Oxidative stress and ADHD

Cells are dependent on a balanced oxidative equilibrium in which neither oxidizing nor reducing substances (oxidants and antioxidants) predominate, as an excess of one side damages the cell.
Oxidative stress is an excess of reactive oxygen species (ROS) or an inadequate breakdown of ROS, which leads to damage to the cells, especially the mitochondria.¹

Oxidants such as antioxidants can be absorbed through food or from the environment or produced in the body itself.
Oxidative stress can be caused by

• Food intake, medication, drugs, dentistry
  • Metals
    • Iron
    • Cadmium
    • Mercury
    • Titanium dioxide²
    • Copper
      • increased copper causes oxidation of dopamine
  • other chemicals
• intense blue and ultraviolet light (e.g. sunburn)
• ionizing radiation (causes DNA damage and cancer)
• Air pollution, in particular
  • Reactive oxygen species (ROS)
  • Reactive nitrogen species

Oxidative stress can impair the dopamine system.³

• 1. Increased oxidative stress in ADHD
• 2. Oxidative stress can increase neuroinflammation
• 3. ADHD medication reduces oxidative stress

1. Increased oxidative stress in ADHD¶

ADHD was found to have a decreased overall antioxidant status as well as an increased total oxidative status and oxidative stress index.¹⁴

Children and adolescents with ADHD were found to have:

• Marker for increased oxidative stress
  • Total antioxidant capacity (TAC), catalase (CAT), glutathione (GSH) and malondiadehyde (MDA)
  • Nitric oxide (ROS) increased in serum⁵
  • Nitric oxide synthase (NOS) increased in serum⁶
  • Nitrogen oxide levels increased⁷
  • Xanthine oxidase (XO) increased in serum⁶
  • Malondialdehyde in serum
    • increased⁵
    • unchanged⁸
• Antioxidants
  • Glutathione
    • increased in erythrocytes⁹
    • in serum is reduced
  • GSH peroxidase reduced in serum⁵
  • Paraoxonase-1 (PON-1) reduced in serum⁶
  • Catalase in serum reduced⁸
  • Superoxide dismutase reduced ⁷
  • Melatonin
    • Acts together with its metabolites as an indirect antioxidant¹⁰
    • Elevated in serum in ADHD¹¹
    • Degradation substances in urine increased throughout the day in ADHD¹²
      • Doubled on a daily average
      • 2.5-fold increase during the day
      • 1.5 times higher at night
    • Melatonin higher in children with ADHD-HI¹³¹⁴
    • MPH decreased melatonin metabolism in all ADHD subtypes¹⁴¹⁵
      • But not the melatonin serum level¹⁵
    • This is exciting in view of the fact that melatonin can cross the blood-brain barrier and the evening melatonin increase is supposed to promote sleep by eliminating light on the retina via a melatonin increase, while 75% of people with ADHD have a chronobiorhythm that is shifted backwards and at the same time melatonin as a spray has been shown to be very effective for sleep problems in ADHD.
  • total enzymatic antioxidant activity (TAC) reduced overall⁵⁸
• Markers of cellular immunity
  • Adenosine deaminase (ADA) activity increased in serum⁶

SHR, an ADHD animal model, showed:¹⁶

• increased production of reactive oxygen species (ROS) in the cortex, striatum and hippocampus
• Reduced activity of glutathione peroxidase in PFC and hippocampus

2. Oxidative stress can increase neuroinflammation¶

In chronic oxidative stress, proteins and lipids oxidize and DNA is damaged. ROS can also lead to the activation of astrocytes and microglia. High ROS concentrations could activate a strong release of proinflammatory chemokines and cytokines and trigger a vicious circle between oxidative stress and neuroinflammation ^{17 1819}
Neuroinflammation is considered a possible developmental pathway for ADHD.²⁰²¹

3. ADHD medication reduces oxidative stress¶

MPH improved the redox profile in humans with reduced levels of advanced oxidation protein products, lipid peroxidation and nitrite plus nitrate (NOx) and increased activities of the ROS-degrading enzymes glutathione reductase and catalase.²²

Single administration of MPH²³

• increased ROS superoxide (hyperoxide) in young rats at both low and high doses in the cerebellum and only at high doses (10 mg/kg) also in the hippocampus
• did not affect superoxide in adult rats
  Chronic administration (as is common as an ADHD medication)²³
• did not affect superoxide in young rats
• decreased superoxide in the cerebellum of adult rats at lower doses

(Reduced) glutathione (GSH) is the most important intracellular antioxidant.
GSH protects against oxidative stress by balancing the production and degradation of ROS, whereby it oxidizes to GSSH. The enzyme glutathione reductase uses NADPH to convert GSSG back into two reduced GSH.
One study found increased levels of glutathione in erythrocytes in ADHD and that oxidative stress in ADHD is not triggered by food choices and that this increases neuroinflammation.⁹