Oxidative Stress

Overview

Oxidative stress is a biological dysfunction that contributes to cognitive, emotional, and behavioral dysregulation in ADHD and other neurodevelopmental conditions. Oxidative stress arises when reactive oxygen/nitrogen species (ROS/RNS) exceed antioxidant capacity, damaging lipids, proteins, DNA, and impairing mitochondrial efficiency. In ADHD, adult cohorts frequently show elevated lipid peroxidation and oxidative indices, while antioxidant status appears normal or variably shifted, consistent with greater oxidative load rather than a primary antioxidant deficit. The BRAIN Diet targets oxidative stress through antioxidant networks, key cofactors, and strategies to reduce oxidative load, treating oxidative stress as a state-sensitive, potentially modifiable contributor to symptom severity (paper.txt, lines 619-620).

Recipes

Therapeutic Areas

Substances

Biological Implications

Definition and Mechanisms

Oxidative stress arises when reactive oxygen/nitrogen species (ROS/RNS) exceed antioxidant capacity, damaging lipids, proteins, DNA, and impairing mitochondrial efficiency. In ADHD, adult cohorts frequently show elevated lipid peroxidation and oxidative indices, while antioxidant status appears normal or variably shifted, consistent with greater oxidative load rather than a primary antioxidant deficit. Multiple real-world factors contribute i.e. sleep and circadian disruption, glycaemic variability/insulin resistance, high-ω-6/oxidised oils, alcohol, smoke/pollution, and dietary source contaminants (metals, Ultra Processed Foods UPFs) (paper.txt, line 619).

The BRAIN Diet targets this network by combining polyphenol-dense foods, omega-3s, sulfur amino acids (cysteine/glycine), and key cofactors (Se/Zn/Cu) with exposure control and gentler cooking to lower dietary AGE/ALE load. We treat oxidative stress as a state-sensitive, potentially modifiable contributor to symptom severity and predefine biomarkers to test whether lowering redox load improves outcomes. In neurodevelopmental conditions such as ADHD, there is increasing recognition that oxidative stress, mitochondrial dysfunction, and neuroinflammation contribute to cognitive, emotional, and behavioral dysregulation (paper.txt, line 620).

Biomarkers and Evidence

Regarding oxidative stress, many studies have isolated potential biomarkers for ADHD, though some studies have sometimes shown marginal results there is a clear positive pattern showing oxidative stress as a correlation with ADHD. A foundational study found significantly higher Malondialdehyde levels in adult ADHD, a lipid-peroxidation marker, compared with healthy controls, indicating increased oxidative stress. More recently, studies reported a shift in thiol/disulfide homeostasis toward oxidation and higher urinary 8-OHdG (DNA oxidation) in adults with ADHD versus controls, consistent with increased oxidative damage. In an independent cohort, studies found elevated oxidative stress index (OSI) / total oxidative status (TOS), supporting impaired redox balance in adult ADHD, suggesting malondialdehyde (MDA) and superoxide dismutase (SOD) levels may be effective biomarkers in diagnosing ADHD while they noted the need to better understand the negative role of oxidative stress in ADHD (paper.txt, line 621).

Testable Hypothesis

Rather than treating MDA/SOD as just diagnostic markers of oxidative stress, they could be framed as a potentially modifiable amplifier of symptom severity of ADHD. Future clinical trials of the BRAIN Diet should explicitly test whether lowering redox load improves clinical outcomes. Comparing Total Antioxidant Capacity (TAC) with oxidative damage markers (e.g., MDA/4-HNE, 8-OHdG) before and after the trial against ADHD related cognitive biomarkers could be a real potential future biomarker for ADHD (paper.txt, line 686).

Link to Mitochondrial Dysfunction

When the amount of anti-oxidants generated is inadequate to offset the detrimental effects of hazardous reactive oxygen species ROS, oxidative stress arises. Increased oxidative stress has been linked to cellular damage, DNA repair system malfunction, and in turn mitochondrial dysfunction (paper.txt, line 735).

Antioxidant Networks

While the body has multiple endogenous antioxidant defenses, including enzymes like superoxide dismutase and glutathione peroxidase, these can become overwhelmed in states of chronic inflammation, nutrient deficiency, or high metabolic demand. Lester Packer introduced the concept of the "antioxidant network", detailing how key compounds like vitamin E, vitamin C, lipoic acid, glutathione, and CoQ10 have been shown to work synergistically and regenerate each other in vivo (paper.txt, line 624).

Although high-dose antioxidant supplements have shown inconsistent or even harmful effects in the rare case of the Vitamin E clinical trials and prostate cancer, diets rich in natural antioxidant compounds have demonstrated robust benefits. The Green Mediterranean Diet DIRECT-PLUS studies, led to significantly greater reductions in visceral adipose and neuroprotective effects. This effect was accompanied by increases in microbiome-derived metabolites like urolithin A, reinforcing the synergistic role of polyphenols, fibre, and gut-derived antioxidants in improving metabolic and cognitive resilience (paper.txt, line 625).

