pro-inflammatory cytokines
    • nitric oxide production (toxic free radical)

Oxidative stress in autistic children can result in (Ramaekers et al., 2020):

  • DNA damage, which affects DNA function and gene expression
  • decreased production of serotonin (which is low in about a third of ASD children)


Jyonouchi, H. (2009). Food allergy and autism spectrum disorders: Is there a link? Current Allergy and Asthma Reports, 9(3), 194–201. https://doi.org/10.1007/s11882-009-0029-y

Karajibani, M., Montazerifar, F., & Khazaei Feizabad, A. (2017). Study of Oxidants and Antioxidants in Addicts. International Journal of High Risk Behaviors and Addiction, 6(2), Article 2. https://doi.org/10.5812/ijhrba.35057

Moghadas, M., Essa, M. M., Ba-Omar, T., Al-Shehi, A., Qoronfleh, M. W., Eltayeb, E. A., Guillemin, G. J., Manivasagam, T., Justin-Thenmozhi, A., Al-Bulushi, B. S., Al-Adawi, S., & Edalatmanesh, M. A. (2019). Antioxidant therapies in attention deficit hyperactivity disorder. Frontiers in Bioscience (Landmark Edition), 24, 313–333. https://doi.org/10.2741/4720

Newmark, S. (2012). Autism Spectrum Disorder. In Integrative Medicine (Third). Elsiver.

Ramaekers, V. T., Sequeira, J. M., DiDuca, M., Vrancken, G., Thomas, A., Philippe, C., Peters, M., Jadot, A., & Quadros, E. V. (2019). Improving Outcome in Infantile Autism with Folate Receptor Autoimmunity and Nutritional Derangements: A Self-Controlled Trial. Autism Research and Treatment. https://doi.org/10.1155/2019/7486431

Folate receptor autoantibodies

  • Folate is an important nutrient in the brain and deficiencies are associated with mental health problems, including ASD.
  • The main way folate is transported into the brain is through the folate receptor alpha (FRα) (Bobrowski-Khoury et al., 2021; Mitchell et al., 2014).
  • Autoantibodies to FRα inhibit folate transport function, which contributes to folate deficiency in the brain.
  • In pregnancy and young children, folate receptor antibodies can block transport of folate into the child’s brain, causing structural and functional abnormalities (Bobrowski-Khoury et al., 2021). Folate deficiency in the womb increases risk of neural tube defects and autism (Ramaekers et al., 2020).
  • Serum folate autoantibodies are frequently found in children with severe infantile autism (Ramaekers et al., 2020).
  • One study showed a prevalence of 76% FRα autoimmunity in children with autism. It also showed the presence of these antibodies in their unaffected siblings and parents – which indicates additional factors are required to initiate the manifestation of ASD (Bobrowski-Khoury et al., 2021).

Folinic acid and ASD

  • Folinic acid (Leucovorin) is a form of folate that does not require the folate receptor alpha to get into cells. 
  • Supplementation with high-dose folinic acid was shown to normalize 5-methyltetrahydrofolate concentration and improve autistic behaviours (Bobrowski-Khoury et al., 2021).
  • Approximately 70% of children with ASD or brain folate deficiency have low cerebral spinal fluid folate levels, and benefit from folinic acid treatment (Ramaekers et al., 2013).
  • A double-blind placebo-controlled trial of children with ASD who were positive for folate receptor alpha autoantibodies, showed improvements in verbal scores after treatment with folinic acid (Frye et al., 2018).
  • Is recommended to test of serum FRα autoantibodies at the earliest age possible once ASD has been diagnosed (Bobrowski-Khoury et al., 2021).

“Since about 90% of patients with cerebral folate deficiency have autoantibodies against the folate receptor, a clinical trial of folinic acid would seem appropriate for autistic children who exhibit the clinical syndrome of cerebral folate deficiency” (Gaby, 2011).


Bobrowski-Khoury, N., Ramaekers, V. T., Sequeira, J. M., & Quadros, E. V. (2021). Folate Receptor Alpha Autoantibodies in Autism Spectrum Disorders: Diagnosis, Treatment and Prevention. Journal of Personalized Medicine, 11(8), 710. https://doi.org/10.3390/jpm11080710

Frye, R. E., Slattery, J., Delhey, L., Furgerson, B., Strickland, T., Tippett, M., Sailey, A., Wynne, R., Rose, S., Melnyk, S., James, S. J., Sequeira, J. M., & Quadros, E. V. (2018). Folinic acid improves verbal communication in children with autism and language impairment: A randomized double-blind placebo-controlled trial. Molecular Psychiatry, 23(2), 247–247. https://doi.org/10.1038/mp.2016.168

Gaby, A. R. (2011). Nutritional Medicine (VitalBook file).

Mitchell, E. S., Conus, N., & Kaput, J. (2014). B vitamin polymorphisms and behavior: Evidence of associations with neurodevelopment, depression, schizophrenia, bipolar disorder and cognitive decline. Neuroscience & Biobehavioral Reviews, 47, 307–320. https://doi.org/10.1016/j.neubiorev.2014.08.006

Ramaekers, V., Sequeira, J. M., & Quadros, E. V. (2013). Clinical recognition and aspects of the cerebral folate deficiency syndromes. Clinical Chemistry and Laboratory Medicine, 51(3), 497–511. https://doi.org/10.1515/cclm-2012-0543

Abnormalities in the biochemical process of methylation are regarded as a contributing factor for the development and manifestation of ASD.

What is methylation?

  • Methylation is the process of adding a methyl group (one carbon and three hydrogen atoms) to a molecule.

The methylation cycle

The methylation cycle consists of three interconnected metabolic systems centred around methylating molecules – the folate cycle, the methionine cycle, and the transsulfuration pathway. These systems are mediated by a series of sequential enzyme reactions.

The main functions of the methylation cycle are:

  • gene regulation
  • DNA and RNA synthesis and maintenance
  • protein and lipid production
  • neurotransmitter production (serotonin, dopamine, norepinephrine)
  • nerve myelination
  • hormone regulation
  • immune cell production (T-cells and natural killer cells)
  • cellular energy production
  • glutathione production
  • detoxification
  • oxidative stress reduction
  • nitric oxide production
  • enzyme regulation

Methylation cycle dysfunction

Normal function of the methylation cycle is disrupted by two main factors:

  • deficiencies of nutrients required for the cycle
  • genetically mediated deficiencies in cycle enzyme function

Key nutrients involved in the methylation cycle include: vitamins B2, B6, B12, and folate, magnesium, and zinc. These nutrients are depleted by:

  • insufficient intake
  • environmental toxins and food additives
  • alcohol, tobacco smoke
  • medications
  • chronic infections
  • mental and emotional stress

Issues with the genes that write methylation cycle enzymes are attributed to:

  • genetic variations in DNA sequences (called single nucleotide polymorphisms (SNPs))
  • environmental influences on normal (non-SNP) genes (epigenetics)

Modifiable factors that affect methylation cycle gene expression, enzymes, and function are (Lynch, 2014; Wilson, 2015):

  • poor diet
  • nutrient deficiencies, especially the B-vitamins, vitamin C, copper, and zinc
  • leaky gut
  • food allergies and sensitivities
  • excess alcohol
  • food, household, and environmental toxins
  • metabolites from yeast die-off due to treatment
  • oxidative stress (excess free radicals)
  • elevated nitric oxide
  • autoimmune antibodies
  • inflammation
  • chronic infections
  • physical and mental stress
  • sleep issues
  • radiation

Common methylation cycle enzymes affected by SNPs

  • MTHFR – Methylene tetrahydrofolate reductase
    • converts folate into methylfolate (the active form of folate)
  • MTR – Methionine Synthase
    • converts homocysteine into methionine using methylfolate and methylcobalamin (vitamin B12)
  • CBS – cystathionine β synthase
    • converts homocysteine for creation of cysteine and glutathione

Methylation cycle abnormalities and autism

  • In many ASD children, the methylation cycle does not function properly, which results in increased susceptibility to chronic infections, poor detoxification of chemicals and toxic metals, and neurocognitive problems (Woeller, n.d.).
  • Polymorphisms in genes, such as MTHFR, MTR and CβS, are linked to psychiatric disorders (Mitchell et al., 2014).
  • Problems with folate metabolism can cause autism-associated physiological abnormalities in DNA synthesis, methylation, and oxidative stress management (Frye et al., 2020; Main et al., 2010).
  • For many children with ASD, the genetic issues with the methylation cycle do not manifest until a child is also impacted by nutritional deficiencies, digestive tract issues, bacteria, yeast, parasites, inflammation, chemicals and heavy metal toxins from vaccines or environmental exposures (Woeller, n.d.).

