Orthomolecular interventions are substances that have roles in promoting or addressing attention deficit hyperactivity disorder, depending on individual biological requirements and the amount present in the body.

Vitamin B6 and mental health

Vitamin B6 is required for:

• conversion of the amino acid tryptophan into serotonin – Low levels of serotonin are associated with ADHD
• the synthesis of monoamine neurotransmitters, such as serotonin, dopamine, and γ-aminobutyrate. PLP, the active form of vitamin B6, is a cofactor in this synthesis process (Food and Nutrition Board, Institute of Medicine, 1998; Skarupski et al., 2010)

Vitamin B6 and ADHD

Deficiency of vitamin B6 can be identified by:

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

Causes of vitamin B6 deficiencies

• inadequate dietary intake
• medications, including anti-tuberculosis drugs, anti-parkinsonians, 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

Vitamin C

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 show 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 (MOA). MOA is responsible for metabolizing serotonin, norepinephrine, and dopamine. (Gaby)

Vitamin C and ADHD

Vitamin C (Greenblatt, 2018):

• Combats oxidative stress
• Acts as an antihistamine
• Regulates dopamine and norepinephrine release
• Promotes nerve cell integrity

Even a small negative change in vitamin C in the brain can cause a significant increase in oxidative damage, showing that vitamin C is extremely important. Vitamin C acts as the primary molecule for protecting the central nervous system from oxidative stress damage (Moghadas et al, 2019).

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)

Vitamin D

Vitamin D, which is made from cholesterol in the skin and UVB radiation, is a neurosteroid hormone that has roles in brain development and normal brain function.

Vitamin D and mental health

• Vitamin D regulates the transcription of genes involved in pathways for synaptic plasticity, neuronal development and protection against oxidative stress (Graham et al., 2015).
• Vitamin D-deficient cells produce higher levels of the inflammatory cytokines TNF-α and IL-6, while cells treated with vitamin D release significantly less.
• In the adrenal glands, vitamin D regulates tyrosine hydroxylase, which is the rate-limiting enzyme for the synthesis of dopamine, epinephrine, and norepinephrine.
• In the brain, vitamin D regulates the synthesis, release, and function of serotonin. Serotonin modulates executive function, sensory gating, social behaviour, and impulsivity (Patrick & Ames, 2015).

Vitamin D and ADHD

• Roles of vitamin D in ADHD include reduction of pro-inflammatory cytokines and oxidative stress, and neurotransmitter synthesis and regulation in the brain and gut.

It has been shown that Vitamin D deficiency is more common in children with ADHD than in healthy children (Hemamy et al 2020).

Vitamin D supplementation caused a significant improvement in ADHD evening symptoms (Hemamy et al 2020).

Causes of vitamin D deficiency

• limited sun exposure
• strict vegan diet (most sources of vitamin D are animal-based)
• darker skin (the pigment melanin reduces the vitamin D production by the skin)
• digestive tract and kidney issues
• obesity (vitamin D is sequestered by fat cells)

Measuring vitamin D

The best indicator of vitamin D status is serum 25(OH)D, also known as 25-hydroxyvitamin D. 25(OH)D reflects the amount of vitamin D in the body that is produced by the skin and obtained from food and supplements.

Vitamin D levels and health status

Institute of Medicine, Food and Nutrition Board. (2010)

Serum (ng/ml)  and Health status

<20  deficient

20–39  generally considered adequate

40–50  adequate

>50–60   proposed optimum health level

>200  potentially toxic

Iron and Mental Health

Iron is required for the synthesis of serotonin and norepinephrine (Gaby).

Iron Deficiency in Children with ADHD

• Average iron levels in children with ADHD were significantly lower than controls (6.04 ng/mL vs. 48.96 ng/mL) (Juneja 2010).
• Ferritin (Iron) levels were low (<12 ng/mL) in the majority of cases with ADHD, and in 0% of controls (Juneja 2010, Calarge 2010).
• Low Iron levels are correlated with inattention, hyperactivity/ impulsivity, difficulty concentrating, and higher total ADHD symptom scores (Calarge 2010, Juneja 2010, Gaby 2011). In many cases, these were improved with iron supplementation (Gaby 2011).
• Individuals with lower iron levels have been found to require higher doses of amphetamine to reach optimal response than those with regular iron levels (Calarge 2010, Juneja 2010).

