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ADHD as a Metabolic Disorder: The Role of Nutrients, Mitochondria, and Oxidative Stress

cells

Emerging research is reshaping our understanding of ADHD and other neurodevelopmental and neurodegenerative conditions, including autism, schizophrenia, and dementia. These conditions are increasingly being recognised as metabolic disorders. At their core lies dysfunction in the body’s ability to transport and utilise energy effectively in the brain. This deficiency disrupts critical cognitive and emotional processes.

Metabolism and Brain Health

The human body comprises trillions of cells, each responsible for transporting energy throughout the body, including the brain. Food provides the essential vitamins, minerals, and nutrients that mitochondria – tiny cellular “powerhouses” – convert into ATP, the body’s energy currency. ATP fuels the countless processes necessary for life. However, when cells lack the nutrients needed to function properly, ATP production declines, leading to cellular damage or even cell death. This is particularly critical in the brain, where energy demands are exceptionally high.

A growing body of evidence suggests that metabolism plays a pivotal role in powering the brain. Maintaining a robust metabolism through a healthy diet (and sometimes supplements) is essential for optimal brain function. Without sufficient nutrients, the brain cannot function effectively, highlighting the importance of a nutrient-rich diet for metabolic and neurological health.

Early Research on Malnutrition and Cognitive Outcomes

Janine Galler’s pioneering research, beginning in 1967, explored the long-term effects of early-life malnutrition on behaviour and neurological development. Her study of 129 children who experienced severe protein-energy malnutrition during their first year of life revealed:

Persistent Cognitive and Behavioural Impacts

  • Malnourished children exhibited lower IQs and long-term deficits in academic, vocational, and social outcomes, despite physical growth improvements with nourishment.
  • Cognitive impairments included reduced stress adaptability and ADHD-like symptoms such as attention problems, restlessness, and memory deficits.

Neurological Changes

  • Participants showed smaller brain volumes, fewer neural connections, and delays in language and sensory integration.
  • These changes led to lifelong ADHD symptoms, with 69% of participants showing clinical ADHD symptoms in middle adulthood.

Global Context

  • Studies such as Walker et al.’s research on stunted Jamaican children found increased hyperactivity, anxiety, and depression in adolescence.
  • A WHO survey linked adolescent attention problems to long-term behavioural and mental health challenges in adulthood, including ADHD and mood disorders.

Micronutrient Deficiencies and ADHD

Global malnutrition and deficiencies in micronutrients such as zinc, magnesium, and iron are closely linked to ADHD symptoms. Studies in both developed and developing nations indicate that poor diet quality contributes to these deficiencies. For instance, a 2017 study in Japan found over 50% of children with ADHD had suboptimal nutrition, with 11% experiencing severe malnutrition.

These findings underscore the critical connection between diet, metabolism, and neurological disorders like ADHD.

The Link Between Metabolic Health and Brain Health

Could it be mere coincidence that the rise of processed foods, “low-fat” alternatives (that contain more sugar!), and excessive carbohydrate intake has paralleled an exponential increase in metabolic syndrome conditions – such as pre-diabetes, high blood pressure, and abnormal cholesterol levels – alongside a surge in mental health issues? Based on the research and the perspectives of world-renowned experts like Harvard psychiatrist Chris Palmer, I think not! Science highlights the profound connection between metabolic health and mental wellbeing, suggesting that the dietary shifts of the modern era may be contributing significantly to our biological and mental health challenges.

As one study suggests, ‘The emerging association between psychiatric and metabolic disorders suggests a fundamental biologic link between these two systems… disparate conditions such as insulin resistance, diabetes, hypertension, syndrome X, obesity, ADHD, depression, psychosis, sleep apnea, inflammation, autism, and schizophrenia may operate through common pathways, and treatments used exclusively for one of these conditions may prove beneficial for the others.’ 1 This link between metabolic dysfunction and neurological conditions is also emphasised in this 2018 study and this 2022 study.