Effects of methylation cycle abnormalities include (Mitchell et al., 2014; Pasca et al., 2009; Woeller, n.d.):

  • poor direct gaze
  • history of self-injurious behavior
  • poor concentration or attention
  • decreased language development and processing
  • reduced environmental awareness
  • decreased sociability
  • complex body movements
  • overactivity

Benefits of addressing methylation cycle abnormalities include improvements in (Zou et al., 2019; Frye et al., 2020):

  • irritability
  • social withdrawal
  • stereotypy
  • hyperactivity and tantrums
  • inappropriate speech
  • affective expression and communication
  • verbal communication
  • non-verbal communication
  • attention
  • aggression

Addressing methylation cycle abnormalities

1. Dietary actions to consider:

  • consume a healthy diet with adequate protein
  • reduce or eliminate sugar and alcohol
  • avoid folic acid-fortified processed foods
  • avoid foods containing additives and pesticides
  • include foods that are rich in natural folate and antioxidants (See “Folate” on this page for food sources of folate).

2. Add basic supplements to support methylation

  • vitamin C, E (antioxidant support)
  • multivitamin and/or B-complex
  • magnesium
  • zinc

3. Ensure adequate good-quality sleep

4. Reduce stress (mental and physical)

5. Work with a health professional to incorporate needed methylation cycle enzyme cofactors based on symptoms or genetic testing.

Methylation cycle cofactors commonly used in the context of ASD include:

  • vitamins B2 and B6
  • methylfolate, folinic acid
  • methylcobalamin
  • SAMe
  • choline, dimethylglycine (DMG) or trimethylglycine (TMG)
  • nutritional lithium


8 Steps to Support Your Methylation Cycle and Address SNPs

Understanding the Methylation Cycle and Its Effect on Health

Understanding the Methylation Cycle

Vitamins and Supplements | Interactive Autism Network


Frye, R. E., Slattery, J., Delhey, L., Furgerson, B., Strickland, T., Tippett, M., Sailey, A., Wynne, R., Rose, S., Melnyk, S., James, S. J., Sequeira, J. M., & Quadros, E. V. (2018). Folinic acid improves verbal communication in children with autism and language impairment: A randomized double-blind placebo-controlled trial. Molecular Psychiatry, 23(2), 247–247. https://doi.org/10.1038/mp.2016.168

Lynch, B. (2018). Dirty Genes: A Breakthrough Program to Treat the Root Cause of Illness and Optimize Your Health (1st edition). HarperOne.

Main, P. A., Angley, M. T., Thomas, P., ODoherty, C. E., & Fenech, M. (2010). Folate and methionine metabolism in autism: A systematic review. The American Journal of Clinical Nutrition, 91(6), 1598–1620. https://doi.org/10.3945/ajcn.2009.29002

Mitchell, E. S., Conus, N., & Kaput, J. (2014). B vitamin polymorphisms and behavior: Evidence of associations with neurodevelopment, depression, schizophrenia, bipolar disorder and cognitive decline. Neuroscience & Biobehavioral Reviews, 47, 307–320. https://doi.org/10.1016/j.neubiorev.2014.08.006

Paşca, S. P., Dronca, E., Kaucsár, T., Crǎciun, E. C., Endreffy, E., Ferencz, B. K., Iftene, F., Benga, I., Cornean, R., Banerjee, R., & Dronca, M. (2009). One carbon metabolism disturbances and the C677T MTHFR gene polymorphism in children with autism spectrum disorders. Journal of Cellular and Molecular Medicine, 13(10), 4229–4238. https://doi.org/10.1111/j.1582-4934.2008.00463.x

Wilson, D. (2015, April 2). 8 Steps to Support Your Methylation Cycle and Address SNPs. Doctor Doni. https://doctordoni.com/2015/04/8-steps-to-support-your-methylation-cycle/

Woeller, K. N. (n.d.). Understanding the Methylation Cycle. Autism Recovery System. https://autismrecoverysystem.com/wp-content/uploads/2017/05/Understanding-the-Methylation-Cycle-1.pdf

Zou, M., Sun, C., Liang, S., Sun, Y., Li, D., Li, L., Fan, L., Wu, L., & Xia, W. (2019). Fisher discriminant analysis for classification of autism spectrum disorders based on folate-related metabolism markers. The Journal of Nutritional Biochemistry, 64, 25–31. https://doi.org/10.1016/j.jnutbio.2018.09.023


  • Pyrroles are a by-product of hemoglobin production and are normally excreted in the urine.
  • Pyroluria is a condition of overproduction of pyrroles (McGinnis 2008a, 2008b). 
  • Excess pyrroles bind vitamin B6 (pyridoxine) and zinc, removing them from the bloodstream.

Signs of high amounts of kryptopyrrole are most prevalent in adolescents and children and include:

  • white areas in their fingernails
  • fragile nails
  • pain in the joints, often the knees
  • lack of pigment in the skin
  • skin infections and acne
  • sometimes morning nausea
  • poor dream recall
  • insomnia
  • psychiatric symptoms

Pyroluria and mental health

Pyroluria is considered by many in the complementary medicine and health field, to be a contributing factor for ASD, and a condition that is common in people with ASD.

The mental symptoms of pyroluria are largely related to zinc and vitamin B6 deficiencies.

Mental symptoms of these deficiencies include:

  • anxiety and depression
  • mood swings
  • poor stress control
  • severe inner tension
  • episodic anger
  • nervousness
  • poor short-term memory

Addressing pyroluria

  • Pyroluria can be objectively diagnosed by elevated levels of HPL (Hydroxyhemopyrrolin-2-one) when measured by the kryptopyrrole quantitative urine test.
  • The amount of kryptopyrrole can fluctuate dramatically. Stress, illness, and injury increase levels.
  • For optimal test results, the urine should be collected during a period of increased stress.

Supplementation support for addressing pyroluria (Greenblatt, 2018):

  • 200-800 mg of vitamin B6 in the pyridoxal-5-phosphate form
  • 25–100 mg of zinc

Dr. Jonathan Prousky (2006) stated, “Although I could test for this compound [HPL], I choose not to, since these nutrients are inexpensive and have minimal side effects. The daily dosages I routinely start with are 250 mg of pyridoxine and 50 mg of zinc”.


McGinnis WR, Audhya T, Walsh WJ, Jackson JA, McLaren-Howard J, Lewis A & Ho er A. (2008a) Discerning the mauve factor, Part 1. Alternative Therapies in Health and Medicine, 14(2), 40–50.

McGinnis WR, Audhya T, Walsh WJ, Jackson JA, McLaren-Howard J, Lewis A & Ho er A. (2008b) Discerning the mauve factor, Part 2. Alternative Therapies in Health and Medicine, 14(3), 56–62.

Prousky J. (2006) The orthomolecular treatment of schizophrenia. Naturopathic Doctor News and Review. https://ndnr.com/neurology/the-orthomolecular-treatment-of-schizophrenia/

Greenblatt J. (2018, May 24) Integrative therapies for schizophrenia and psychosis, Module 1 [Webinar]. Retrieved from: https://isom.ca/schizophrenia-psychosis/

Orthomolecular interventions for autism

Orthomolecular interventions are substances like vitamins and minerals that have roles in promoting or addressing autism, depending on the amount present inthe body.

