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2. Minerals and ADHD

2. Minerals and ADHD

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2.1. Zinc

2.1.1. Zinc Deficiency Affects Dopamine Transporters and Melatonin

Zinc can increase dopamine levels by reducing DAT activity.12

  • Prevalence of zinc deficiency:
    • Across the entire population
      • Europe: 11% (0.8 to 28.8%)3
      • In Germany, the intake was reported to be too low for adults (ages 19 to 64)—9.8% for women and 10.3% for men—and for older adults (age 65 and older), the figures were 13.4% (women) and 8% (men).
    • Healthy children ages 1 to 3:
      • Western Europe: 31.3%4
    • In children under five years of age (Disease Control Priorities in Developing Countries 2006).
      • East Asia/Pacific: 7%
      • Eastern Europe and Central Asia: 10%
      • Latin America and the Caribbean: 33%
      • Middle East and North Africa: 46%
      • Sub-Saharan Africa: 50%
      • South Asia: 79%
    • Zinc deficiency manifests itself, among other things, as a deficiency of T and B lymphocytes
    • Zinc deficiency is often accompanied by vitamin A deficiency

ADHD medications, nicotine, and zinc block the dopamine transporters (DAT)—which are present in excess in the brain in people with ADHD—and thereby reduce their overactivity.5 Zinc thus acts as a dopamine reuptake inhibitor.

Zinc deficiency can affect melatonin regulation. Melatonin regulates dopamine function.6 Melatonin deficiency can cause sleep disorders.7

A dysregulation of zinc or copper can increase susceptibility to oxidative damage to tissues or oxidative stress in the brain by impairing the body’s antioxidant defenses, which may be a potential cause of ADHD.8

Zinc oxide nanoparticles, such as those used in mouthwashes, cosmetics, sunscreen, toothpaste, and root canal irrigants, cause a significant increase in dopamine (nearly doubling), norepinephrine (more than doubling), and serotonin (nearly doubling), while simultaneously reducing the levels of K⁺, Ca²⁺, and Na⁺ ions.9

2.1.2. Zinc Deficiency and ADHD

Zinc may potentially complement and enhance methylphenidate therapy.10 However, the zinc dosage used in the aforementioned study requires medical supervision to prevent iron or copper deficiency, as well as gastrointestinal symptoms or “zinc flu.” The reported improvements were, however, impressive.
It is unknown whether this effect occurs independently of MPH therapy. As noted by Krause.11

In ADHD, metabolism may be altered with regard to cobalt, copper, lead, zinc, and vanadium. Reduced cycle stability (determinism), duration (mean diagonal length), and complexity (entropy) of the exposure profiles were observed.12

Meta-analyses (4: zinc reduces, 1: zinc has no effect):

  • Reduced zinc levels correlate bidirectionally with ADHD; low zinc increases IL-6; maternal depression reduces zinc levels, maternal stress increases IL-6 in children, and reduced zinc levels in umbilical cord blood correlate with ADHD in children aged 8 to 9 years (meta-analysis, k = 3, n = 39,600)13
  • Zinc levels are lower in individuals with ADHD; zinc levels correlate with the severity of ADHD symptoms (meta-analysis)14
  • reduced serum zinc levels in children with ADHD (SMD: 1.33, meta-analysis, k = 17 studies, n = 5,077)15
  • Zinc deficiency was primarily associated with ADHD-I (meta-analysis)16
  • No significant differences in blood or hair zinc levels were found between people with ADHD and those without the condition. The results of the individual studies were highly heterogeneous. (Meta-analysis, k = 11, n = 1,311)17

Individual studies:

7 studies found reduced zinc levels in ADHD:

  • in the blood serum of children with ADHD:18
    • Zinc: 7% lower
    • Chromium: reduced by 21%
    • Magnesium: reduced by 4%
    • Copper-to-zinc ratio: increased by 11%
  • in the hair of children with ADHD19
    • Zinc: reduced by 19%. At the same time, low zinc levels in hair samples were found to be a predictor of ADHD.
  • in the blood of children with ADHD (large study)20
    • reduced zinc levels
    • Magnesium, copper, iron, and lead remain unchanged
  • Zinc reduces21
  • Zinc reduces22
  • Zinc deficiency in 60% of the study participants (Egyptian children)23
  • A 1 SD increase in zinc levels in red blood cells (65 μmol/L) was associated with an 8% reduction in the risk of ADHD24
    • A 1 SD increase in magnesium (0.08 mmol/L) was associated with a 16% reduction in the risk of ASS
    • A 1 SD increase in vitamin B12 (173 pmol/L) was associated with a 19% reduction in the risk of Tourette syndrome