For me, and the reason I started this blog, is that we need to start approaching mental health challenges from a biological and neurological perspective. To truly understand the root of these issues, we must examine our body’s biological responses – not just to the food and drinks we consume, but also to what we take in through our environment via our sensory system. These inputs affect our body and brain on a cellular level, and it is vital to recognise that we are composed of trillions of cells and molecules, some of which – like DNA (the hereditary material in humans) – are shaped and mutated by generations of life experiences.2

If the cells that sustain our lives become dysfunctional – whether through generational trauma, a lack of essential nutrients, or exposure to harmful chemicals that our biology cannot process – it is no wonder that they would malfunction. Understanding what is causing the dysfunction and addressing these factors at the cellular level is key to unraveling the complex interplay between our physical and mental health.

So how does this relate to ADHD and other neurological conditions?

Mitochondrial Dysfunction in ADHD

Mitochondria are central to energy production and cellular health. Dysfunction in mitochondria contributes to reduced ATP production, limiting energy available for brain functions.

Research has identified mutations in the PARK2 locus, particularly in the cell model PARK2 CNV, as critical contributors to mitochondrial dysfunction. The PARK2 locus is essential for maintaining mitochondrial function, which plays a key role in brain development and plasticity. These mutations impair the production of ATP (the body’s energy currency) during sensitive developmental periods, such as embryonic development. This disruption in mitochondrial energy production has been strongly linked to ADHD and related neurodevelopmental disorders, such as autism and schizophrenia. These findings underscore the role of metabolic dysfunction in the development of these conditions. (Scielo Study).

Brain scans of individuals with ADHD show reduced activity, particularly in the prefrontal cortex, a region essential for decision-making, attention, and impulse control. These “dark areas” indicate poor blood flow, oxygenation, and nutrient supply, leading to dysfunction in these regions.

Disrupted Metabolic Pathways in Individuals with ADHD

Recent research has illuminated the intricate links between ADHD and five primary metabolic pathways:

  1. Amino Acid Metabolism and The Kynurenine Pathway, also involved in amino acid metabolism. Dysregulation in either pathway can lead to metabolic imbalances that contribute to oxidative stress and inflammation)
  2. Neurotransmitter Dysregulation
  3. Oxidative and Nitrosative Stress
  4. Fatty Acid Metabolism

The findings from various studies explore how these pathways interconnect and contribute to ADHD’s manifestation.

Amino Acid Metabolism and Homocysteine in ADHD

Homocysteine Metabolism

Homocysteine, an amino acid metabolised with the help of vitamins B6, B12, and folate, plays a critical role in brain health. Dysfunction in this process, termed hyperhomocysteinemia, is associated with ADHD and an increased risk of:

  • Hyperactivity and impulsivity: Oppositionality and hyperactivity/impulsivity symptoms in the ADHD group were related to vitamin B12 (MDPI Study).
  • Intellectual Disability: Elevated homocysteine levels disrupt protein and neurotransmitter synthesis, affecting brain structure and function. Folate–homocysteine pathway gene variants may affect ADHD etiology through mild hyperhomocysteinemia and vitamin B12 deficiency, factors known to be associated with cognitive deficit (Journal of Human Genetics).
  • Late-Life Depression: Low folate and B12 levels predict depression risk (a misdiagnosis often given to those who have ADHD), as shown in a prospective study of 732 Korean adults (Scielo Study).
  • Poor Cognitive Performance and Dementia: Elevated homocysteine levels correlate with neurotoxic effects (such as oxidative stress), impaired memory, and early cognitive decline (MDPI Study).