Specialized diets

[BOX] Gluten-free casein-free diet

The gluten-free casein-free (GFCF) diet

  • The GFCF diet is one of the most popular elimination diets used in ASD, with frequent reports by parents of beneficial effects (Jyonouchi, 2009).
  • The GFCF diet eliminates all grains, dairy, and products that contain them, in order avoid the protein molecules gluten and casein.
  • Rationale for the  diet is based on the theory that grains and dairy products cause digestive tract disturbances which lead to digestive-tract inflammation and leaky gut. In this context the improperly digested gluten and casein molecules enter the bloodstream, where they access the brain, promoting ASD neurological manifestations (Newmark, 2012).
  • A 1-year study of the GFCF diet in ASD showed significantly higher development in the diet children versus the controls (Knivsberg et al., 2002).

Gluten, casein, and immune response

  • In a study of 149 children diagnosed with ASD, 87% of the children showed higher antibodies to gliadin (a metabolite of gluten), and 30% showed high concentrations of antibodies to gluten or casein. After following a GFCF diet for three months improvement in symptoms was seen in 81% of the children (Elder et al., 2006).
  • Researchers have found higher proinflammatory cytokines in ASD children compared to non-autistic children with known food allergies, after consumption of gluten, casein, and soy (Pennesi & Klein, 2012).

The gluten-free casein-free diet and autism

Reported effects from GFCF diet can be categorized into the following areas of improvement (Whiteley et al., 2013):

  • communication and use of language
  • attention and concentration
  • social integration and interaction
  • self-injurious behaviour/altered pain perception
  • repetitive or stereotyped patterns of behaviour
  • motor co-ordination
  • hyperactivity

Observed benefits of the GFCF diet include (Pennesi & Klein, 2012):

  • resolution of digestive tract symptoms
  • improvements in speech and communication skills
  • decreased hyperactive behaviour
  • improved ability to focus
  • reduced sleep issues

GFCF diet: foods to include and eliminate

Gluten-containing foods:

  • all grains and products made from them
  • processed foods containing gluten (often undisclosed)

Gluten-free foods:

  • fresh fruit and vegetables
  • unprocessed meat, poultry, and seafood
  • eggs
  • legumes and beans
  • nuts and seeds
  • oils
  • herbs and spices

Casein-containing foods:

  • all dairy foods
  • products made from dairy or containing dairy
  • processed food ingredients that contain casein

No evidence of nutritional deficiencies was found in a study of autistic children on the GFCF diet versus those not on the diet  (Jyonouchi, 2009).

It is, however, important to ensure children on any restricted diets due to food sensitivities, have adequate intake of protein and other essential nutrients (Gaby, 2011).

Recommendations for implementing the GFCF diet

  • Gradually decrease existing consumption levels of gluten and dairy foods to decrease risk of withdrawal symptoms (Loo, 2009). 
  • Allow at least 60 days on the diet to fully evaluate efficacy. Some practitioners recommend longer.
  • It is advisable to eliminate artificial colours and flavours along with gluten and dairy (Newmark, 2012).
  • A good strategy is to not make other changes when first implementing the GFCF diet, so that effects can be clearly attributed to the diet and not to other factors.

Resources for implementing the GFCF diet

GFCF Diet for Autism – Casein & Gluten Free Diet and Autism

Gluten-Free Casein-Free Diet


Elder, J. (2008). Invited Review: The Gluten-Free, Casein-Free Diet in Autism: An Overview With Clinical Implications. Nutrition in Clinical Practice, 23(6), 583–588. https://doi.org/10.1177/0884533608326061

Gaby, A. R. (2011). Nutritional Medicine (VitalBook file).

Jyonouchi, H. (2009). Food allergy and autism spectrum disorders: Is there a link? Current Allergy and Asthma Reports, 9(3), 194–201. https://doi.org/10.1007/s11882-009-0029-y

Knivsberg, A. M., Reichelt, K. L., HØien, T., & NØdland, M. (2002). A Randomised, Controlled Study of Dietary Intervention in Autistic Syndromes. Nutritional Neuroscience, 5(4), 251–261. https://doi.org/10.1080/10284150290028945

Kushner, K. (n.d.). Gluten-Free Casein-Free Diet. Mindd. Retrieved January 19, 2022, from https://mindd.org/diet/gluten-free-casein-free-diet/

Loo, M. (2009). CHAPTER 14—Autism. In M. Loo (Ed.), Integrative Medicine for Children (pp. 193–206). W.B. Saunders. https://doi.org/10.1016/B978-141602299-2.10014-3

Newmark, S. (2012). Autism Spectrum Disorder. In Integrative Medicine (Third). Elsiver.

Pennesi, C. M., & Klein, L. C. (2012). Effectiveness of the gluten-free, casein-free diet for children diagnosed with autism spectrum disorder: Based on parental report. Nutritional Neuroscience, 15(2), 85–91. https://doi.org/10.1179/1476830512Y.0000000003

Whiteley, P., Shattock, P., Knivsberg, A.-M., Seim, A., Reichelt, K., Todd, L., Carr, K., & Hooper, M. (2013). Gluten- and casein-free dietary intervention for autism spectrum conditions. Frontiers in Human Neuroscience, 6, 344. https://doi.org/10.3389/fnhum.2012.00344


Folate is a water-soluble vitamin. “Folate” is the form that is naturally occurring in foods. Since folate is unstable, the synthetic form “folic acid” is often used in supplements and food fortification.

Folate has important roles in maintaining mental health, including: 

  • biosynthesis of neurotransmitters
  • amino acid metabolism
  • myelination of neurons
  • DNA replication
  • regulation of gene expression
  • cell division
  • reduction of homocysteine

Causes of folate deficiencies

  • low dietary intake
  • poor absorption
  • gastrointestinal issues
  • chronic alcoholism
  • smoking
  • oral contraceptives (Gaby, 2011)
  • drug interactions (Folate, 2014)
  • genetic variations in folate metabolism, for example variations the MTHFR gene (Folate, 2014)

MTHFR polymorphisms and brain folate levels

  • The methylenetetrahydrofolate reductase (MTHFR) enzyme converts folate to 5-MTHF (methylfolate), the most bioavailable form of folate. Methylfolate is the form of folate that crosses the blood-brain barrier.
  • Polymorphisms in the genes that make the MTHFR enzyme result in decreased function of the enzymes and reduced conversion of folate to methylfolate.
  • Negative effects of the MTHFR polymorphism can, to a degree, be compensated for by supplementing methylated folate.

Some symptoms of cerebral folate deficiency include (Gaby, 2011):

  • marked irritability
  • slow head growth
  • psychomotor retardation
  • movement disorders
  • seizures
  • autism

Top food sources of folate by serving size:

  • lentils
  • chickpeas
  • asparagus
  • spinach
  • lima beans

Comprehensive food list:

Table 2. Some Food Sources of folate and folic acid (Folate, 2014)


Referenced Dietary Intakes

RDAs for folate (mcg/day)
Adolescents (14-18 years): 400 (M) 400 (F)
Adults (19-50 years): 400 (M) 400 (F)
Adults (51 years and older): 400 (M) 400 (F)

Tolerable Upper Intake:
Not establish due to low potential for toxicity.

The Food and Nutrition Board of the US Institute of Medicine recommends a maximum intake of 1000 mcg of the folic acid form of folate – from supplements and fortified food.

Folic acid supplementation

It has been suggested that supplementation with folic acid (synthetic form of folate) should be avoided in favour of folate, as folic acid impairs methylation by binding to and blocking receptors required for natural folate (Lynch, 2018).

Supplementing folate

Amounts of folate/folic acid used in practice and research range from 100–5000 mcg/day in divided doses (Office of Dietary Supplements, n.d.).

A good quality multivitamin/mineral supplement typically contains 400 mcg of folate.

If methylation abnormalities are suspected, consider supplementing methylfolate either on its own, or as part of a B-complex formula


  • Folate supplementation may mask an underlying vitamin B12 deficiency.
  • In order to be very sure of preventing irreversible neurological damage in vitamin B12-deficient individuals, the Food and Nutrition Board of the US Institute of Medicine advises that all adults limit their intake of folic acid (supplements and fortification) to 1000 μg (1 mg) daily (Folate, 2014).


