Annual Research Review: Micronutrients and their role in the treatment of paediatric mental illness

Abstract

The aim of this narrative review is to summarize evidence relating the importance of nutrient intake from diet and supplementation for paediatric mental health. We begin by reviewing several mechanisms by which nutrients maximize brain health, including enabling metabolic reactions to occur, supporting mitochondrial function, reducing inflammation and assisting with detoxification. Circumstances that may contribute to an individual requiring additional nutrients beyond what are available in the diet, such as consumption of nutritionally depleted food, individual differences in biological need, long-term medication use and gut–brain health needs are then reviewed. These factors underpin the importance of tackling deficiencies relative to individual metabolic requirements with a broad spectrum of micronutrients, as opposed to a single nutrient approach, to address personal metabolic needs and/or environmentally induced nutrient depletions. The evidence for treating psychological symptoms with supplementary micronutrients is presented, summarizing research using broad-spectrum micronutrients in the treatment of mental health issues including aggression, autism spectrum disorder, attention-deficit/hyperactivity disorder and emotional dysregulation, often with medium between-group effect sizes compared with placebo, with clinically meaningful changes. The breadth and consistency of the findings highlight the importance of receiving a complete foundation of nutrients to optimize brain health; however, the small number of studies identifies the importance of future work to replicate these preliminary findings. Documented safety in 8-week randomized controlled trials with open-label extensions up to 16 weeks and longer-term follow-up for 1.5–5 years in smaller samples provide reassurance that this treatment approach does not result in serious adverse events. We provide recommendations for future research including consistency in micronutrient interventions, scalable delivery models, effectiveness and implementation studies and the need to investigate these interventions in the prevention and management of less-studied childhood psychiatric conditions.

Introduction

In this article, we begin by reviewing several of the mechanisms by which nutrients optimize brain health. Next, we briefly summarize the evidence base relating diet to mental health, followed by considering the circumstances that may predispose an individual to require additional nutrients beyond what they can get from food. Next, the evidence for treating psychological problems in children with supplementary micronutrients is reviewed, with an emphasis on double-blind randomized controlled trials (RCTs) and meta-analyses, where possible. Finally, we discuss future research in this area.

The essential role of nutrition in optimizing mental health

The term ‘nutrition’ encompasses many food constituents that contribute to the development and maintenance of cellular function including macronutrients (fats, carbohydrates and proteins), micronutrients (minerals, vitamins and amino acids), as well as other nutritional components like phytonutrients. Minerals are stable chemical substances listed in the periodic table of elements. Plants absorb minerals from the soil and use them to synthesize vitamins, which are organic molecules (meaning they contain carbon). Humans must eat the plants (or eat animals that eat the plants) to obtain most of the minerals and vitamins required for physical and mental health.

There are other nutritional components that are important for brain health, such as essential fatty acids (especially omega3s) that are particularly critical for brain development in children’s early years (Huffman, Harika, Eilander, & Osendarp, 2011; McNamara & Carlson, 2006), amino acids (building blocks of proteins), carbohydrates (for energy) that North Americans usually consume in sufficient quantities and thousands of phytonutrients (plant-based nutrients), which help prevent physical disease. The reason for focusing on minerals and vitamins in this article is, in part, because they are generally taken for granted, despite their vital influence on mental health. Although the importance of minerals and vitamins for brain function has been understood for decades (Kaplan, Crawford, Field, & Simpson, 2007), this information is often not considered essential in understanding the development and maintenance of mental health problems in children.

The role of minerals and vitamins in the physiological functioning of the human body is complex and extensive. Although only required in small amounts, they are critical to a variety of biochemical processes. From a physical health perspective, minerals and vitamins are involved in electrolyte balance, support bone health, are essential for blood clotting, act as antioxidants and support the immune system. Relevant to brain function, minerals and vitamins serve as cofactors for enzymes that facilitate the brain’s metabolic functioning, support mitochondrial activities, modify gene expression, fight excess inflammation and protect from environmental toxins. Each of these functions will be discussed in turn.

Enabling the brain’s metabolism to function

In adults, every minute the heart beats about a litre of blood passes through the brain. That litre represents 15%–20% of the entire blood supply, but the brain is only about 2% of adult body weight. This fact underscores the brain’s high blood demand, requiring up to 10 times more blood than one might expect for an organ of its size. These ratios hold true for children as well, with some variation depending on their age and weight. In general, the brain consumes a disproportionate 20%–40% of the nutrients and energy obtained through our diet, emphasizing its dynamic metabolic needs (Leonard, Robertson, Snodgrass, & Kuzawa, 2003).

Metabolism, a set of biochemical processes involved in the transformation of one compound into another (as depicted in Figure 1), is integral to brain function. Enzymes play a pivotal role in facilitating these biochemical transformations within the brain, and they rely on a consistent supply of cofactors and coenzymes to perform their functions. These cofactors predominantly comprise micronutrients, including minerals and vitamins. Given that humans are unable to produce most of these minerals and vitamins internally, we have evolved to obtain these essential micronutrients from our dietary intake.