Key Findings:

  1. Vitamin B12 Deficiency:
    • Impairs dopamine-stimulated phospholipid methylation (PLM), essential for attention and neuronal synchronisation, particularly in ADHD and autism (PubMed Study).
    • Linked to greater learning problems and psychosomatic symptoms in children with ADHD (Tandfonline Study).
  2. Folate Deficiency:
  3. Counter Evidence:
    • Some studies report variability in homocysteine levels in ADHD due to differences in age, subtype, and comorbidities4 5 6

The evidence strongly links elevated homocysteine and reduced B12/folate levels with ADHD symptoms, neuropsychiatric disorders, and neurodegenerative conditions. Addressing these deficiencies through dietary changes and supplementation may improve cognitive and emotional outcomes.

In addition, studies with patients diagnosed with autism (ASD) have also shown low serum vitamin B12 levels7 and folate as well as increased levels of homocysteine8 9. These results were interpreted to reflect increased levels of oxidative stress and impaired DNA methylation which can be an important factor in the pathophysiology of ASD. I mention this because many people diagnosed with autism are also diagnosed with ADHD.

Oxidative and Nitrosative Stress (O&NS)

Mitochondrial Dysfunction has been linked to oxidative stress resulting from an imbalance between free radicals (unstable atoms that can change cells, damage DNA, and cause cell death) and the body’s antioxidant defenses that neurtalise free radicals. This imbalance damages cells, contributing to the pathophysiology of ADHD and other brain-related disorders.

The Frontiers Study demonstrates how Mitochondrial-generated oxidative stress affects a molecule involved in neuroplasticity, learning, and memory, called the BDNF.

The Role of Antioxidants in Preventing Oxidative and Nitrosative Stress (O&NS)

Antioxidants are substances that fight free radicals. Antioxidants play a key role in preventing oxidative and nitrosative stress (O&NS) by reducing the imbalance between reactive oxygen and nitrogen species (ROS/RNS) and the body’s antioxidant defenses.

Key Antioxidants:

  • Vitamins E and C: Found in fruits, vegetables, nuts, and seeds.
  • Omega-3 Fatty Acids: Improve brain function and reduce inflammation.
    • Sources: Fatty fish (e.g., salmon, mackerel), walnuts, flaxseeds.
  • Zinc: Plays a protective role against oxidative stress10 .
    • Sources: Nuts, seeds, seafood.

Omega-3 fatty acids play a role in brain health by supporting the structure of brain cells (neurons) and promoting efficient communication between them. Decreased blood levels of omega-3 fatty acids have been associated with several neuropsychiatric conditions, including Attention Deficit (Hyperactivity) Disorder, Alzheimer’s Disease, Schizophrenia and Depression. DHA is the predominant n-3 fatty acid found in the brain and Omega-3 (EPA) plays an important role as an anti-inflammatory precursor. Both DHA and EPA can be linked with many aspects of neural function, including neurotransmission, membrane fluidity, ion channel and enzyme regulation and gene expression.

They are essential for:

  1. Neuronal Structure: Omega-3s, particularly DHA (docosahexaenoic acid), are key components of neuronal membranes, maintaining their flexibility and integrity. Recent evidence indicates that in addition to the positive effects seen in chronic neurodegenerative conditions, omega-3 PUFA may also have significant neuroprotective potential in acute neurological injury11. 
  2. Cognitive Function: They enhance learning, memory, and overall cognitive performance by facilitating synaptic plasticity, the ability of brain cells to form and reorganise connections12. Some of nutritional factors have been described as a significant modifiers, which can influence brain elasticity and thus, effect on central nervous system functioning (Bentham Science).
  3. Neurotransmitter Regulation: Omega-3s influence the production and function of neurotransmitters like dopamine and serotonin, which are critical for mood regulation and attention.
  4. Anti-Inflammatory Effects: Omega-3s reduce brain inflammation, protecting neurons from damage associated with conditions like depression, ADHD, and neurodegenerative diseases13.
  5. Neuroprotection: They help prevent oxidative stress and promote the repair of damaged brain cells, supporting long-term brain health14 15.

In short, omega-3 fatty acids are essential for maintaining the brain’s structural and functional health throughout life.