BRAIN Diet Framework

The framework of the BRAIN Diet embraces:

The acknowledge of the theoretical strength of the antioxidant network i.e. working many different antioxidants into the diet and precursors for endogenous antioxidants
Emphasize food-based sources rich in polyphenols, flavonoids, and balanced antioxidants.
Avoid promoting high-dose single-nutrient supplementation unless there's clinical justification and consultation and agreement with healthcare professionals
Highlight synergy in whole-foods, not megadoses of any one food source (paper.txt, lines 626-630).

Complex Antioxidant Networks and Mineral Cofactors

By supplying a spectrum of antioxidants (vitamins C and E, polyphenols, carotenoids, and omega 3 alongside mitochondrial supports (CoQ₁₀, lipoic acid, B-vitamins, k2) and trace minerals (selenium, zinc, copper), we can potentially increase the protection of neurons, preserve mitochondrial energy production, and reduce harmful inflammatory cascades, creating a better basis for optimal cognitive and emotional resilience (paper.txt, lines 632-634).

The antioxidant family also includes essential minerals that serve as cofactors for antioxidant enzymes. Selenium, zinc, and manganese, for instance, are crucial for the proper functioning of various antioxidant systems within the body. This intricate network of antioxidants works synergistically, with each component complementing the others to maintain cellular health and prevent oxidative damage (paper.txt, lines 636-638).

Key Antioxidant Compounds

Isothiocyanates (ITCs) like sulforaphane, created through enzymatic activity from glucoraphanin in broccoli, have also shown promising results in reducing oxidative stress and offering protection against various chronic diseases, including cancer and cardiovascular disorders while also showing higher bioavailability than other polyphenol-based dietary supplements that also activate Nrf2 (paper.txt, line 640).

Phenolic acids represent some of the most abundant antioxidants in plant-based foods, with whole grains and bran being especially rich sources. Among these, ferulic acid stands out as a key compound illustrating how food matrix effects translate into brain resilience. Processing methods such as sprouting and fermentation profoundly shape polyphenol bioavailability releasing bound ferulic acid, and enhancing bioavailability. Once ferulic acid is absorbed, it crosses the blood–brain barrier, scavenges reactive oxygen species, and synergizes with vitamins C and E to stabilize neuronal membranes and preserve DHA. Such mechanisms highlight why dietary patterns emphasizing whole, minimally processed grains may deliver neuroprotective effects beyond their macronutrient profile (paper.txt, lines 642-645).

Carotenoids, particularly lutein, zeaxanthin, and β-carotene, play a neuroprotective role through their antioxidant and anti-inflammatory properties. These fat-soluble pigments accumulate selectively in neural tissues, including the retina and brain, where they help scavenge reactive oxygen species and stabilize cell membranes. Lutein and zeaxanthin, for instance, have been associated with improved cognitive performance, especially in domains such as memory, processing speed, and visual-spatial function. β-carotene, as both an antioxidant and vitamin A precursor, also supports immune regulation and neuronal development (paper.txt, line 647).

Quercetin is an effective antioxidant agent which scavenges ROS and has antioxidant, anti-inflammatory, and anti-neuroinflammatory and neuroprotective properties. Isoquercetin (glycosylated quercetin) is more completely absorbed than quercetin in the aglycone form, and that the simultaneous ingestion of quercetin with vitamin C, folate and additional flavonoids improves bioavailability (paper.txt, line 675).

Genistein, a soy-derived isoflavonoid, has shown potential as a modulator of several biochemical pathways, including the endocannabinoid system and neuroinflammation. It has been confirmed to have the ability to alleviate the deleterious effects of oxidative stress on neuronal injury, such as preventing neuronal death, increasing the production of hippocampal glutathione (GSH) and superoxide dismutase (SOD), and lowering lipid peroxidation, ROS, and nitric oxide production. Since genistein is believed to pass the blood–brain barrier to exert its neuroprotective effect, it is extensively applied in the investigation of the treatment of neurodegenerative diseases, such as Alzheimer's and Huntington's (paper.txt, line 677).

Glutathione (GSH) is one of the body's major antioxidants. Low levels may suggest oxidative stress; elevated GSH levels which have been recorded against ADHD subjects may reflect a compensatory response to increased oxidative stress. Furthermore, mitochondrial metabolism of lactate depends on GSH for ROS neutralization, optimizing mitochondrial energy use (paper.txt, line 653).