Figure 1.

Brain metabolism involves the conversion of one chemical to another with the assistance of enzymes whose activity is dependent on an adequate supply of cofactors

The synthesis and breakdown of neurotransmitters, such as dopamine, underscore the crucial role played by micronutrients in brain metabolism. Figure 2 illustrates a simplified portion of the complex pathway from l-phenylalanine to dopamine to adrenaline (epinephrine), highlighting the multitude of enzymatic steps involved. Each arrow signifies a distinct metabolic process regulated by enzymes, with the necessary cofactors denoted in boxes. In this limited view of this abridged dopamine pathway, the brain relies on six different vitamins and six different minerals. These same principles apply to the synthesis and breakdown of other neurotransmitters like serotonin, adrenaline and γ-aminobutyric acid (GABA). Consequently, a comprehensive spectrum of micronutrients is indispensable for the efficient metabolism of neurotransmitters; no single micronutrient can independently optimize brain function. The figure underscores the interconnectedness of these micronutrients, mirroring the synergistic effects observed when consuming whole fruits and vegetables in our diet, where the simultaneous intake of multiple micronutrients enhances absorption and utilization.

Figure 2.

A part of the tryptophan-serotonin pathway, illustrating just a few metabolic steps out of thousands

Enabling mitochondria to function

Intricately dispersed within every cell throughout the brain and body are billions of mitochondria, often referred to as the cellular ‘energy factories’. Some cells, like muscle cells, may have thousands per cell given their requirement for more energy, others might have fewer or none. These mitochondria play a pivotal role in energy generation, a process vital for the sustenance of life (Karp, 2012). This energy production unfolds through a series of complex biochemical reactions primarily involving the Krebs cycle (also known as the citric acid cycle), and the electron transport chain.

The Krebs cycle, a fundamental component of cellular respiration, serves as a hub for nutrient metabolism. It orchestrates the breakdown of various nutrients, ultimately yielding vital energy in the form of adenosine triphosphate (ATP). The electron transport chain, operating in tandem with the Krebs cycle, plays an essential role in channelling the energy harnessed during nutrient catabolism into the synthesis of ATP, the energy currency of biological systems.

The orchestration of the Krebs cycle and the electron transport chain is contingent upon a rich array of nutrients. Just as in the metabolism of dopamine, multiple micronutrients are indispensable for these processes. There is no solitary, specialized nutrient that can singularly facilitate the intricacies of these energy-producing pathways. Instead, a diverse and interconnected spectrum of micronutrients is required to ensure the optimal functioning of these cellular energy-generation systems.

Modifying genetic expression

Methylation represents a crucial biochemical process for gene regulation. In this process, a methyl group, composed of one carbon atom and three hydrogen atoms, is transferred to various molecules, including DNA. These newly methylated compounds serve as indispensable factors for a multitude of biological functions. These functions encompass DNA synthesis and repair, neurotransmitter synthesis (such as serotonin), energy generation, detoxification processes, gene regulation, hormonal control, cellular membrane maintenance, myelination and immune system function. The methylation-folate cycle, also known as one-carbon metabolism, relies on specific micronutrients, such as vitamins B₂, B₆ and B₁₂, acting as essential cofactors to facilitate intricate metabolic reactions. In the absence of an adequate nutrient supply, methylation processes may become impaired, subsequently impacting genetic expression and potentially leading to adverse physical and mental health outcomes. Studies have indicated that augmenting the nutrient supply can modestly enhance genomic methylation, underscoring the potential role of micronutrients in epigenetic gene modifications (Stevens et al., 2018).

Methyl groups function akin to a dimmer switch, effectively modulating the expression of genes, much like adjusting the brightness of a ceiling light. In essence, methylation can exert influence over gene regulation. The presence or absence of methyl groups can determine whether DNA remains tightly coiled, rendering a gene unreadable or whether it remains relaxed and readily accessible for decoding. The predominant factors influencing gene modification appear to stem from the environment, particularly the nutritional environment. Emerging evidence suggests that nutrients may possess epigenetic modifying properties in the context of mental health (Stevens, Rucklidge, Darling, et al., 2018). One of the most compelling illustrations of nutrition’s role in genetic expression is observed in honeybees.

Honeybees have highly complex societies comprising sterile worker bees and a solitary fertile queen. What is fascinating, though, is that worker bees and honeybees start their lives as genetically identical larvae. However, they undergo distinct developmental trajectories and exhibit markedly different behaviours, a phenomenon known as phenotypic variation, due to variations in their nutritional environments. A colony selects a single larva to receive a diet rich in royal jelly, resulting in the development of ovaries and the emergence of a queen bee. Conversely, larvae destined to become worker bees predominantly receive diets consisting of pollen, nectar, honey and beebread (Mao, Schuler, & Berenbaum, 2015). It is evident that nutrition profoundly shapes the genetic expression of honeybees. The same epigenetic phenomenon illustrated with the honeybee exists to modulate behaviour in other species as well (Stevens, Rucklidge, & Kennedy, 2018).