Folate. (2014, April 22). Linus Pauling Institute. https://lpi.oregonstate.edu/mic/vitamins/folate

Gaby, A. R. (2011). Nutritional Medicine. Alan R. Gaby, VitalBook file.

Office of Dietary Supplements—Folate. (n.d.). Retrieved October 28, 2020, from https://ods.od.nih.gov/factsheets/Folate-HealthProfessional/

Vitamin B6 is required for:

  • The conversion of the amino acid tryptophan into serotonin and tyrosine to dopamine
  • The conversion of glutamate into GABA – improper glutamate metabolism is implicated in mental health symptoms including psychosis and schizophrenia (Kraal et al., 2020).
  • Reduction of homocysteine – elevated homocysteine has been implicated in mental health conditions
  • Synthesis of glutathione and metallothionein – molecules important for detoxification of toxic metals

Vitamin B6 and autism

Children with autism may require higher intake of vitamin B6 due to poor conversion of vitamin B6 to its active form – pyridoxal-5-phosphate (Newmark, 2012).

Vitamin B6, in doses between 100 and 600 mg per day, was shown to significantly improve behaviour in 12 of 16 autistic children (Pfeiffer & Norton, 1995).

Vitamin B6 has been found in several studies to be beneficial for patients with ASD. Vitamin B6 supplementation, alone, or with magnesium has shown improvements in (Gaby, 2011):

  • alertness
  • communication
  • social interactions
  • Intelligence Quotient (IQ)
  • emotional outbursts
  • self-injurious behaviour

Causes of vitamin B6 deficiencies

  • inadequate dietary intake
  • medications, including anti-tuberculosis drugs, antiparkinsonians, nonsteroidal anti-inflammatory drugs, and oral contraceptives, may interfere with vitamin B6 metabolism. (Vitamin B6, 2014)
  • alcoholism – due to low intake and impaired metabolism of vitamin B6

Deficiency of vitamin B6 can be identified by:

  • the absence of dreams, or the inability to remember dreams
  • having disturbing dreams or nightmares

Top sources of vitamin B6 based on serving size

  • salmon
  • potato
  • turkey
  • avocado

Comprehensive food list:

Table 2. Some Food Sources of vitamin B6 (Vitamin B6, 2014)


Referenced Dietary Intakes

RDAs for vitamin B6 (mg/day)
Adolescents (14-18 years): 1.3 (M) 1.2 (F)
Adults (19-50 years): 1.3 (M) 1.3 (F)
Adults (51 years and older): 1.7 (M) 1.5 (F)

Tolerable Upper Intake: 100 mg/day (Office of Dietary Supplements, 2020)

Vitamin B6 Supplementation

  • Amounts of vitamin B6 used in practice and research range from 20–6000 mg/day in divided doses (Office of Dietary Supplements, 2020).


  • Doses above 100 mg/day may, in some people, cause side effects that include nausea, vomiting, stomach pain, diarrhea, headache, tingling, and sleepiness. The risk of negative effects can be reduced by supplementing  magnesium 6.6–8.8 mg /kg as well as a B-complex vitamin (Prousky, 2015).
  • Monitoring for symptoms of sensory neuropathy should be considered with long-term supplementation of more than 200 mg/day of vitamin B6 (Gaby, 2011).


  • High doses of vitamin B6 have been found to decrease the efficacy of phenobarbital, phenytoin, and L-Dopa (Vitamin B6, 2014).


Gaby, A. R. (2011). Nutritional Medicine (VitalBook file).

Kraal, A. Z., Arvanitis, N. R., Jaeger, A. P., & Ellingrod, V. L. (2020). Could Dietary Glutamate Play a Role in Psychiatric Distress? Neuropsychobiology, 79(1–2), 13–19. https://doi.org/10.1159/000496294

Newmark, S. (2012). Autism Spectrum Disorder. In Integrative Medicine (Third). Elsiver.

Office of Dietary Supplements—Vitamin B6. (n.d.). Retrieved October 28, 2020, from https://ods.od.nih.gov/factsheets/VitaminB6-HealthProfessional/

Pfeiffer, S., & Norton, J. (1995). Efficacy of Vitamin B6 and Magnesium in the Treatment of Autism: A Methodology Review and Summary of Outcomes. Journal of Autism & Developmental Disorders, 25(5), 481–493. https://search.ebscohost.com/login.aspx?direct=true&db=c8h&AN=106100549&site=ehost-live

Prousky J, (2015) Anxiety: Orthomolecular diagnosis and treatment, Kindle Edition. CCNM Press.

Vitamin B6. (2014, April 22). Linus Pauling Institute. https://lpi.oregonstate.edu/mic/vitamins/vitamin-B6

[BOX] Vitamin B6 and magnesium supplementation

Vitamin B6 and magnesium in ASD

  • Both vitamin B6 and magnesium are considered to be beneficial in the context of ASD. However, these nutrients have been shown to be more effective when given together than when either nutrient was given separately (Gaby, 2011; Garreau et al., n.d.).
  • The mechanism of action for the combined nutrients is thought to be by regulating the metabolism of dopamine (Martineau et al., 1988).
  • In a study of vitamin B6 and magnesium, thirty-three children with autism or pervasive developmental disorder were given 0.6 mg/kg/day of vitamin B6 and 6 mg/kg/day of magnesium for an average of 8 months. Significant improvements were seen in communication, stereotyped restricted behaviour, and abnormal or delayed functioning. Within a few weeks of stopping supplementation, the symptoms returned indicating the observed benefits were from the supplementation (Mousain-Bosc et al., 2006).
  • Urinary homovanillic acid (H.V.A) is a marker of disturbed metabolism of the neurotransmitter dopamine. In another study of 52 autistic children, H.V.A. levels were normalized by supplementation of both vitamin B6 and magnesium, but not when the nutrients were given separately (Garreau et al., n.d.).

See the Vitamin B6 and Magnesium sections for more information on these nutrients.


Gaby, A. R. (2011). Nutritional Medicine (VitalBook file).

Garreau, B., Leddet, I., Ernouf, D., Muh, P., & Lelord, G. (n.d.). Behavioral and biological effects of oral magnesium, vitamin B6 and combined magnesium -vitamin B6 administration in autistic children*)**). 4.

Martineau, J., Barthelemy, C., Cheliakine, C., & Lelord, G. (1988). Brief report: An open middle-term study of combined vitamin B6-magnesium in a subgroup of autistic children selected on their sensitivity to this treatment. Journal of Autism and Developmental Disorders, 18(3), 435–447. https://doi.org/10.1007/BF02212198

Mousain-Bosc, M., Roche, M., Polge, A., Pradal-Prat, D., Rapin, J., & Bali, J. P. (2006). Improvement of neurobehavioral disorders in children supplemented with magnesium-vitamin B6. II. Pervasive developmental disorder-autism. Magnesium Research, 19(1), 53–62.

Vitamin B12 and mental health

A deficiency of vitamin B12 can affect mood, emotions, sleep, and can result in psychiatric disorders. (Valizadeh & Valizadeh, 2011).

Roles of vitamin B12 in the brain

  • Required for the synthesis of neurotransmitters including serotonin and dopamine
  • Required for preservation of the protective myelin sheath around neurons
  • Important for homocysteine metabolism

Psychiatric manifestations of vitamin B12 deficiency include (Oh & Brown, 2003; Dommisse, 1991):

  • agitation, restlessness, irritability
  • dementia
  • depression, fatigue
  • mild memory impairment
  • negativism
  • panic/phobic disorders
  • personality changes
  • psychosis

Vitamin B12 and autism

Vitamin B12 supplementation is considered an effective first-line treatment for autism (Jory, 2011).

Vitamin B12 deficiency

  • 40% of Americans have low levels of vitamin B12, and 20% of elderly people have severe vitamin B12 deficiencies. This is due to a decreased ability to absorb B12 with older age (Wolters et al., 2004) (Andrès et al., 2004) (Greenblatt & Brogan, 2016).
  • Vitamin B12 levels can be normal in blood tests but be deficient in the cerebral spinal fluid. (Prousky, 2015).