Dietary Sources of Contamination and Heavy Metals

Heavy metals are detoxified in the body by metallothionein (MT) metal carrier proteins that must bind with Zn and copper (Cu). In women, a high-fiber (vegetarian) pattern showed near-complete fecal recovery of dietary cadmium and no increase in blood/urine Cd despite higher Cd intake, suggesting fibre/phytate-mediated inhibition of absorption; low ferritin was the key predictor of higher body Cd (paper.txt, lines 658-659).

Repleting essential minerals (calcium, iron, zinc) together with dietary fibres, phytates, and polyphenols reduces gastrointestinal absorption of toxic metals (lead, cadmium, mercury, aluminium). This lowers systemic levels and blood–brain barrier transport, reduces brain metal accumulation, and ultimately decreases oxidative-stress burden and neurotransmission disruption (paper.txt, lines 661-663).

ADHD has been linked with metals contamination and UPFs which contain among other additives high amounts of metals, particularly in food colourings; ADHD and other neuropsychiatric disorders have been also linked to maternal food habits such as high UPF consumption. Besides heavy metals micro/nanoplastics (MNPs) are being linked to many diseases, reproductive health and ADHD. Anthocyanins, especially C3G-rich sources like berries, purple potatoes, and black goji, serve as natural chelation agents for heavy metals and environmental contaminants, neuroprotective molecules that support synaptic resilience and detox pathways, and detox allies against microplastics and hormone-disrupting pollutants (paper.txt, lines 665-668).

Multiple meta-analyses show blood lead levels <5 µg/dL are associated with increased ADHD risk, even at "low" environmental levels. Lead interferes with prefrontal cortex development, synaptic pruning, and dopamine signaling. While ADHD is associated with higher oxidative stress and weaker antioxidant defense (e.g. reduced glutathione, increased lipid peroxidation). Metals will generate ROS, so this adds another layer of vulnerability (paper.txt, line 669).

Dietary patterns common in ADHD (e.g. low micronutrient density, irregular meals, high sugar/processed food intake) can increase absorption of toxic metals while also sometimes containing lower competing minerals like calcium, iron, and zinc which bind to toxic metals. This leaning towards a poor Western diets, characterised as Western diets are characterized by excess consumption of saturated fats, over-refined sugars, and animal-based protein and low consumption of plant-based fiber, have been shown to have higher levels of oxidative stress and a greater risk of chronic disease (paper.txt, line 670).

Advanced Glycation End Products (AGEs) and Cooking Methods

Higher cooking temperature/time increases Maillard products/AGEs, elevating oxidative stress and microglial activation, which reduces synaptic plasticity. Favoring gentler cooking methods to limit AGE formation can better preserve neuronal function (paper.txt, line 226).

Advanced Glycation & Lipoxidation End Products (AGEs / ALEs): High-heat cooking of fats and proteins produces AGEs/ALEs, which can cross the BBB, activate microglia, and impair synaptic plasticity—mechanisms implicated in cognitive decline (paper.txt, line 203).

Integration with Other Systems

These findings reinforce the importance of nutrient strategies within the BRAIN Diet that support NAD⁺ availability, glutathione synthesis, and mitochondrial health, such as niacin-rich foods (e.g., salmon, chicken breast, turkey, peanuts, and mushrooms), sulphur-containing vegetables that provide glutathione precursors (e.g., broccoli, Brussels sprouts, garlic, onions), and polyphenol-rich sources (e.g., blueberries, green tea, dark chocolate, extra virgin olive oil) (paper.txt, line 701).