A study found elevated zinc levels in people with ADHD:

  • Elevated zinc levels in the blood and hair of children with hyperactivity and comorbid ODD or CD,25 although the study apparently equated hyperactivity with ADHD. Furthermore, the study found a common deficiency in magnesium. In children with magnesium deficiency, magnesium supplementation also improved ADHD symptoms.

Zinc Supplementation for ADHD:

Meta-analyses:
A meta-analysis found that zinc has a positive effect on ADHD.26

Individual studies:
Zinc supplementation in people with ADHD who have a zinc deficiency but no iron deficiency27

  • Improved by a statistically significant amount
    • Hyperactivity
    • Attention
    • Impulsivity
    • Mood stability
  • Remained unchanged
    • Intelligence
    • Cognitive problems
    • Opposition-related issues

Zinc and Iron Supplementation for People with ADHD Who Have Zinc and Iron Deficiencies27

  • Improved by a statistically significant amount
    • Verbal IQ
    • Total IQ
    • Hyperactivity
    • Impulsivity
    • Mood stability
  • Remained unchanged
    • Performance IQ
    • Attention
    • Cognitive problems
    • Opposition-related issues

A randomized, double-blind study found that zinc supplementation in addition to existing treatment with MPH (only) further improved inattention, but not hyperactivity, impulsivity, or the overall ADHD score.28

In conclusion, it can be stated that zinc levels are not generally altered in ADHD. However, the results of zinc supplementation in individual people with ADHD suggest that an existing zinc deficiency may contribute to the exacerbation of ADHD symptoms in some people with ADHD. Therefore, zinc levels and the functionality of zinc receptors should be assessed on an individual basis during diagnosis. If deficiencies are found, zinc supplementation may help reduce ADHD symptoms in people with ADHD.

Even in the case of an existing deficiency, one should not expect that taking zinc or other vitamins or minerals will even come close to achieving the same effect size as medication. However, correcting any vitamin or mineral deficiencies can be helpful as a complementary measure in the treatment of ADHD.

2.2. Magnesium

In all 7 studies included in a meta-analysis, people with ADHD were found to have reduced blood magnesium levels (meta-analysis, n = 7).2930
A systematic review of k = 45 meta-analyses found an increased risk of ADHD associated with lower blood magnesium levels.31
A study identified magnesium deficiency as one of the 15 most important blood biomarkers indicating a diagnosis of ADHD in children and adolescents. Magnesium deficiency achieved an accuracy (AUC) of 54%. When combined with 14 other blood markers, the AUC rose to 87%.32 The model can be tested experimentally using your own blood test results at https://adhdrisk.streamlit.app.

In 15q11.2 BP1-BP2 microdeletion syndrome (Burnside-Butler syndrome), the following symptoms were observed in 200 people with ADHD:

  • Developmental disorders (73%)
  • Speech disorders (67%)
  • Memory problems (60%)
  • Writing problems (60%)
  • Reading difficulties (57%)
  • Verbal IQ below 76 (50%)
  • Behavioral problems (55%)
  • Ear malformations (46%)
  • Anomalies of the anterior palate (46%)
  • Motor slowing (42%)
  • Abnormalities in brain imaging (43%)
  • ADHD (35%)
  • Autism Spectrum Disorders (27%)
  • Epilepsy (26%)
  • Schizophrenia / paranoid psychoses (20%)

It is believed that taking magnesium may be helpful in this case.33

Children with ADHD were found to have 29% lower magnesium levels in their hair. However, low hair magnesium levels could not be used as a diagnostic tool for ADHD.19

A study found that children with ADHD had average blood serum levels compared to those without the condition:18

  • Zinc: 7% lower
  • Chromium: reduced by 21%
  • Magnesium: reduced by 4%
  • Copper-to-zinc ratio: increased by 11%