Fighting excess inflammation and protecting from environmental toxins

Inflammatory responses represent indispensable components of our immune system’s defense mechanisms, invoked whenever an infection or the intrusion of foreign substances (antigens) necessitates action. However, there are instances where these inflammatory processes can escalate beyond necessary levels, leading to harmful physiological consequences. Homeostatic mechanisms exist to regulate and confine inflammation within a delimited range. Within our cellular apparatus, mitochondria serve as both contributors to and mitigators of inflammation, yielding a modest quantity of inflammatory molecules termed reactive oxygen species (ROS), whilst concurrently producing ATP, a paramount agent in mitigating excessive inflammation (Kaplan, Rucklidge, Romijn, & McLeod, 2015; Karp, 2012). Adequate micronutrient provision is essential for ATP synthesis.

Beyond its role in reducing excessive inflammation, suitable nutrition plays an essential role in safeguarding against the adverse effects of environmental toxins, including those that potentially jeopardize brain well-being. For example, vitamin D deficiency may modulate the associations between air pollution and poor mental health outcomes such as depression and suicidal ideation (Kim et al., 2023). A review of the research concerning human health in the context of environmental pollution concluded that nutrition holds such profound significance as a modulator of toxicity induced by environmental chemicals that all methodologies for risk assessment should incorporate dietary intake as an integral component of risk evaluation (Hennig et al., 2012). Suboptimal dietary habits appear to heighten susceptibility to the deleterious impacts of environmental chemicals across the life-span. Conversely, a diet rich in antioxidants may serve to diminish this vulnerability. This holds particular relevance for pregnant people and their children, as compelling evidence demonstrates that prenatal exposure to certain environmental contaminants, such as phthalates found in plastics, significantly escalates the risk of neurodevelopmental issues in offspring; including cognitive deficits, notably lower intelligence quotient (IQ) scores, as well as challenges related to attention, hyperactivity and social communication (Ejaredar, Nyanza, Ten Eycke, & Dewey, 2015).

Research on dietary patterns and paediatric mental health

All these outlined biological mechanisms highlight the importance of consuming an adequate supply of minerals and vitamins through diet. This could not be more relevant given that over two-thirds of the calories consumed by children in the United States and in the United Kingdom, on a population basis, come from ultra-processed products (Chavez-Ugalde et al., 2024; Wang et al., 2021). Numerous observational studies, both cross-sectional and prospective, across multiple countries, have confirmed a strong association between a nutrient-rich diet and better mental health in children and adolescents, especially the symptoms of attention-deficit/hyperactivity disorder (ADHD) and depression (Beigrezaei et al., 2023; Gumma, Elotla, Ibrahim, & Rizkalla, 2024; Howard et al., 2011; Jacka et al., 2011; Kim et al., 2018; O’Neil et al., 2014; Rios-Hernandez, Alda, Farran-Codina, Ferreira-Garcia, & Izquierdo-Pulido, 2017; Shareghfarid, Sangsefidi, Salehi-Abargouei, & Hosseinzadeh, 2020). Furthermore, some of these studies have shown that a diet characterized by ultra-processed foods, containing synthetic chemicals and typically high in poor-quality fats, salt and sugar, generally precedes poor mental health. Whilst ultra-processed products are often criticized because of their high sugar, fat and salt content, often overlooked is that these ultra-processed products are typically low in micronutrient content as well.

In the realm of prospective longitudinal research concerning children’s mental health, a notable Canadian study examined the health behaviours of more than 3,000 children, aged 10–11 (Loewen et al., 2019). This study investigated six dietary health behaviours as well as three related to exercise and daily screen time. Subsequently, government data were utilized to ascertain which children had sought medical treatment from a physician for mental health disorders 2 years later. The results revealed a significant correlation: children adhering to a higher number of positive health behaviours exhibited better mental health over time. For each additional health guideline followed, there was a 15% reduction in medical visits for mental health issues. These findings were adjusted for gender, body weight, parental educational levels, household income and regional residence. Further examination of the data identified a noteworthy connection between fewer diagnoses of ADHD and adherence to dietary guidelines for fruit and vegetable intake, meat consumption, saturated fat and added sugar intake (Loewen et al., 2020). These positive effects of adherence to these health behaviours (healthy diet, exercise and sleep) on depression and anxiety scores have been replicated in Canadian high school students over a year follow-up (Dabravolskaj et al., 2023).