Vitamin B12 and Vegetarians

When comparing omnivores and vegetarians, it was found that vegetarians had (Kapoor et al., 2017):

  • significantly lower serum B12 levels
  • significantly higher methylmalonic acid (MMA) levels

The most common causes of vitamin B12 deficiency:

  • vitamin B12-deficient diet
  • vegetarianism or veganism
  • decreased stomach acid production
  • bacterial overgrowth in the small intestine

Top food sources of vitamin B12 by serving size:

  • clams, mussels
  • mackerel
  • crab
  • beef

Comprehensive food list:

Table 2. Some Food Sources of vitamin B12 (Vitamin B12, 2014)


Referenced Dietary Intakes

RDAs for vitamin B12 (mcg/day)

Adolescents (14-18 years): 2.4 (M) 2.4 (F)

Adults (19-50 years): 2.4 (M) 2.4 (F)

Adults (51 years and older): 2.4 (M) 2.4 (F)

Tolerable Upper Intake

Not established due to low potential for toxicity.

1. Vitamin B12 Supplementation

  • Amounts of vitamin B12 used in practice and research range from 1000–5000 IU/day in divided doses.
  • The preferred form of vitamin B12 is methylcobalamin, due to its greater tissue retention (“Methylcobalamin”, 1998).
  • Vitamin B12 is best absorbed in sublingual form.
  • “Those strict vegetarians who eat no animal products (vegans) need supplemental vitamin B12 to meet their requirements” (Vitamin B12, 2014).
  • Vitamin B12 supplementation may have the best clinical response when used in the context of anxiety and fatigue or depression (Prousky, 2015).

2. Vitamin B12 injections

  • A typical injection regimen is 1000 mcg every 2 weeks.
  • Patients who respond to vitamin B12 injections typically need ongoing injections to maintain symptom improvement (Gaby, 2011).
  • Many anxiety patients benefit from B12 injections even though they have no clinical evidence of deficiency (Prousky, 2015).
  • Daily 5 mg B12 injections for two weeks in men and women with normal serum B12 were found to improve appetite, mood, energy, and sleep to the 4-week follow-up (Ellis & Nasser, 1973).
  • “Methyl vitamin B12 injections, given every 3 days … elicit the most positive responses from parents. Some families have stated that methyl vitamin B12 was the most clearly effective of the entire range of biomedical interventions [in the context of autism]” (Newmark, 2012).


  • The Institute of Medicine states that “no adverse effects have been associated with excess vitamin B12 intake from food and supplements in healthy individuals” (Vitamin B12, 2014).


Andrès, E., Loukili, N. H., Noel, E., Kaltenbach, G., Abdelgheni, M. B., Perrin, A. E., Noblet-Dick, M., Maloisel, F., Schlienger, J.-L., & Blicklé, J.-F. (2004). Vitamin B12 (cobalamin) deficiency in elderly patients. CMAJ: Canadian Medical Association Journal = Journal de l’Association Medicale Canadienne, 171(3), 251–259. https://doi.org/10.1503/cmaj.1031155

Dommisse, J. (1991). Subtle vitamin-B12 deficiency and psychiatry: A largely unnoticed but devastating relationship? Medical Hypotheses, 34(2), 131–140. https://doi.org/10.1016/0306-9877(91)90181-w

Ellis, F. R., & Nasser, S. (1973). A pilot study of vitamin B12 in the treatment of tiredness. British Journal of Nutrition, 30(2), 277–283. https://doi.org/10.1079/BJN19730033

Gaby, A. R. (2011). Nutritional Medicine (VitalBook file).

Greenblatt, J. M., & Brogan, K. (Eds.). (2016). Integrative Therapies for Depression: Redefining Models for Assessment, Treatment and Prevention (1st edition). CRC Press.

Jory, J. (2011, April 30). Autism: An Evidence Base for Orthomolecular Intervention. Orthomolecular Medicine Today Conference, Toronto Canada.

Kapoor, A., Baig, M., Tunio, S. A., Memon, A. S., & Karmani, H. (2017). Neuropsychiatric and neurological problems among Vitamin B12 deficient young vegetarians. Neurosciences (Riyadh, Saudi Arabia), 22(3), 228–232. https://doi.org/10.17712/nsj.2017.3.20160445

Methylcobalamin. (1998). Alternative Medicine Review: A Journal of Clinical Therapeutic, 3(6), 461–463.

Oh, R., & Brown, D. L. (2003). Vitamin B12 deficiency. American Family Physician, 67(5), 979–986.

Prousky, J. (2015). Anxiety: Orthomolecular diagnosis and treatment (Kindle). CCNM Press.

Valizadeh, M., & Valizadeh, N. (2011). Obsessive Compulsive Disorder as Early Manifestation of B12 Deficiency. Indian Journal of Psychological Medicine, 33(2), 203–204. https://doi.org/10.4103/0253-7176.92051

Vitamin B12. (2014, April 22). Linus Pauling Institute. https://lpi.oregonstate.edu/mic/vitamins/vitamin-B12

Wolters, M., Ströhle, A., & Hahn, A. (2004). Cobalamin: A critical vitamin in the elderly. Preventive Medicine, 39(6), 1256–1266. https://doi.org/10.1016/j.ypmed.2004.04.047

Vitamin C is required for the synthesis of many compounds important for good mental health. Some of these are:

  • tyrosine
  • thyroxine
  • norepinephrine
  • epinephrine
  • serotonin
  • carnitine
  • corticosteroids.

Vitamin C has been shown in research to (Meister, 1994):

  • reduce psychological stress
  • decrease blood pressure
  • lower cortisol levels

Functions of vitamin C in the brain (Smythies, 1996):

  • Prevents oxidation of dopamine into toxic derivatives (Baez, Segura-Aguilar, Widerslen, Johansson, & Mannervik, 1997)
  • Protects NMDA receptors from glutamate toxicity
  • Counteracts the effects of amphetamines
  • Enhances the effects of older antipsychotic medications like haloperidol

Vitamin C and mental health

  • 3 g/day of vitamin C supplementation in healthy volunteers significantly decreased monoamine oxidase activity (MAO). MAO is responsible for metabolizing serotonin, norepinephrine, and dopamine (Gaby, 2011).

Vitamin C and Autism

  • Some mechanisms of action for vitamin C in the context of autism include:
    • antioxidant protection
    • inflammation reduction
    • antimicrobial action
    • regulation of dopamine
  • A 30-week, double-blind, placebo-controlled trial of adjunctive vitamin C (8 g/70 kg), resulted in reduction of autism symptom severity (Dolske et al., 1993).

Causes of vitamin C deficiency

  • restrictive diets
  • diet lacking in sources of vitamin C, especially fresh fruit and vegetables
  • digestive tract disorders, e.g. diarrhea, Crohn’s and colitis
  • smoking
  • alcoholism
  • chronic inflammatory conditions

Signs of vitamin C deficiency

  • bleeding or swollen gums
  • frequent nosebleeds
  • dry hair, split ends
  • easy bruising
  • slow wound healing
  • fatigue
  • moodiness
  • depression and cognitive impairment (Plevin & Galletly, 2020)

Top sources of vitamin C based on serving size

  • grapefruit and orange juice
  • strawberries
  • kiwifruit
  • orange
  • sweet pepper
  • broccoli

Comprehensive food list:

Table 3. Some Food Sources of vitamin C (Vitamin C, 2014)


Referenced Dietary Intakes

RDAs for vitamin C (mg/day)

Adolescents (14-18 years): 75 (M) 65 (F)

Adults (19-50 years): 90 (M) 75 (F)

Smokers: 125 (M) 110 (F)

Tolerable Upper Intake: 2000 mg /day

(Office of Dietary Supplements – Vitamin C, n.d.)

Vitamin C supplementation

  • Amounts of vitamin C used in practice and research range from 500–6000 mg/day in divided doses.