In a double-blind, placebo-controlled study of children with ADHD aged 6 to 12, it was found that 50,000 IU of vitamin D3 per week and 6 mg/kg/day of magnesium significantly improved symptoms related to behavioral problems, social behavior, and anxiety, but not psychosomatic symptoms.3435

A study found a common deficiency of magnesium in the blood and hair of children with hyperactivity. In children with magnesium deficiency, magnesium supplementation also improved ADHD symptoms,25 although the study apparently equated hyperactivity with ADHD.
A study of Egyptian children found that 65% had a magnesium deficiency.23

2.3. Iron, ferritin

Iron is a cofactor for tyrosine hydroxylase, which is the rate-limiting enzyme in monoamine synthesis. Iron is therefore involved in the synthesis of dopamine and norepinephrine.36 Severe iron deficiency can reduce levels of dopamine, oxytocin, irisin, MAO-A, β-endorphin, and α-MSH in the brain and increase synaptophysin levels.37 Male rodents with iron deficiency exhibit typical dopaminergic neuronal changes, such as those commonly seen in restless legs syndrome (RLS), including reduced striatal D2 receptors. They also develop hyperarousal.38 Iron deficiency reduced dopamine transporter binding and serotonin transporter binding only in males.36
In addition, iron is an essential trace element and is needed in particular for the formation of hemoglobin. Ferritin is a protein that stores the body’s iron reserves. A low ferritin level is an indicator of depleted iron stores in the body. Therefore, long-term iron levels are determined by measuring ferritin.
Iron can cross the blood-brain barrier via the transferrin receptor.39

Iron supplementation improved (meta-analysis, k = 16):40

  • in RCT
    • Anxiety (d = 0.34)
    • Fatigue (d = 0.34)
    • physical well-being (d = 0.42)
    • cognitive intelligence (d = 0.46)
    • Short-term memory (d = 0.53)
    • but not attention problems or depression.
  • in before-and-after studies (= no placebo controls)
    • Depression (d = 0.93)
    • Fatigue (d = 1.01)
    • general psychiatric symptoms (d = 1.13)

Subgroup analyses suggest that iron deficiency can impair brain function even in the early stages of anemia.40

While ferritin deficiency correlates quite clearly with ADHD, the same cannot be said for iron deficiency.

Even when serum ferritin levels were within the so-called “normal” range (22–322 μg/L), there was a very strong negative correlation between ferritin levels and the severity of Restless Legs Syndrome symptoms. A multiple regression analysis identified serum ferritin levels (p < 0.001) and age (p = 0.001) as independent and significant predictors of the severity of RLS.41

2.3.1. Ferritin

For ADHD, 4 meta-analyses and 4 recent studies found reduced serum ferritin levels:

  • Ferritin deficiency increased the risk of ADHD by 63% (METASTUDY, k = 18, n = 6,251).42
  • Correlation between ferritin deficiency in children (but not iron or transferrin deficiency) and ADHD (METASTUDY, n = 1,560) and more severe ADHD symptoms (METASTUDY, k = 7, , n = 19,005)42’
  • Serum ferritin levels are reduced in ADHD (meta-analysis, k = 10, n = 3,387)43 (METASTUDY, k = 17, n = 6,251)44
  • an association between ferritin levels—as a peripheral marker of iron status in ADHD—and the risk of ADHD in children (meta-analysis, k = 5, n = 258)45
  • Ferritin deficiency was found in 9 of 32 children with ADHD (serum ferritin 30 ng/ml or lower). Neuropsychometric tests conducted at the start of the study showed no differences between children with adequate ferritin levels and those with ferritin deficiency. A six-week course of iron therapy significantly improved inattention and hyperactivity in all children (including those without a deficiency).46
  • Low ferritin levels were associated with ADHD in children aged 6 to 1347
  • Significantly lower serum ferritin levels in children with ADHD48 This correlated with a higher intake of nutrient-poor foods—such as those high in sugar and fat—and a lower intake of vegetables, fruits, and protein-rich foods compared to healthy children. It remains unclear whether the dietary changes are a cause, a consequence, or a vicious cycle of ADHD.
  • reduced ferritin levels in ADHD and CDS49

A study found that ferritin levels remained unchanged in children with ADHD or ASD.50

2.3.2. Iron

Serum iron is a genetically associated candidate for an increased risk of ADHD.51

Regarding ADHD, 5 sources on iron found evidence of reduced iron levels in people with ADHD, 5 sources found no correlation, and one study found evidence of elevated iron levels in the brain of adults with ADHD.