Jacka et al.’s (2011) study of 3,000 Australian adolescents aged 11–18, underscored the prospective link between dietary habits and mental health. The study illuminated that heightened consumption of unhealthy, ultra-processed foods corresponded to diminished mental health functioning, whilst a diet rich in whole, healthy foods was associated with enhanced psychological well-being. Notably, the study’s longitudinal aspect unveiled a compelling trend: those who improved their dietary habits over a 2-year period experienced an amelioration in mental health, whereas those whose diets deteriorated exhibited poorer psychological functioning. The study adjusted its findings for gender, socioeconomic status, body mass index, physical activity and dieting behaviours. This study holds significance in the realm of prevention, especially during adolescence, a period marked by challenges in parental supervision of dietary habits and increased vulnerability to mental health issues.

However, it is important to note that not all studies corroborate these associations. A study encompassing almost 4,000 adolescents at 17 years of age, even after rigorous adjustments for pertinent factors, did not establish a definitive link between fruit and vegetable consumption and the subsequent development of depression 12 years later (Hoare, Hockey, Ruusunen, & Jacka, 2018). This highlights the complexity and multifaceted nature of predicting mental health disorders over extended periods.

There is also a wealth of research that spans many decades showing that manipulation of diet, especially elimination of suspected allergens, can lead to significant improvement in brain function in children, including a reduction in the risk of developing mental health issues, again highlighting that diet is intricately related to mental health (Kavale & Forness, 1983; Uldall Torp & Thomsen, 2020). Examining research spanning back to the 1980s reveals a dietary component potentially contributing to poor mental health: certain food preservatives and artificial colours have been found to influence the behaviour of specific children (Jacobson & Schardt, 1999). A recent review identified 27 clinical trials of children exposed to food dyes, with half of them showing a statistically significant association between food dyes and adverse behavioural outcomes for children (Miller et al., 2022). Approximately one-third of children with ADHD exhibit positive responses (25% improvement in symptoms) to dietary interventions focused on eliminating additives such as colours and preservatives, along with other foods causing adverse effects (Ly et al., 2017; Nigg, Lewis, Edinger, & Falk, 2012).

Finally, RCTs provide some causal evidence that manipulating diet by increasing consumption of foods abundant in micronutrients and/or removing allergens can improve existing mental health problems in young people, such as ADHD and depression (Bayes, Schloss, & Sibbritt, 2022; Francis et al., 2019; Huberts-Bosch et al., 2024; Pelsser et al., 2011). It is important, however, to recognize that there are inherent challenges in conducting these types of studies due to the difficulties associated with diet manipulation and bias in dietary reporting that require consideration when interpreting the strength of these studies. Further, the existing literature does not definitively establish whether children improve due to the removal of ultra-processed foods with artificial additives or because the diet replacing these ultra-processed foods contained more nutrient-dense, whole foods. Thus, further research is imperative to unravel these intricate connections.

Diet during pregnancy and mental health of the offspring

Research concerning the offspring of people subjected to dietary monitoring during pregnancy offers valuable insights into the significance of maternal nutrition for children’s mental health. Notable instances of extreme dietary restrictions during pregnancy, such as the Dutch Hunger Winter 1944–1945 and a severe famine in China 1959–1961, underscored the importance of women being well nourished during pregnancy. Women experiencing malnutrition during pregnancy exhibited a significantly elevated risk, over twice as much, of giving birth to offspring later diagnosed with conditions like schizophrenia or depression (Brown & Susser, 2008; Li et al., 2018).

Beyond these extreme cases, maternal dietary patterns, including the consumption of highly processed foods during pregnancy, have been linked to significant impacts on a child’s development. A comprehensive study involving more than 23,000 Norwegian mother–child pairs identified a connection between maternal consumption of processed foods during pregnancy and the manifestation of behavioural problems in children at the age of 5 (Jacka et al., 2013). The study controlled for confounding variables such as gender, parental age, gestational age, maternal education, household income, maternal smoking, maternal depression, marital status and maternal locus of control.

Similarly, an investigation encompassing over 3,000 children in the Netherlands examined the maternal adherence to the traditional Dutch Diet, characterized by high consumption of fresh and processed meats and potatoes, elevated margarine intake and minimal consumption of eggs, vegetables, fish and dairy products. This dietary pattern was associated with heightened aggression in the offspring (Steenweg-de Graaff et al., 2014), even after adjusting for factors like maternal pre-pregnancy body mass index, maternal smoking, parental education, maternal age, marital status and family income.

A French study involving approximately 1,200 mother–child pairs unveiled that a typical Western diet during pregnancy was linked to an increased likelihood of detecting hyperactivity and inattention problems in children at ages 3, 5 and 8 years (Galera et al., 2018). The study controlled for confounding variables such as dietary patterns at 2 years of age, maternal stress, maternal depression, gestational diabetes and socioeconomic factors. Conversely, a study examining around 700 mother–infant pairs in Norway discovered a positive association between increased fruit consumption during pregnancy and enhanced cognitive development in infants at the age of 1 year (Bolduc et al., 2016). This association persisted even after controlling for gender, gestational age, family income, ethnicity and gestational diabetes. These findings emphasize the intricate relationship between maternal diet during pregnancy and the subsequent mental and cognitive well-being of their offspring.