  • Vitamin C has low toxicity and is not believed to cause serious adverse effects at high intakes (Office of Dietary Supplements – Vitamin C, n.d.).
  • Vitamin C at higher doses can, in some people, cause side effects such as nausea, abdominal cramps, and other digestive tract disturbances

Vitamin C and medications

  • Vitamin C has been shown beneficial and safe when used in conjunction with depression medications.


Baez, S., Segura-Aguilar, J., Widersten, M., Johansson, A. S., & Mannervik, B. (1997). Glutathione transferases catalyse the detoxication of oxidized metabolites (o-quinones) of catecholamines and may serve as an antioxidant system preventing degenerative cellular processes. Biochemical Journal, 324(Pt 1), 25–28.

Dolske, M. C., Spollen, J., McKay, S., Lancashire, E., & Tolbert, L. (1993). A preliminary trial of ascorbic acid as supplemental therapy for autism. Progress in Neuro-Psychopharmacology & Biological Psychiatry, 17(5), 765–774. https://doi.org/10.1016/0278-5846(93)90058-z

Gaby, A. R. (2011). Nutritional Medicine (VitalBook file).

Meister, A. (1994). Glutathione, ascorbate, and cellular protection. Cancer Research, 54(7 Supplement), 1969s–1975s

Office of Dietary Supplements—Vitamin C. (n.d.). Retrieved December 4, 2020, from https://ods.od.nih.gov/factsheets/VitaminC-HealthProfessional/

Plevin, D., & Galletly, C. (2020). The neuropsychiatric effects of vitamin C deficiency: A systematic review. BMC Psychiatry, 20(1), 315. https://doi.org/10.1186/s12888-020-02730-w

Smythies, J. (1996). Oxidative reactions and schizophrenia: A review-discussion. Schizophrenia Research, 24(3), 357–364. https://www.academia.edu/24021570/Oxidative_reactions_and_schizophrenia_A_review_discussion

Vitamin C. (2014, April 22). Linus Pauling Institute. https://lpi.oregonstate.edu/mic/vitamins/vitamin-C

Magnesium and mental health

Magnesium in the context of mental health (Kirkland, Sarlo, & Holton, 2018):

  • calms neurotransmission by regulating glutamate and GABA
  • modulates the HPA axis
  • has roles in the synthesis of serotonin and dopamine
  • regulates cortisol levels
  • increases Brain-derived neurotrophic factor (BDNF)
  • is required for enzyme systems that use thiamine (vitamin B1) and pyridoxine (vitamin B6) – these vitamins are cofactors in the production of serotonin, GABA, and melatonin (Kanofsky, & Sandyk, 1991)
  • decreases activation of the NMDA receptor which in turn, decreases excitatory neurotransmission (Bartlik, Bijlani, & Music, 2014)

Causes of magnesium deficiencies include:

  • loss of soil magnesium due to farming practices
  • following the standard American diet pattern, as it is high in processed and nutrient-deficient foods,
  • decreased magnesium levels in foods, especially cereal grains (Guo, Nazim, Liang, & Yang, 2016)
  • low dietary protein (needed for magnesium absorption)
  • gastrointestinal disorders (e.g. Crohn’s disease, malabsorption syndromes, and prolonged diarrhea)
  • stress, which causes magnesium to be lost through urine (Deans, 2011),
  • chronically elevated cortisol, which depletes magnesium (Cuciureanu, & Vink, 2011).
  • high doses of supplemental zinc (competes for absorption)
  • alcoholism
  • certain diuretic medications
  • Elderly adults tend to have lower dietary intake, absorption, and increased loss of magnesium.

Top sources of magnesium based on serving size

  • Brazil nuts
  • oat bran
  • brown rice (whole grain)
  • mackerel

Comprehensive food list:

Table 2. Some Food Sources of Magnesium (Magnesium, 2014)


Referenced Dietary Intakes

RDAs for magnesium (mg/day)

Adolescents (14-18 years): 410 (M) 360 (F)

Adults (19-30 years): 400 (M) 310 (F)

Adults (31 years and older): 420 (M) 320 (F)

Supplementing magnesium

  • Amounts of magnesium used in practice and research range from 100–750 mg a day in divided doses (elemental magnesium dose).
  • Correction of magnesium deficiency with magnesium supplementation has resulted in significant improvement in psychiatric symptoms (Kanofsky & Sandyk, 1991).

Magnesium supplementation – beneficial forms and dosing (Greenblatt, 2018)

  • Magnesium glycinate supplementation of 120-240 mg per meal and at bedtime has been shown to benefit mood
  • Magnesium glycinate or citrate supplementation of 240-360 mg before bed supports sleep onset and sleeping through the night
  • Some beneficial forms of magnesium include magnesium aspartate, magnesium glycinate, magnesium threonate
  • The magnesium oxide form is less beneficial


  • Side effects of magnesium supplementation are rare, but can include a laxative effect, dizziness or faintness, sluggishness, cognitive impairment, and depression.
  • An effective strategy for dosing magnesium is to gradually increase the amount to bowel tolerance, then reduce slightly.
  • Magnesium is best taken in divided doses throughout the day. Caution is required for high doses of magnesium with existing kidney disease.


Bartlik, B., Bijlani, V., & Music, D. (2014, July 22). Magnesium: An Essential Supplement for Psychiatric Patients—Psychiatry Advisor. Psychiatry Advisor. https://www.psychiatryadvisor.com/home/therapies/magnesium-an-essential-supplement-for-psychiatric-patients/

Cuciureanu, M. D., & Vink, R. (2011). Magnesium and stress. In R. Vink & M. Nechifor (Eds.), Magnesium in the Central Nervous System. University of Adelaide Press. http://www.ncbi.nlm.nih.gov/books/NBK507250/

Deans, E. (2011, June 12). Magnesium and the Brain: The Original Chill Pill. Psychology Today. http://www.psychologytoday.com/blog/evolutionary-psychiatry/201106/magnesium-and-the-brain-the-original-chill-pill

Greenblatt, J. (2018). Orthomolecular Apllications in Integrative Psychiatry, Depression [Pdf].

Guo, W., Nazim, H., Liang, Z., & Yang, D. (2016). Magnesium deficiency in plants: An urgent problem. The Crop Journal, 4(2), 83–91. https://doi.org/10.1016/j.cj.2015.11.003

Kanofsk, J. D., & Sandyk, R. (1991). Magnesium Deficiency in Chronic Schizophrenia. International Journal of Neuroscience.

Kirkland, A. E., Sarlo, G. L., & Holton, K. F. (2018). The Role of Magnesium in Neurological Disorders. Nutrients, 10(6). https://doi.org/10.3390/nu10060730

Magnesium. (2014, April 23). Linus Pauling Institute. https://lpi.oregonstate.edu/mic/minerals/magnesium

Zinc and mental health

  • Zinc regulates the storage and release of neurotransmitters (Zinc Regulates, 2017).
  • Zinc has critical roles in axonal and synaptic transmission development and brain cell growth and metabolism (Pfeiffer & Braverman, 1982).
  • Zinc is required for the production of the enzyme, superoxide dismutase, and therefore helps to provide antioxidant support in the body.  (Preston, “Cigarette Smoking-Nutritional Implications.”) 
  • Zinc has anti-anxiety and antidepressant effects, and  is critical for regulating excitatory glutamate and NMDA receptor activity in the brain. (Andrews, 1990; Joshi, Akhtar, Najmi, Khuroo, & Goswami, 2012).

Zinc and autism

Zinc is the most recommended mineral in the treatment of autism (Newmark, 2012).

Many symptoms of zinc deficiency in children overlap with symptoms shown by children on the autism spectrum, including:

  • poor muscle development
  • altered height development
  • decreased appetite
  • decreased range of food preference
  • digestive disorders, such as diarrhea

Due to a limited range of foods consumed by many ASD children, foods that are rich in zinc, like red meat, fish, organ meats, and eggs, are often avoided.