Evidence of reduced peripheral iron levels in ADHD (5 sources, including 2 meta-analyses and 1 review):

  • The positive effects of iron on ADHD
    • meta-analysis52
    • Meta-analysis53
  • Iron deficiency was associated with ADHD54
    • Iron deficiency was associated with sleep problems in people with ADHD.55
    • Iron deficiency was also associated with restless legs syndrome and sleep problems.55
  • significantly reduced iron levels in the brains of children with ADHD in
    • Globus pallidus56
    • Putamen56
    • Caudate nucleus56
    • Thalamus56
    • Nucleus ruber56
    • Bilateral limbic region of the striatum57
      • Which correlated with a higher severity of ADHD symptoms, while lower tissue iron levels in the left limbic striatum correlated only with the severity of anxiety, depression, and affective symptoms.
  • Iron deficiency in the brain associated with ADHD is resolved by stimulant medication. The increase in iron levels in the brain correlated with the duration of stimulant use and was greater in older children than in younger children.56 Iron deficiency may therefore be a consequence rather than a cause of ADHD, which is consistent with the very modest effect size of treating iron deficiency in ADHD on ADHD symptoms.

Five sources found no clear correlation between serum iron levels and ADHD: (meta-analysis)14 (meta-analysis, k = 6, n = 986)58596061

One source found evidence of elevated iron levels in the brain among adults with ADHD:

  • particularly in the right precentral cortex62

The prevalence of insufficient iron intake was reported as

  • in Europe, between 8% and 24%3
  • 20% of preschool-aged children55
  • between 0% and 20% in Europe 3
  • for adults in Germany
    • 7.1% (men aged 19 to 64)
    • 4.5% (men aged 65 and older)
    • 6.1% (women aged 65 and older)
  • About 10% of Europeans. People with ADHD are particularly affected by it
    • Women
      In particular:
      • of childbearing age
      • after menstruation
        • Heavy menstrual bleeding in women was associated with ADHD symptoms63
      • during pregnancy
      • while breastfeeding
    • Children
    • Teens
    • People on dialysis
    • for acute inflammation
      • chronic intestinal diseases
      • Gastritis
    • Heart failure
    • Cancers

Symptoms of iron deficiency may include:

  • Brittle, dull, and fragile hair
  • Hair Loss
  • Rough, chapped skin
  • Cracked corners of the mouth
  • Brittle nails
  • Hollow nails (nails that curve inward)
  • Burning sensation in the tongue with pain when swallowing
  • Abnormal food cravings, such as for chalk, dirt, or ice cubes (pica)
  • Impair (athletic) performance
  • Depression
  • Headaches
  • Fatigue
  • Concentration problems
  • Restless legs
  • Sleep Disorders

Excess iron is just as harmful as iron deficiency. As with all vitamins and minerals, the following applies:

  1. Take measurements first (repeat annually)
  2. Then just make up the shortfall

During acute infections, iron supplementation may be harmful.64

2.4. Manganese

Manganese is an essential mineral and is obtained from food. Important sources of manganese include tea, juices, grains, rice, nuts, seafood, chocolate, fruits, vegetables, seeds, and spices.
Manganese acts as a coenzyme. It is involved in and essential for:6566

  • Bone formation
  • Macronutrient Metabolism
  • Neutralizing free radicals
    • Manganese is a component of manganese superoxide dismutase (MnSOD), which, as a primary antioxidant, neutralizes reactive oxygen species in the mitochondria during oxidative stress
  • Brain function and development67
  • Antioxidant activator
  • necessary for insulin synthesis and secretion

Manganese deficiency can cause{Visternicu M, Rarinca V, Burlui V, Halitchi G, Ciobică A, Singeap AM, Dobrin R, Mavroudis I, Trifan A (2024): Investigating the Impact of Nutrition and Oxidative Stress on Attention Deficit Hyperactivity Disorder. Nutrients. September 15, 2024;16(18):3113. doi: 10.3390/nu16183113. PMID: 39339712; PMCID: PMC11435085. REVIEW}}

