Orthomolecular interventions are substances that have roles in promoting or addressing autism spectrum disorder, depending on individual metabolic requirements and the amount present in the body.

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

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

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.).

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

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)

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.

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.).

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.

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
  

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

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

BH4

• 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

• 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.