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

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:

https://www.healthline.com/nutrition/mediterranean-diet-meal-plan

(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:

https://www.healthline.com/nutrition/paleo-diet-meal-plan-and-menu

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

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)

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).

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)

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).

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)

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).

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

Resources

8 Steps to Support Your Methylation Cycle and Address SNPs
https://doctordoni.com/2015/04/8-steps-to-support-your-methylation-cycle/

Understanding the Methylation Cycle and Its Effect on Health
https://doctordoni.com/2015/03/understanding-the-methylation-cycle-and-its-effect-on-health/

Understanding the Methylation Cycle
https://autismrecoverysystem.com/wp-content/uploads/2017/05/Understanding-the-Methylation-Cycle-1.pdf

Vitamins and Supplements | Interactive Autism Network
https://iancommunity.org/cs/what_do_we_know/vitamins_and_supplements

Pyroluria

• 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”.