Maternal low adherence to a ‘Healthy dietary pattern’ in the third trimester is significantly associated with children’s depression and anxiety symptom trajectories from 3 to 8 years (OR = 1.87; 95% CI = 1.40–2.51; Collet et al., 2021). High consumption of a ‘Western diet’ during pregnancy is associated with higher trajectories of hyperactivity and inattention from 3 to 8 years in offspring (OR = 1.67; 95% CI = 1.13–2.47; Galera et al., 2018). Every additional serving of sugar-sweetened beverages (including diet sodas) consumed per day in pregnancy is associated with an average lowering of the child IQ between 1.2 and 1.7 points in mid-childhood (3–7 years; Cohen, Rifas-Shiman, Young, & Oken, 2018).

Given how important the early start to life is on long-term health outcomes, the studies associating poor quality diet during pregnancy with poorer mental health outcomes in offspring are of particular concern. Changing the diets of people during pregnancy, especially reducing consumption of ultra-processed foods, could have a substantial positive effect on the mental health of the next generation. Nutritional inequity during pregnancy puts offspring at a neurological disadvantage from conception (Rucklidge & Mulder, 2023). Overseas initiatives have shown that ensuring mothers receive adequate nutrition during pregnancy, especially fish, leads to better mental health outcomes for their offspring.

As one example, the Special Supplemental Nutrition Program for Women, Infants and Children (WIC) programs in the United States provide state funding for supplemental food, healthcare referrals and nutritional education for low-income pregnant, breastfeeding and non-breastfeeding post-partum women for infants up to 5 years identified as nutritionally at risk. Children whose mothers participate in WIC whilst pregnant score higher on assessments of mental development and cognition at age 2, and later performed better on reading assessments whilst in school, had a lower incidence of ADHD and other common childhood mental health conditions, and lower incidence of grade repetition compared to non-participating WIC siblings (Caulfield et al., 2022).

Circumstances that influence paediatric nutritional requirements

It is increasingly established that dietary patterns exert a significant influence on the development of mental health disorders in children. However, numerous factors can predispose an individual to necessitate additional nutrients beyond what their diet provides. In this context, this discussion will switch to critically review the evidence supporting the treatment of pediatric psychiatric conditions with broad-spectrum micronutrients. The term ‘broad-spectrum’ denotes the comprehensive array of approximately 30 essential minerals and vitamins essential for optimizing brain health, encompassing not just a select few. Herein, we shall delve into specific circumstances that may necessitate an augmented intake of nutrients, surpassing the typical dietary reference ranges.

Individual differences

Beyond the essential nutrient requirements dictated by metabolic pathways, individual differences can significantly influence an individual’s demand for heightened nutrient intake. Certain individuals may inherit an unusually elevated need for specific nutrient cofactors, a phenomenon well-documented in the realm of physical health. Fifty genetic mutations associated with decelerated metabolic pathways due to an excessively heightened requirement for specific vitamin cofactors have been documented (Ames, Elson-Schwab, & Silver, 2002).

Research has illuminated that some individuals may inherit a necessity for an above-average nutrient supply to ensure the efficient operation of metabolic pathways, crucial for optimal physical health (Ames et al., 2002). It is conceivable that certain psychiatric symptoms might stem from metabolic dysfunctions engendered by insufficient vitamin and mineral cofactors within the brain. This concept was first posited by Nobel Laureate Linus Pauling in the 1960s (Pauling, 1968). Given the hereditary nature of numerous mental disorders, Pauling hypothesized that genes associated with mental illness might regulate essential nutrients crucial for brain metabolism. If so, elevating these nutrient levels through supplementation could prove beneficial. Ames demonstrated the feasibility of restoring near-normal physical functioning when enzymes with markedly diminished activity become saturated with requisite co-factors through micronutrient supplementation (Ames et al., 2002).

Stress

Stress, an inherent facet of life, can exacerbate various health issues. Prolonged stress, characterized by sustained activation of the fight/flight response, can result in chronic depletion of essential nutrients. Children face numerous stressors such as academic pressures, challenges in family and peer relationships and concerns about existential threats like climate change and COVID-19. These stressors can deplete their bodies and brains of vital micronutrients.

Nature prioritizes micronutrient-dependent functions necessary for immediate survival, such as the fight/flight response, over longer-term functions like concentration (McCann & Ames, 2009). This preferential sequence, known as the ‘Triage Theory’, ensures that managing the flight/fight response takes precedence over other bodily functions (McCann & Ames, 2009). This implies that under stress, nutritional needs may be higher than what can be provided in food alone.