Causes of deficiencies (Iron, 2014)

Chronic blood losses due to:

• parasitic infestations
• frequent blood donation
• regular intense exercise

Decreased iron absorption due to:

• celiac disease
• gastritis
• Helicobacter pylori infection
• inflammatory bowel diseases (IBD)
• gastric bypass surgery

Other causes of iron deficiency include:

• vegetarian diet with inadequate sources of iron
• chronic kidney disease
• pregnancy (due to increased need)
• chronic inflammation

Deficiency of iron can be identified by (10 Signs and Symptoms of Iron Deficiency, 2020):

• unusual tiredness
• pale skin, inner eyelids, gums, or nails
• cracks at the corners of the mouth
• mouth ulcers
• swollen, pale or smooth tongue
• shortness of breath
• headaches
• dizziness, lightheadedness
• heart palpitations
• dry or damaged skin or hair

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)

Magnesium and ADHD

Several observational studies showed that serum magnesium levels are lower in children with ADHD than in controls (Hemamy et al., 2020).

• Magnesium deficiency was found in 95% of hyperactive children with ADHD (Kozielec & Starobrat-Hermelin 1997)
• Adolescents with the highest intake of dietary magnesium were the least likely to show behaviors like hyperactivity, aggression, and delinquency (Black 2015)
• Low magnesium levels of children with ADHD correlated with more hyperactivity and lower IQ (Greenblatt, 2018)

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), and
• 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.

Zinc and mental health

Roles of zinc in the central nervous system (Prasad 1995) include:

• maintaining protein structures
• promoting enzymatic activity
• maintaining neurotransmitter activity
• supporting structural function in the hippocampus

Zinc and ADHD

Serum zinc concentration has been found to be significantly lower in children with ADHD than in healthy individuals (Gaby, 2011).

Zinc Deficiency in ADHD

• Zinc levels in red blood cells, hair, and urine have been found to be lower in children with ADHD
• When testing children for their zinc levels, 30.2% of children with ADHD had severe serum zinc deficiency (levels below 8.3 μmol/L), while no healthy controls showed these levels (Toren 1996)
• Zinc level has been found to be inversely correlated with the severity of ADHD symptoms and parent/teacher rating scales of ADHD (Arnold 2005)
• Hair zinc levels have been correlated to inattention, hyperactivity and impulsivity (Elbaz 2016)
• Zinc levels of ADHD children were in the lowest 30% of the zinc level reference range (Arnold 2005)
• 70% of children with ADHD were deficient in zinc (Elbaz 2016)

Zinc Supplementation

• Zinc monotherapy (150 mg/day) for 12 weeks significantly reduced hyperactivity, impulsivity, and impaired socialization in some children with ADHD (Bilici et al 2004).
• Supplementing with Zinc Sulfate (55 mg/ day) for 6 weeks significantly lowered ADHD ratings at each 2-week evaluation.
• Supplementing with Zinc Glycinate (30mg/day) reduced optimal amphetamine dose needed in children with ADHD (Greenblatt 2018).

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.

Essential fatty acids and ADHD

• Omega 3 fatty acids and their metabolites help regulate inflammation, neuroinflammation, and neurotransmission (Larrieu, & Layé, 2018).
• The concentrations of certain omega-3 and omega-6 fatty acids were significantly lower in children with ADHD than in healthy controls (Gaby, 2011).
• Children with ADHD have lower blood levels of long-chain omega-3 fatty acids than control children (Antalis et al. 2006).

Lower DHA concentrations in children were found to be associated with (Montgomery 2013):

• Reduced working memory performance
• More oppositional behavior and emotional lability
• Poorer reading ability

ADHD and SNPs

• Children with ADHD are 60% more likely to have a Single Nucleotide Polymorphism (SNP, a change in one nucleotide in DNA) for fatty acid desaturase 2 (FADS2) gene (Brookes 2006).
• This SNP results in less omega-3’s being incorporated into the cell membrane, which potentially explains why low omega-3 concentrations have been seen in ADHD subjects who do not lack dietary omega-3 intake (Brookes 2006).