Top sources of zinc based on serving size

  • oyster, cooked
  • beef, chuck, blade roast, cooked
  • beef, ground, 90% lean meat, cooked 
  • crab, Dungeness, cooked
  • fortified, whole-grain toasted oat cereal

Comprehensive food list:

Table 2. Some Food Sources of Zinc


Referenced Dietary Intakes

RDAs for zinc (mg/day)

Adolescents (14-18 years): 11 (M) 9 (F)

Adults (19 years and older): 11 (M) 8 (F)

Supplementing zinc

  • Amounts of zinc used in practice and research range from 10–200 mg/day in divided doses (Zinc, 2014).
  • “Long-term zinc supplementation should be accompanied by a copper supplement (1–4 mg/day, depending on the zinc dose), in order to prevent zinc-induced copper deficiency” (Gaby, 2011).
  • Zinc is best taken with food to prevent nausea.


  • High zinc intakes can inhibit copper absorption, sometimes producing copper deficiency and associated anemia (Office of Dietary Supplements, 2014).
  • Intakes of zinc should not exceed the UL (40 mg/day for adults) in order to limit the risk of copper deficiency in particular
  • Milder gastrointestinal distress has been reported at doses of 50 to 150 mg/day of supplemental zinc (Zinc, 2014).


Andrews, R. R. (1990). Unification of the  findings in schizophrenia by reference to the effects of gestational zinc deficiency. Medical Hypotheses, 31(2), 141-153.

Newmark, S. (2012). Autism Spectrum Disorder. In Integrative Medicine (Third). Elsiver.

Office of Dietary Supplements—Zinc. (n.d.). Retrieved October 29, 2020, from https://ods.od.nih.gov/factsheets/Zinc-HealthProfessional/

Pfeiffer, C. C., & Braverman, E. R. (1982). Zinc, the brain and behavior. Biological Psychiatry, 17(4), 513–532.

Preston, A. M. (1991). Cigarette smoking-nutritional implications. Progress in Food & Nutrition Science, 15(4), 183–217.

Zinc. (2014, April 23). Linus Pauling Institute. https://lpi.oregonstate.edu/mic/minerals/zinc

Essential fatty acids and mental health

  • Polyunsaturated fatty acids (PUFAs) (omega 3 and 6 fatty acids) are necessary for normal development and function of the brain.
  • Omega 3 fatty acids and their metabolites have roles in regulating inflammation, neuroinflammation, and neurotransmission (Larrieu, & Layé, 2018).

Essential fatty acids and autism

  • Lower levels of polyunsaturated fatty acids are found in ASD patients. Children with autism have been shown to have 23% lower plasma omega 3 fatty acid levels (Vancassel et al., 2001).
  • Lower levels of the fatty acids arachidonic acid (AA) and docosahexaenoic acid (DHA) have been found in autistic people versus controls (Brigandi et al., 2015).
  • Lower levels of essential fatty acids in autism are potentially a result of:
    • increased metabolism of the fatty acids into signaling molecules (prostaglandins) (Brigandi et al., 2015).
    • increased damage to the fatty acids due to lipid peroxidation (Chauhan et al., 2004).

Fatty acids and neuroinflammation

  • Neuroinflammation is a known contributor to ASD expression.
  • Inflammation in the brain affects proper growth, development, and migration of neurons (Tassoni et al., 2008).
  • Rapid metabolism of fatty acids (including AA and DHA), as seen in autism, create a pro-inflammatory context in the brain (Brigandi et al., 2015).
  • Resolvins and neuroprotectins derived from DHA, and lipoxins derived from AA, have roles in reducing neuroinflammation (Bradbury, 2011).
  • DHA increases levels of the anti-inflammatory molecule glutathione.

Reasons for EFA deficiencies:

  • inadequate dietary intake
  • poor absorption
  • deficiencies of nutrients required for EFA metabolism
  • issues with metabolism that cause decreased incorporation of, or increased removal of, fatty acids from cell membranes

Top EPA and DHA (omega 3) food sources by serving size

  • herring, Pacific
  • salmon, Chinook
  • sardines, Pacific
  • salmon, Atlantic
  • oysters, Pacific

Comprehensive food list:

Table 4. Food Sources of EPA (20:5n-3) and DHA (22:6n-3) (Office of Dietary Supplements, n.d.)


Commonly suggested amounts for dietary fatty acid consumption:

  • cold water fish – 2 to 3 times a week, or
  • flaxseed oil – 2 to 6 tbsp daily, or
  • ground flax seed – 2 tbsp daily

Flaxseed oil may have negative effects in about 3% people, including: hypomania, mania, behaviour changes. (Prousky, 2015

Referenced Dietary Intakes

Adequate Intakes for Alpha linolenic acid (Omega 3) (g/day) (Institute of Medicine, 2002)

Adolescents (14–18 years): 1.6 (M) 1.1 (F)

Adults (19 years and older):  1.6 (M) 1.1 (F)

Recommendations for long-chain omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (mg/day) (European Food Safety Authority, 2009)

Adults: 250 mg/day (M+F)

Supplementing omega 3 fatty acids

  • Amounts of omega 3 fatty acids used in practice and research range from 1–4 g/day of combined EPA and DHA, in divided doses.
  • Fish oil and E-EPA are generally well tolerated, but may cause gastrointestinal side effects in some individuals (Gaby, 2011
  • Long-term supplementation with EPA and DHA should be accompanied by a vitamin E supplement (Gaby, 2011), as polyunsaturated fatty acids increase vitamin E requirements in the body.
  • Combined supplementation of AA and DHA was shown to improve social withdrawal and communication in ASD patients versus controls (Yui et al., 2012).
  • DHA-dominant fatty acid supplementation significantly decreased the Childhood Autism Rating Score (CARS) in autistic individuals (Meguid et al.; Yui et al., 2012).


  • Common side effects of high dose EPA and DHA supplementation include heartburn, nausea, gastrointestinal discomfort, diarrhea, headache, and odoriferous sweat.
  • The European Food Safety Authority considers long-term consumption of EPA and DHA supplements at combined doses of up to about 5 g/day to be safe.
  • The FDA recommends not exceeding 3 g/day EPA and DHA combined, with up to 2 g/day from dietary supplements (Office of Dietary Supplements, n.d.).


  • Use caution when supplementing omega 3 fatty acids while taking blood-thinning medications, or with blood-sugar issues (Essential fatty acids, 2014).


Bradbury, J. (2011). Docosahexaenoic Acid (DHA): An Ancient Nutrient for the Modern Human Brain. Nutrients, 3(5), 529. https://doi.org/10.3390/nu3050529

Brigandi, S. A., Shao, H., Qian, S. Y., Shen, Y., Wu, B.-L., & Kang, J. X. (2015). Autistic Children Exhibit Decreased Levels of Essential Fatty Acids in Red Blood Cells. International Journal of Molecular Sciences, 16(5), 10061–10076. https://doi.org/10.3390/ijms160510061

Chauhan, A., Chauhan, V., Brown, W. T., & Cohen, I. (2004). Oxidative stress in autism: Increased lipid peroxidation and reduced serum levels of ceruloplasmin and transferrin–the antioxidant proteins. Life Sciences, 75(21), 2539–2549. https://doi.org/10.1016/j.lfs.2004.04.038

Essential Fatty Acids. (2014, April 28). Linus Pauling Institute. https://lpi.oregonstate.edu/mic/other-nutrients/essential-fatty-acids

Labelling reference intake values for n-3 and n-6 polyunsaturated fatty acids. (2009, July 10). European Food Safety Authority. https://www.efsa.europa.eu/en/efsajournal/pub/1176

Medicine, I. of. (2002). Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids. https://doi.org/10.17226/10490

Gaby, A. R. (2011). Nutritional Medicine (VitalBook file).

Larrieu, T., & Layé, S. (2018). Food for Mood: Relevance of Nutritional Omega-3 Fatty Acids for Depression and Anxiety. Frontiers in Physiology, 9. https://doi.org/10.3389/fphys.2018.01047

Office of Dietary Supplements—Omega-3 Fatty Acids. (n.d.). Retrieved October 29, 2020, from https://ods.od.nih.gov/factsheets/Omega3FattyAcids-HealthProfessional/

Prousky, J. (2015). Anxiety: Orthomolecular diagnosis and treatment (Kindle). CCNM Press.