Taking certain medications

Certain medications, when used long-term, can impact micronutrient levels and potentially affect brain health. For instance, mood stabilizers can deplete essential nutrients like folic acid, vitamin D, vitamin B6, vitamin B12, copper, selenium and zinc (Kaplan & Shannon, 2007). Metformin (a medication used to help lower blood sugar levels in people with Type 2 diabetes) reduces vitamin B12 levels, contraceptives decrease vitamin B6, folate, magnesium, vitamin C and E, and aspirin negatively affects vitamin C levels (Mohn, Kern, Saltzman, Mitmesser, & McKay, 2018). It is crucial to recognize that these medications may deplete nutrients, potentially influencing brain health in children. Augmenting an individual’s nutrient intake through micronutrient supplementation might both counteract these depletions as well as result in a reduced need for some psychotropic medications (Mehl-Madrona & Mainguy, 2017; Rucklidge, Gately, & Kaplan, 2010).

Dysbiosis

Dysbiosis, an imbalance in gut microbial communities associated with disease, has been linked to digestive issues and low mood for centuries (Phillips, 1910). The gut microbiome’s role in mental health has gained attention, with studies demonstrating that transplanting gut microbes can influence behaviour, including mouse models of autism spectrum disorder (Hsiao et al., 2013). Human studies examining the impact of gut microbiota on behavioural symptoms, such as ADHD, have shown differential brain structure and function in mice transplanted with microbiota from individuals with and without ADHD (Tengeler et al., 2020). Communication pathways between the microbiome and the brain involve immunity, metabolism, endocrine function (Cenit, Sanz, & Codoner-Franch, 2017; Mathee, Cickovski, Deoraj, Stollstorff, & Narasimhan, 2020) and the vagus nerve, regulating emotional responses and the autonomic nervous system (Breit, Kupferberg, Rogler, & Hasler, 2018).

Whilst specific bacterial strains have been associated with mental disorders like ADHD and depression, the results have been inconsistent (Cryan et al., 2019), and it remains unclear whether these changes cause mental illness or are a result of treatment or other factors (Berding et al., 2021). Preliminary research has shown that micronutrient supplementation increases bacterial diversity, correlating with symptom improvement in children with ADHD (Stevens et al., 2019).

Currently, defining an ideal gut microbiome for optimal brain function remains a challenge. Nevertheless, research suggests that microbial diversity is essential (Bastiaanssen, Cowan, Claesson, Dinan, & Cryan, 2019), with poorer mental health associated with less diverse microbiomes. Factors such as antibiotics, stress, infection and environmental toxins can negatively impact microbial diversity, whilst a plant-rich diet supports diversity (Cryan et al., 2019; Robertson et al., 2017). Therefore, improving the quality of dietary intake and reducing ultra-processed food consumption are vital recommendations for enhancing gut health.

When food is nutritionally depleted

Both plants and humans are incapable of synthesizing minerals. Plants absorb minerals from the soil, utilizing them to synthesize vitamins. Concerns have emerged regarding the diminishing nutrient density in our food supply over the past 70 years (Davis, Epp, & Riordan, 2004). Whilst criticisms of methodologies used for comparing nutrient content over time have been raised (Marles, 2017), substantial changes observed across various countries suggest a genuine cause for concern.

Several factors contribute to the depletion of nutrients in crops. Modern agricultural practices, driven by the pursuit of higher yields and financial gains, resulting in a ‘dilution effect’, leading to lower nutrient levels (Marles, 2017). Prolonged tilling of the soil, even with crop rotation, depletes essential minerals. Fertilizers primarily composed of nitrogen, phosphorous and potassium (NPK) are commonly used, yet plants require 15–16 essential minerals for optimal growth, defence against insects and vitamin synthesis (Ali, Riaz, Mamtaz, & Haider, 2023; Datnoff, Elmer, & Huber, 2007). Encouragingly, modern regenerative agricultural methods, such as no-till farming, can enhance soil mineral content (Montgomery, Bikle, Archuleta, Brown, & Jordan, 2022).

Glyphosate, an herbicide widely used in agriculture and a key component of Roundup^®, might also contribute to nutrient depletion. Studies have shown that glyphosate disrupts the human blood–brain barrier, increasing permeability and potentially allowing harmful molecules to enter the brain (Martinez & Al-Ahmad, 2019). Additionally, concerns have been raised about glyphosate’s impact on the availability of dietary minerals like iron, manganese and nickel for absorption by the body (Zobiole et al., 2010). Glyphosate might also adversely affect soil health, influencing plant nutrient density (Kanissery, Gairhe, Kadyampakeni, Batuman, & Alferez, 2019). Increased atmospheric carbon dioxide, linked to global warming, poses another challenge. Although carbon dioxide aids plant growth, elevated levels lead to plants containing more sugars and fewer micronutrients. Whilst larger plants may taste sweeter, they offer fewer nutrients crucial for brain health. Studies on rice exposed to elevated carbon dioxide levels found reduced levels of vitamins, minerals and protein (Zhu et al., 2018). Similar trends were observed in spring wheat, where higher carbon dioxide levels led to increased carbohydrates but decreased protein, iron and manganese (Hogy et al., 2009). As our planet warms, resulting crop yields may be higher in carbohydrates and lower in protein and micronutrients. These changes hold significant implications for human brain health, necessitating further in-depth research.

