Mental Health Information – Autism Spectrum Disorder

[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
https://www.autism360.com/casein-free-gluten-free-diet-for-autism/

Gluten-Free Casein-Free Diet
https://mindd.org/diet/gluten-free-casein-free-diet/

References

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)

https://lpi.oregonstate.edu/mic/vitamins/folate

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

SAFETY, SIDE EFFECTS

• 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).

References

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)

https://lpi.oregonstate.edu/mic/vitamins/vitamin-B6

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).

SAFETY, SIDE EFFECTS

• 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).

VITAMIN B6 AND MEDICATIONS

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

References

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.

References

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)

https://lpi.oregonstate.edu/mic/vitamins/vitamin-B12

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).

SAFETY, SIDE EFFECTS

• 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).
  

References

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)

https://lpi.oregonstate.edu/mic/vitamins/vitamin-C

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.
  

SAFETY, SIDE EFFECTS

• 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.

References

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)

https://lpi.oregonstate.edu/mic/minerals/magnesium

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

SAFETY, SIDE EFFECTS

• 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.
  

References

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

https://lpi.oregonstate.edu/mic/minerals/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.

SAFETY, SIDE EFFECTS

• 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).
  

References

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.)

https://lpi.oregonstate.edu/mic/other-nutrients/essential-fatty-acids

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).

SAFETY, SIDE EFFECTS

• 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.).

OMEGA 3 FATTY ACIDS AND MEDICATIONS

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

References

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.

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.

References

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

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

References

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