EPA, DHA, and Omega 6 and ADHD

• The ratio of omega 3 to omega 6 fatty acids is important in ensuring proper function of the body. Too much omega 6 compared to omega 3 has been shown to negatively affect health. However, too little omega 6 is also a problem.
• Adolescents with ADHD had lower total omega-3 fatty acids, lower DHA levels, higher linoleic acid levels, and a lower omega-3:omega-6 ratio than controls. This ratio still was seen despite no difference in consumption of fatty acids (Colter et al 2008).
• Higher Omega-6 levels predicted poorer reading, vocabulary, spelling, and attention in children with ADHD (Milte 2011).
• Higher levels of EPA, DHA, and total Omega-3s were associated with better reading skills (Milte 2011).
• A potential block in converting linoleic acid to gamma-linolenic acid (GLA) by the enzyme delta-6-desaturase was seen in boys with ADHD, suggesting a possible mechanism (Gaby, 2011).

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

Amino Acids and ADHD

• ADHD is potentially linked to abnormal absorption or transport of amino acids (Bornstein 1990).
• Children with ADHD had lower phenylalanine, tyrosine, and tryptophan levels (Gaby 2011).
• Lower levels of amino acids were associated with more ADHD symptoms on the Conners Parent Rating Scale for behaviour (Bornstein 1990).

Tyrosine and mental health

Tyrosine is a dietary amino acid that also functions as a neurotransmitter. The body can also make tyrosine from the amino acid phenylalanine.

Tyrosine is a precursor molecule for the neurotransmitters dopamine, noepinephrine, and epinephrine, and is also required for the production of thyroid hormones.

Causes of deficiencies of tyrosine

• a low-protein diet

Amino Acids and ADHD

• ADHD is potentially linked to abnormal absorption or transport of amino acids (Bornstein 1990).
• Children with ADHD had lower phenylalanine, tyrosine, and tryptophan levels (Gaby 2011).
• Lower levels of amino acids were associated with more ADHD symptoms on the Conners Parent Rating Scale for behaviour (Bornstein 1990).

Tryptophan and 5-HTP and mental health

• Serotonin, regarded as the happy, feel good neurotransmitter, is synthesized from the amino acid tryptophan. Tryptophan is converted in the body to 5-HTP , which is then converted into the neurotransmitter serotonin.
•  Tryptophan depletion can lead to (Mette 2013):
  • decreased attention
  • increased impulsivity
• Tryptophan depletion in adults with ADHD decreased reaction times.

OPCs

• Oligomeric Proanthocyanidins (OPCs) are plant chemicals called polyphenols and are produced by plants to protect themselves from environmental harm.
• OPCs help address ADHD symptoms by several mechanisms.

OPCs and ADHD

Roles of OPCs in the body include (Greenblatt, 2018):

• decreasing theta waves, and improve theta:beta ratio
• supporting antioxidant activity (e.g. GSH)
• moderating catecholamine levels
• helping to maintain blood brain barrier
• decreasing copper levels
• acting as antihistamines

Pycnogenol was found to reduce oxidative damage to DNA, normalize TAS, and improve attention in children with ADHD (Moghadas et al, 2019).

OPC’s and allergies

OPCs act as antihistamines by inhibiting histidine decarboxylase from binding to collagen microfibrils. This moderates the production and release of immune-activating molecules which would cause an allergic reaction.

ADHD EEGs

An individual’s theta/beta ratio is predictive of ADHD, as it shows abnormal cortical activity patterns at all ages (Bresnahan 1999). These patterns include:

• increased slow-wave (theta) activity, which may be due to hyperactivity in individuals with ADHD
• decreased fast-wave (beta) activity (beta activity expresses concentration, suggesting that low beta activity may be due to hyperactivity)
• high theta/beta ratio

Neurofeedback vs. Stimulants

• Theta/beta training sessions and methylphenidate treatment (1 mg/kg/d) in children with ADHD led to reductions in primary symptoms and functional impairment. The neurofeedback group also improved significantly in academic performance (Meisel 2013).
• Improvements from neurofeedback remained at 2-month and 6-month follow-ups (Meisel 2013).

B-complex vitamins and mental health

• Symptoms including stress, illness, poor diet and nutrient absorption, as well as certain medications can increase needs for B-vitamins.
• A good quality B-complex can address the minimum nutrient requirements for the important B-vitamins including vitamins B1, B3, B6, B12, and folate.

“A trial of B-complex supplement seems advisable, especially in older persons and in persons taking medications that may deplete this vitamin” (Rakel, 2012).