Evidence of supplementary micronutrients supporting pediatric psychiatric challenges

We have examined various factors indicating that dietary changes may not suffice for everyone in meeting their nutritional needs. Individual differences, stress levels, medication usage and gut health all present potential reasons for divergent nutrient requirements, necessitating a higher intake for some individuals than what can be acquired through diet alone. Furthermore, environmental factors like depleted soil minerals and climate change can impact the nutritional content of our food (Zhu et al., 2018). This prompts the inquiry of whether there is substantial evidence supporting the use of supplementary micronutrients, especially in the context of mental health problems, particularly in children.

Initially, researchers explored this question by investigating individual micronutrients in isolation, such as zinc, magnesium, or vitamin B12. Whilst certain studies demonstrated minor positive effects (Benton & Cook, 1991; Benton, Griffiths, & Haller, 1997; Thys-Jacobs, Starkey, Bernstein, & Tian, 1998), much of the research yielded predominantly negative results. Numerous systematic reviews and meta-analyses have emphasized the concentrated efforts to identify a singular nutrient capable of alleviating symptoms related to complex psychiatric conditions such as mood disorders (Kaplan et al., 2007; Sarris, Mischoulon, & Schweitzer, 2011), psychosis (Firth et al., 2017), ADHD (Rucklidge, Johnstone, & Kaplan, 2009) or antisocial behaviours (Benton, 2007). These studies have reported modest to low benefits from a singular nutrient approach, with many individual nutrients proving ineffective as primary treatments for mental illnesses (Firth et al., 2019). The intricate interplay of nutrients in brain metabolism described above likely accounts for the unrealistic pursuit of a single nutrient to resolve multifaceted psychiatric symptoms. Therefore, in evaluating the evidence base for micronutrient supplementation in mental health, our focus will centre on RCTs, though open-label or observational studies will also be discussed. Micronutrient interventions that used a substantial combination of nutrients (>10 in one supplement) were the preferred treatment strategy. Given the increasing emphasis on treating symptoms, not diagnoses, our search included studies of children with diagnoses (e.g., autism spectrum disorder [ASD] and ADHD) as well as impairing psychiatric symptoms (e.g., anger and emotional dysregulation).

We followed the SANRA guidelines for this narrative review (Baethge, Goldbeck-Wood, & Mertens, 2019). The PubMed/MEDLINE, PsychInfo, Cochrane Central Register of Controlled Trials (CENTRAL) and Google Scholar databases were searched (see Appendix S1 for example of the search strategy). Based on the results of the search, studies were divided into symptom clusters of ADHD, ASD and emotional dysregulation. Characteristics of the included randomized, double-blind, placebo-controlled trials can be seen in Table 1, with study results in Table 2.

Table 1.

Characteristics of the included randomized controlled trials

Study, country	Population	N	Study design	Intervention group details	Intervention	Comparison Group details	Comparison	Daily dose	Concurrent treatments
Autism spectrum disorder
Adams 2011; US	5–16 yo with ASD or PDD-NOS	53	RCT; 3 months	n = 26; mean age 9.3; 96% male	Micronutrient supplement by Yassoo Health, liquid formula	n = 27, mean age 10.5; 81% male	Identical looking liquid placebo	Based on body weight	Concurrent medications were allowed; 40% of participants were on psychoactive medications. Melatonin and PUFAs allowed
Adams 2004; US	3–8 yo with ASD or PDD-NOS	25	RCT; 3 months	n = 13; mean age 5.2; 91% male	Spectrum Support II or III, by Brainchild Nutritionals, liquid formula	n = 12; mean age 5.4; 90% male	Identical looking liquid placebo	3 mL/5 pounds of body weight	Concurrent medications allowed. Previous treatments had to be stable for 2 months prior to study
Attention-deficit/hyperactivity disorder
Johnstone 2022; USA and AB, CA	6–12 yo with symptoms of ADHD and emotional dysregulation	135	RCT, 8 weeks; open-label extension, 8 weeks	n = 78; mean age 9.9; 79% male	Daily Essential Nutrient capsules by Hardy Nutritionals	n = 57; mean age 9.7; 65% male	Identical looking placebo capsule	6–12 capsules/day depending on age and response	Concurrent psychotropic medications not allowed; occupational therapy and counseling permitted; supplements permitted if they did not contain ingredients in the intervention
Rucklidge 2018; NZ	7–12 yo with ADHD	93	RCT; 10 weeks	n = 47; mean age 10.1; 74% male	Daily Essential Nutrients capsules by Hardy Nutritionals	n = 46; mean age 9.4; 78% M	Identical looking placebo capsule	12–15 capsules/day based on response	Concurrent psychotropic medications are not allowed; counseling and supplementation with PUFAs are permitted
Sinn and Bryan 2007; AU	7–12 yo with ADHD	104	RCT, 15 weeks; crossover, 15 weeks; 3 groups (PUFA + MV, MV, placebo)	PUFA + MV (n = 41, mean age 9.2; 71% male); PUFA (n = 36, mean age 9.4; 81% male)	Chewable MV tablet by Blackmores; PUFA capsules were EyeQ by Equazen and Novasel	n = 27; mean age 9.7; 70% male	Palm oil capsules	6 capsules daily	No concurrent stimulant use allowed
Emotional dysregulation
Johnstone 2022; USA and AB, CA			Described above
Rucklidge 2018; NZ			Described above
Schoenthaler 1997; US	13–17 yo in juvenile detention	66	RCT, 13 weeks	n = 33; mean age 15.2; 72% male	Vitamin and mineral supplement by Klaire Laboratory	n = 33; mean age 15.2; 60% male	Identical looking placebo	1 vitamin tablet, 2 mineral tablets	48% of participants were taking concurrent medication.