By adding antioxidants to our diet, we can help prevent oxidative and nitrosative stress (O&NS) to support neuroplasticity, learning, and memory.

The Gut Microbiota and Its Relationship with Diet

The metabolic compounds of the gut microbiota might also be involved in maintaining the body’s oxidative balance.

The gut microbiota refers to the trillions of microorganisms – bacteria, viruses, fungi, and other microbes – that live in our digestive tract. These microbes play a crucial role in maintaining our overall health, influencing digestion, immune function, and brain health through the gut-brain axis, a bidirectional communication system between the gut and the central nervous system, , influencing brain function, mood, and behaviour.

Gut microbiota supports digestion and nutrient absorption, regulates our immune system, preventing excessive inflammation and reducing susceptibility to diseases, and produces key neurotransmitters like dopamine and serotonin.

A poor diet, particularly one high in processed foods, refined sugars, and unhealthy fats can negatively affect the gut microbiota, leading to several health issues, including metabolic disorders, inflammation, and mental health conditions, such as anxiety, depression, and attention-related issues (like ADHD!).

How to Support a Healthy Gut Microbiota

  • Increase Fiber Intake: Fiber-rich foods such as fruits, vegetables, whole grains, and legumes feed beneficial gut bacteria.
  • Incorporate Fermented Foods: Foods like yogurt, kefir, sauerkraut, and kimchi introduce probiotics (beneficial bacteria) to the gut.
  • Limit Processed Foods and Sugars: Reducing these minimises the growth of harmful bacteria.
  • Consume Prebiotics: Foods like garlic, onions, bananas, and asparagus act as food for beneficial bacteria.
  • Stay Hydrated: Adequate water intake supports digestion and microbial health.

A poor diet doesn’t just affect physical health – it also compromises gut health, which can ripple through to impact immune function, inflammation, and brain health. Supporting a balanced and diverse gut microbiota is essential for both mental and physical wellbeing.

Conclusion

Research shows that ADHD is not merely a behavioural or psychological condition – it is deeply rooted in metabolic dysfunction. Research, from early malnutrition studies to the impact of micronutrient deficiencies and mitochondrial impairments, demonstrates that the nutrients we consume directly affect the brain’s ability to function. Poor diet quality, whether through processed foods, nutrient insufficiencies or even undiagnosed allergies to food products, harms the intricate metabolic pathways that sustain brain health.

By focusing on a nutrient-rich diet, supporting mitochondrial function, and addressing oxidative stress, researchers say we can target the root causes of ADHD and related conditions. This integrative approach, rooted in biology and metabolism, has the potential to transform both physical and mental health outcomes, offering a path toward greater wellbeing.

References:

  1. Kimberly A. Bazar, Anthony J. Yun, Patrick Y. Lee, Stephanie M. Daniel, John D. Doux,
    Obesity and ADHD may represent different manifestations of a common environmental oversampling syndrome: a model for revealing mechanistic overlap among cognitive, metabolic, and inflammatory disorders, Medical Hypotheses, Volume 66, Issue 2, 2006, Pages 263-269, ISSN 0306-9877, https://doi.org/10.1016/j.mehy.2005.02.042.
    (https://www.sciencedirect.com/science/article/pii/S0306987705001672) ↩︎
  2. There are many studies now looking at the contribution of epigenetics (such as DNA contributions) in neurodevelopmental conditions such as ADHD and ASD. ↩︎
  3. Tanusree Saha, Mahasweta Chatterjee, Deepak Verma, Anirban Ray, Swagata Sinha, Usha Rajamma, Kanchan Mukhopadhyay,
    Genetic variants of the folate metabolic system and mild hyperhomocysteinemia may affect ADHD associated behavioral problems, Progress in Neuro-Psychopharmacology and Biological Psychiatry,
    Volume 84, Part A, 2018, Pages 1-10, ISSN 0278-5846, https://doi.org/10.1016/j.pnpbp.2018.01.016.
    (https://www.sciencedirect.com/science/article/pii/S0278584617307613) ↩︎
  4. Genetic variants of the folate metabolic system and mild hyperhomocysteinemia may affect ADHD associated behavioral problems ↩︎
  5. Micronutrient Deficiencies in ADHD: A Global Research Consensus. ↩︎
  6. Homocysteine, pyridoxine, folate and vitamin B12 levels in children with attention deficit hyperactivity disorder ↩︎
  7. Yektaş Ç, Alpay M, Tufan AE. Comparison of serum B12, folate and homocysteine concentrations in children with autism spectrum disorder or attention deficit hyperactivity disorder and healthy controls. Neuropsychiatr Dis Treat. 2019 Aug 6;15:2213-2219. doi: 10.2147/NDT.S212361. PMID: 31496704; PMCID: PMC6689552. ↩︎
  8. Altun H, Kurutaş EB, Şahin N, Güngör O, Fındıklı E. The Levels of Vitamin D, Vitamin D Receptor, Homocysteine and Complex B Vitamin in Children with Autism Spectrum Disorders. Clin Psychopharmacol Neurosci. 2018 Nov 30;16(4):383-390. doi: 10.9758/cpn.2018.16.4.383. PMID: 30466210; PMCID: PMC6245292. ↩︎
  9. https://www.frontiersin.org/journals/molecular-neuroscience/articles/10.3389/fnmol.2022.947513/full ↩︎
  10. David J Eide, The oxidative stress of zinc deficiency, Metallomics, Volume 3, Issue 11, November 2011, Pages 1124–1129, https://doi.org/10.1039/c1mt00064k ↩︎
  11. Dyall, S.C., Michael-Titus, A.T. Neurological Benefits of Omega-3 Fatty Acids. Neuromol Med 10, 219–235 (2008). https://doi.org/10.1007/s12017-008-8036-z ↩︎
  12. Marianna Mazza, Massimiliano Pomponi, Luigi Janiri, Pietro Bria, Salvatore Mazza,
    Omega-3 fatty acids and antioxidants in neurological and psychiatric diseases: An overview,
    Progress in Neuro-Psychopharmacology and Biological Psychiatry, Volume 31, Issue 1, 2007, Pages 12-26, ISSN 0278-5846, https://doi.org/10.1016/j.pnpbp.2006.07.010.
    (https://www.sciencedirect.com/science/article/pii/S0278584606002983) ↩︎
  13. Tortosa-Caparrós, E., Navas-Carrillo, D., Marín, F., & Orenes-Piñero, E. (2017). Anti-inflammatory effects of omega 3 and omega 6 polyunsaturated fatty acids in cardiovascular disease and metabolic syndrome. Critical Reviews in Food Science and Nutrition, 57(16), 3421–3429. https://doi.org/10.1080/10408398.2015.1126549 ↩︎
  14. Javad Heshmati, Mojgan Morvaridzadeh, Saman Maroufizadeh, Abolfazl Akbari, Mahsa Yavari, Ali Amirinejad, Arezoo Maleki-Hajiagha, Mahdi Sepidarkish, Omega-3 fatty acids supplementation and oxidative stress parameters: A systematic review and meta-analysis of clinical trials, Pharmacological Research, Volume 149, 2019, 104462, ISSN 1043-6618, https://doi.org/10.1016/j.phrs.2019.104462.
    (https://www.sciencedirect.com/science/article/pii/S1043661819311910) ↩︎
  15. Mahadik, S. P., Pillai, A., Joshi, S., & Foster, A. (2006). Prevention of oxidative stress-mediated neuropathology and improved clinical outcome by adjunctive use of a combination of antioxidants and omega-3 fatty acids in schizophrenia. International Review of Psychiatry, 18(2), 119–131. https://doi.org/10.1080/09540260600581993 ↩︎