  • Carbohydrate metabolism disorder
  • Brain Dysfunctions

Excess manganese can cause:68

  • cognitive deficits69
  • Attention and learning difficulties6970
  • Executive problems71
  • Hyperactivity (meta-analysis)72
  • emotional problems69
  • A study found that this depends on the genotype of the manganese transporter and that girls are more sensitive to manganese than boys in terms of ADHD symptoms.73

Manganese can affect the dopaminergic system.746870

A meta-analysis found elevated manganese levels in the hair, but not in the blood, of children with ADHD.75 Another study found 27% less manganese in the hair of children with ADHD. However, low hair manganese levels could not be used as a diagnostic tool for ADHD.19

Another study reports that methylphenidate administration significantly reduced manganese levels.76

2.5. Copper

In ADHD, metabolism may be altered with regard to cobalt, copper, lead, zinc, and vanadium. Reduced cycle stability (determinism), duration (mean diagonal length), and complexity (entropy) of the exposure profiles were observed.12

A dysregulation of copper or zinc can increase susceptibility to oxidative damage to tissues or oxidative stress in the brain by impairing the body’s antioxidant defenses, which may be a potential cause of ADHD.77

Several enzymes believed to play a key role in the neurophysiology of ADHD are copper-dependent.78

Excess copper can promote the oxidation of dopamine and its metabolite, salsolinol, leading to the degeneration of dopaminergic neurons.79

Children with ADHD were found to have 10% less copper in their hair. However, low hair copper levels could not be used as a diagnostic tool for ADHD.19

A study found that children with ADHD had average serum blood levels of the following, compared to those without ADHD:18

  • Zinc: 7% lower
  • Chromium: reduced by 21%
  • Magnesium: reduced by 4%
  • Copper-to-zinc ratio: increased by 11%
    • So, copper has increased

Another study of children with type 1 diabetes and ADHD also found an elevated copper-to-zinc ratio.80

A study found reduced levels in plasma, red blood cells, urine, and hair in children with increased hyperactivity of81

  • Magnesium
  • Zinc
  • Copper
  • Iron
  • Calcium

One study found no change in blood copper levels among children with ADHD. Changes in blood copper levels or blood ceruloplasmin levels also did not correlate with ADHD symptoms within the group of participants with ADHD.82
A study found slight evidence suggesting a role for copper in ADHD. No evidence of a link was found for other micronutrients.83
A study of Egyptian children found that 70% had a copper deficiency.23

A large study found reduced zinc levels in the blood of children with ADHD, while levels of magnesium, copper, iron, and lead remained unchanged.20

2.6. Cobalt

Children with ADHD were found to have 18% less cobalt in their hair. However, low hair cobalt levels could not be used as a diagnostic tool for ADHD.19

2.7. Silicon

Children with ADHD were found to have 16% less silicon in their hair. However, low hair silicon levels could not be used as a diagnostic tool for ADHD.19

2.8. Chromium

A study found altered blood serum levels in children with ADHD compared to those without the condition:18

  • Zinc: 7% lower
  • Chromium: reduced by 21%
  • Magnesium: reduced by 4%
  • Copper-to-zinc ratio: increased by 11%

Another study found altered levels of84

  • Bismuth: 8-fold increase
  • Chromium: 15% reduction (and the strongest predictor of ADHD symptoms)
  • Germanium: reduced by 11%

2.9. Vanadium

In ADHD, metabolism may be altered with regard to cobalt, copper, lead, zinc, and vanadium. Reduced cycle stability (determinism), duration (mean diagonal length), and complexity (entropy) of the exposure profiles were observed.12

2.10. Bismuth

A study found altered levels of [substance] in the hair of children with ADHD84

  • Bismuth: 8-fold increase
  • Chromium: 15% reduction (and the strongest predictor of ADHD symptoms)
  • Germanium: reduced by 11%

2.11. Germanium

A study found altered levels of [substance] in the hair of children with ADHD84

  • Bismuth: 8-fold increase
  • Chromium: 15% reduction (and the strongest predictor of ADHD symptoms)
  • Germanium: reduced by 11%

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