References

Significantly higher Malondialdehyde levels in adult ADHD compared with healthy controls, indicating increased oxidative stress Bulut et al. 2007
Shift in thiol/disulfide homeostasis toward oxidation and higher urinary 8-OHdG (DNA oxidation) in adults with ADHD versus controls Kurhan and Alp 2021
Elevated oxidative stress index (OSI) / total oxidative status (TOS) in adult ADHD, suggesting malondialdehyde (MDA) and superoxide dismutase (SOD) levels may be effective biomarkers Miniksar et al. 2023
Increased oxidative stress linked to cellular damage, DNA repair system malfunction, and mitochondrial dysfunction Solleiro-Villavicencio and Rivas-Arancibia 2018
The "antioxidant network" concept: key compounds like vitamin E, vitamin C, lipoic acid, glutathione, and CoQ10 work synergistically and regenerate each other in vivo Packer et al. 1997
High-dose antioxidant supplements have shown inconsistent or even harmful effects in the Vitamin E clinical trials and prostate cancer Klein et al. 2011
The Green Mediterranean Diet DIRECT-PLUS studies led to significantly greater reductions in visceral adipose and neuroprotective effects Zelicha et al. 2022
Green Mediterranean Diet effects accompanied by increases in microbiome-derived metabolites like urolithin A, reinforcing the synergistic role of polyphenols, fibre, and gut-derived antioxidants Pachter et al. 2024
Dietary antioxidant treatment of ADHD accounted for substantial alterations in the immune system, epigenetic regulation of gene expression, and oxidative stress regulation Verlaet et al. 2018
Selenium, zinc, and manganese are crucial for the proper functioning of various antioxidant systems within the body Mocchegiani and Malavolta 2019
The intricate network of antioxidants works synergistically, with each component complementing the others to maintain cellular health Vertuani, Angusti, and Manfredini 2004
Sulforaphane shows higher bioavailability than other polyphenol-based dietary supplements that activate Nrf2 Houghton, Fassett, and Coombes 2016
Ferulic acid crosses the blood–brain barrier, scavenges reactive oxygen species, and synergizes with vitamins C and E to stabilize neuronal membranes and preserve DHA Shi et al. 2021
Carotenoids accumulate selectively in neural tissues, including the retina and brain, where they help scavenge reactive oxygen species and stabilize cell membranes Johnson 2014
Lutein and zeaxanthin have been associated with improved cognitive performance, especially in domains such as memory, processing speed, and visual-spatial function Yagi et al. 2021
Quercetin is an effective antioxidant agent which scavenges ROS Boots, Haenen, and Bast 2008
Isoquercetin (glycosylated quercetin) is more completely absorbed than quercetin in the aglycone form, and simultaneous ingestion with vitamin C, folate and additional flavonoids improves bioavailability Li et al. 2016
Genistein has the ability to alleviate the deleterious effects of oxidative stress on neuronal injury, such as preventing neuronal death, increasing the production of hippocampal glutathione (GSH) and superoxide dismutase (SOD), and lowering lipid peroxidation, ROS, and nitric oxide production Fuloria et al. 2022
Elevated GSH levels recorded in ADHD subjects may reflect a compensatory response to increased oxidative stress Verlaet et al. 2019
Heavy metals are detoxified in the body by metallothionein (MT) metal carrier proteins that must bind with Zn and copper (Cu) Zhai et al. 2015
A high-fiber (vegetarian) pattern showed near-complete fecal recovery of dietary cadmium and no increase in blood/urine Cd despite higher Cd intake, suggesting fibre/phytate-mediated inhibition of absorption Berglund et al. 1994
ADHD has been linked with metals contamination and UPFs which contain among other additives high amounts of metals, particularly in food colourings Dufault et al. 2024
Micro/nanoplastics (MNPs) are being linked to many diseases, reproductive health and ADHD Zhang et al. 2025
Western diets characterized by excess consumption of saturated fats, over-refined sugars, and animal-based protein and low consumption of plant-based fiber have been shown to have higher levels of oxidative stress and a greater risk of chronic disease Jiang et al. 2021
Higher cooking temperature/time increases Maillard products/AGEs, elevating oxidative stress and microglial activation, which reduces synaptic plasticity Uribarri et al. 2010
High-heat cooking of fats and proteins produces AGEs/ALEs, which can cross the BBB, activate microglia, and impair synaptic plasticity Uribarri et al. 2010

Overview​

Recipes​

Chocolate Quinoa Crisp Clusters

Ginger Yogurt and Blueberries

Matcha Mitochondria Smoothie

Turmeric Lentil Dahl

Turmeric Milk

Mitochondrial Power Bowl

Rocket Lentil Avocado Midday Salad (Gut-Supporting)

Therapeutic Areas​

ADHD

Alzheimer's Disease

Anxiety & GAD

Bipolar Disorder

Depression & MDD

Substances​

β-Carotene

Lutein

Lycopene

Zeaxanthin

Coenzyme Q10 (CoQ10)

Curcumin (Turmeric)

EGCG (Green Tea Catechin)

Quercetin (and Isoquercetin)

Genistein

Hydroxytyrosol (Olive Polyphenol)

Tyrosol

Oleacein

Oleuropein

Saffron (Crocin, Safranal)

Butyrate

Short-Chain Fatty Acids (SCFAs)

Urolithin A

ALA (Alpha-Linolenic Acid)

Omega-3 Fatty Acids

Arachidonic Acid (AA, n-6)

Linoleic Acid (LA, n-6)

Copper

Manganese

Selenium

Zinc

Vitamin A (Retinoids; β-Carotene precursor)

Vitamin C (Ascorbate)

Vitamin E (Tocopherols/Tocotrienols)

Biological Implications​

Definition and Mechanisms​

Biomarkers and Evidence​

Testable Hypothesis​

Link to Mitochondrial Dysfunction​

Antioxidant Networks​

BRAIN Diet Framework​

Complex Antioxidant Networks and Mineral Cofactors​

Key Antioxidant Compounds​

Dietary Sources of Contamination and Heavy Metals​

Advanced Glycation End Products (AGEs) and Cooking Methods​

Integration with Other Systems​

References​