We write in response to the editorial on dietary supplementation for the treatment of attention-deficit hyperactivity disorder (ADHD). Although Rajyaguru & Cooper adequately reviewed some of the literature, ^{Reference Rajyaguru and Cooper1} they missed an opportunity to challenge current methodologies and they simultaneously perpetuated an outdated model of disease pathophysiology.

These authors promote the idea that one single nutrient can effect a consistent change in ADHD symptoms. However, such magic bullet thinking is at odds with human physiology (which requires the ingestion of many nutrients in balance) and largely explains why the single-nutrient strategy has yielded only modest benefits. ^{Reference Rucklidge, Johnstone and Kaplan2} Supplementing with broad-spectrum formulations ensures the patient's safety as the combination prevents imbalances, such as one nutrient causing a deficiency in another (e.g. taking zinc alone may cause copper deficiency). Recommending that researchers first understand how one nutrient functions on its own, in isolation, ignores the inevitable changes and potential for harm occurring in other nutrient levels.

In the authors' brief review of nutrients as part of a complex formula, they failed to highlight that this multi-ingredient method has the potential to be more beneficial for treating mental health symptoms than any one nutrient. ^{Reference Rucklidge and Kaplan3} The concept underlying the use of micronutrients for the amelioration of mental health symptoms is that mental illness may be a manifestation of suboptimal nutrition, relative to genetically determined needs for optimal brain metabolic activity. ^{Reference Ames, Elson-Schwab and Silver4} Neurotransmitters go through many metabolic steps to ensure synthesis, uptake and breakdown. Each step requires enzymes, and every enzyme is dependent on multiple co-enzymes (cofactors). A variety of vitamins and minerals are required as cofactors in most, if not all, of those steps. Some people may inherit an in-born error of metabolism that results in less-than-optimal use of nutrients that are present. ^{Reference Ames, Elson-Schwab and Silver4} Flooding the system with high doses of nutrients ensures that the body receives what it requires for optimal brain functioning.

We also challenge the article's focus on serum nutrient levels, as the authors often fail to identity individual nutrient requirements unless a frank nutritional deficiency is present. Serum levels are simply too crude to provide a complete picture of the metabolic needs of the brain. How accurately can peripheral metabolites and biomarkers predict change in a complex, multifactorial disorder such as ADHD and reflect what might be going on at a subcellular level in a metabolically active brain? ^{Reference Benton5} To date, no single biomarker for ADHD has achieved clinical utility as a diagnostic tool or a predictor of treatment outcome. ^{Reference Scassellati, Bonvicini, Faraone and Gennarelli6} We are not convinced that a single biological marker exists.

The one-disease, one-nutrient solution to mental disorders is outdated and needs to be replaced by a model that is responsive to the broad spectrum of human nutritional needs. Perhaps the perpetuation of single-nutrient studies continues because this methodology fits comfortably within the pharmaceutical paradigm and traditional scientific methodology where drugs are typically single ingredient and independent variables are manipulated one at a time. However, shifting psychiatric research towards a consideration of multi-ingredient formulations requires rethinking the scientific paradigm that has thus far shaped this field.