Tassoni, D., Kaur, G., Weisinger, R. S., & Sinclair, A. J. (2008). The role of eicosanoids in the brain. Asia Pacific Journal of Clinical Nutrition, 17 Suppl 1, 220–228.

Vancassel, S., Durand, G., Barthélémy, C., Lejeune, B., Martineau, J., Guilloteau, D., Andrès, C., & Chalon, S. (2001). Plasma fatty acid levels in autistic children. Prostaglandins, Leukotrienes and Essential Fatty Acids (PLEFA), 65(1), 1–7. https://doi.org/10.1054/plef.2001.0281

Many other nutrients have been used with beneficial effect in the context of autism. Some are listed here.


  • Tetrahydrobiopterin (BH4) is a cofactor for the enzyme tyrosine hydroxylase, which has a role in converting tyrosine into the neurotransmitter dopamine.
  • Reduced cerebral spinal fluid concentrations of BH4, have been found in autistic children.
  • Supplementation of BH4 at a dose of 3 mg/kg of body weight for three months in autistic children resulted in improvements in social functioning and in the number of sounds and words used by the child (Fernell et al., 1997).

Dimethylglycine (DMG)

  • DMG provides glycine to be used as an energy source for the brain and muscles.
  • DMG also supports the methylation cycle by donating a methyl group to homocysteine – converting it back into methionine. Methylation cycle problems can be a factor in autism. (See “Methylation abnormalities on this page for more information)
  • Supplementing DMG has been reported to lead to improved speech and behaviour in some autistic patients.
  • A study of DMG supplementation in autistic children resulted in 42% of the children seeing improvement, based on parent ratings (Klotter, 2008). Recommended dosing of DMG in autism by weight was (Kern et al., 2001):
    • less than 40 lbs – 125 mg/day
    • 41–70 lbs – 250 mg/day
    • 71–100 lbs – 375 mg/day
    • 100–130 lbs – 500 mg/day
    • more than 130 lbs – 625 mg
  • If DMG is going to work in a particular person, some positive effects will usually be seen within one to two weeks. However it is recommended to supplement for one month before concluding DMG is not effective (Gaby, 2011).


  • Melatonin has been found to be effective and well tolerated as treatment for insomnia in ASD children (Gaby, 2011).
  • In a study of melatonin in ASD children with insomnia (Andersen et al., 2008), melatonin supplementation resulted in resolution of the insomnia in 25% of the children, and improvement in an additional 60% of the children. 
    • Children who were 6 years old or over received 1.5 mg of melatonin 30–60 minutes before bed. 
    • If no improvement was seen after 2 weeks the dose was increased to 3 mg.
    • If no improvement was seen after 4 weeks the dose was increased to 6 mg.
    • Only 3 of 107 children had side effects which included morning sleepiness and increased involuntary urination.


Sears, M. E. (2013). Chelation: Harnessing and Enhancing Heavy Metal Detoxification—A Review. The Scientific World Journal, 2013. https://doi.org/10.1155/2013/219840

Fernell, E., Watanabe, Y., Adolfsson, I., Tani, Y., Bergström, M., Hartvig, P., Lilja, A., von Knorring, A. L., Gillberg, C., & Långström, B. (1997). Possible effects of tetrahydrobiopterin treatment in six children with autism–clinical and positron emission tomography data: A pilot study. Developmental Medicine and Child Neurology, 39(5), 313–318. https://doi.org/10.1111/j.1469-8749.1997.tb07437.x

Gaby, A. R. (2011). Nutritional Medicine (VitalBook file).

Kern, J. K., Miller, V. S., Cauller, L., Kendall, R., Mehta, J., & Dodd, M. (2001). Effectiveness of N,N-Dimethylglycine in Autism and Pervasive Developmental Disorder. Journal of Child Neurology, 16(3), 169–173. https://doi.org/10.1177/088307380101600303

Multinutrient formulas

Multivitamins and mental health

  • Conditions including stress, illness, poor diet and nutrient absorption, as well as certain medications can increase needs for many different vitamins and minerals.
  • A good quality multivitamin/mineral formula can address the minimum nutrient requirements for the important vitamins and minerals.

Multivitamin-multimineral formulas and autism

  • Supplementing autistic children with a moderate-potency multivitamin-multimineral formula in a double-blind trial, resulted in significantly improved sleep, and reduced digestive tract issues (Adams & Holloway, 2004).

Hardy-Stephan micronutrient regimen

The Hardy-Stephan regimen is a multi-vitamin, mineral and amino acid supplement that may be of benefit in the context of bipolar disorder. The supplement is sold under the name EMPowerPlus (Synergy Group of Canada).

  • In a study 44 autistic children were given the micronutrient formula and were were pair-matched with 44 autistic children who received conventional medical treatment.
  • The micronutrient group had significantly greater improvement on the Childhood Autism Rating Scale and Childhood Psychiatric Rating Scale.
  • The micronutrient group also had (Mehl-Madrona et al., 2010): 
    • lower activity level
    • less social withdrawal
    • less anger
    • better spontaneity
    • less irritability
    • lower intensity self-injurious behaviour
    • markedly fewer adverse events
    • less weight gain


Adams, J. B., & Holloway, C. (2004). Pilot study of a moderate dose multivitamin/mineral supplement for children with autistic spectrum disorder. Journal of Alternative and Complementary Medicine (New York, N.Y.), 10(6), 1033–1039. https://doi.org/10.1089/acm.2004.10.1033

Mehl-Madrona, L., Leung, B., Kennedy, C., Paul, S., & Kaplan, B. J. (2010). Micronutrients Versus Standard Medication Management in Autism: A Naturalistic Case–Control Study. Journal of Child and Adolescent Psychopharmacology, 20(2), 95. https://doi.org/10.1089/cap.2009.0011


This section contains useful information and tools for getting started as well as exploring further the orthomolecular approach to addressing ASD.


1. Eat a healthy diet

  • ensure sufficient protein, fats, and cholesterol
  • eat a variety of colourful vegetables and fruit
  • avoid sugar and starches

2. Supplement basic nutrients for support for ASD:

Reason:  broad spectrum nutrient support
Typical dosing: 1–2x day


B-complex (supports brain function, blood sugar control)
Reason: full spectrum of B-vitamins, supports methylation cycle function
Typical dosing: B50 2–4/day

Vitamin C
Reason: antioxidant, anti-inflammatory, supports neurotransmitter production
Typical dosing: 1000–6000 mg/day

Vitamin D
Reason: regulates serotonin production, protects against neuronal oxidative stress
Typical dosing: 1000–5000 IU

Reason: help restore and maintain healthy digestive tract flora
Typical dosing: 10–25 billion bacteria/day

Reason: calms neurotransmission, anti-stress, serotonin and dopamine production, supports action of vitamin B6
Typical dosing: 300–600 mg/day

Fish oil
Reason: anti-inflammatory, brain supportive
Typical dosing: 1000–4000 mg (of fish oil)

3. Identify and remove sources of environmental toxins


1. Consider a trial of GFCF diet

  • Gluten-free, casein-free diet
    • this is the most often recommended diet with ASD
    • allow at least 2 months to assess benefits
    • See “GFCF diet” on this page for more information

2. Continue with basic nutrients for support for ASD, consider including additional nutrients shown to be beneficial with ASD:

Vitamin B6 (in pyridoxal-5-phosphate (P5P) form)
Reason: neurotransmitter metabolism, supports action of magnesium
Typical dosing: 50–100 mg/day

Vitamin B12 (methylcobalamin form)
Reason: neurotransmitter synthesis, brain cell preservation, supports methylation cycle
Typical dosing: 1000–5000 mcg/day

Reason: antioxidant support, neurotransmitter regulation
Typical dosing: 30–50 mg/day

3. Ensure good sleep

Consider supplementing melatonin 1–3 mg if required.

Further information on improving sleep:


4. Work with a health professional who is trained in nutrition and integrative medicine approaches

Trained health professionals can help with:

  • testing for nutrient deficiencies and metabolic contributors to ASD
  • providing custom dietary and supplement protocols


Your Autism Game Plan
Joya Van Der Laan