Randomization and completion details: Adams 2004: 13 participants were randomized and 11 completed in the intervention group; 12 were randomized and 9 completed in the comparison group. Adams 2011: had 26 participants in the intervention group, and 21 finished the study and had complete data; 27 in the placebo group, and 24 finished the study and had complete data. Johnstone 2022: 78 participants were randomized to the intervention group, 71 in the ITT population and 69 completed; and 57, 55 and 54 in the placebo group, respectively. Rucklidge 2018: 47 participants were randomized and 45 completed in the intervention group; 46 were randomized and 44 completed in the placebo group Sinn and Bryan 2007: 167 participants total were randomized, 132 completed the RCT and only 104 had complete data and were analyzed. Schoenthaler 1997: 33 participants were randomized to each group; 32 and 30 completed in the intervention and placebo groups, respectively. AB, Alberta, Canada; ADHD, attention-deficit/hyperactivity disorder; ASD, autism spectrum disorder; AU, Australia; CA, Canada; ML, millilitre; MV, multivitamin, multimineral supplement; NZ, New Zealand; PDD-NOS, pervasive developmental disorder, not otherwise specified; PUFA, polyunsaturated fatty acids (omega-3 oils); RCT, randomized controlled trial; US, United States; Yo, year olds.

Table 2.

Outcomes from the included randomized controlled trials

Study	Primary outcomes	Results
Autism spectrum disorder
Adams 2011	Parent Global Impressions-Revised (PGI-R)	Results were combined with another larger study in children and adults (N = 59). For the micronutrient group, PGI-R had significant decreases in 3 of 10 subscales [hyperactivity (effect size [ES] = 0.37; p < .01), tantrums (ES = 0.51; p < .01), receptive language (ES = 0.40; p = .03)] and overall function (mean difference: 0.33; ES = 0.46; p = .02) compared to the placebo group
Adams 2004	Parent Global Impressions (PGI)	In participants who received micronutrients, 2/7 domains of the PGI (sleep, p = .03; and gastrointestinal symptoms, p = .03) improved significantly compared to those who received a placebo
Attention-deficit/hyperactivity disorder
Johnstone 2022	Clinician-report Clinical Global Impression-Improvement (CGI-I), dichotomized as treatment responder (score of 1–2) or non-responder (3–7); parent-report Child & Adolescent Symptom Inventory-5 (CASI-5) composite scorea	In intention-to-treat analysis (ITT; n = 126) participants who received the micronutrients were 3× as likely to be treatment responders as those who received placebo (54% vs. 18%, respectively; risk ratio = 2.97; p < .001). Both groups improved significantly on CASI-5 with no between-group differences
Rucklidge 2018	CGI-I Overall and CGI-I ADHD; revised Conner’s Parent Rating Scale, Long (CPRS-R-L); clinician-report ADHD Rating Scale-IV (ADHD-RS-IV)	In ITT analysis (n = 93), participants who received the micronutrients had significant improvements in overall function via the CGI-Overall (ES = 0.46; p = .03) and CGI-ADHD (ES = 0.53; p = .01) compared to those who received placebo. ADHD-RS-IV and CPRS improved in both groups with no significant between-group differences
Sinn and Bryan 2007	Conners’ Parent Rating Scale-Long Version (CPRS-L); Conner’s Teacher Rating Scale-Long Version (CPRS-L)	CPRS-L score improved significantly on all 5 domains which assessed ADHD symptoms in both the PUFA+MG and PUFA groups compared to placebo [cognitive problems/inattention (ES = 0.52; p < .01b), hyperactivity (ES = 0.17; p < .05), global restless/impulsive (ES = 0.45; p < .01), DSM-IV inattentive (ES = 0.61; p < .01) and DSM-IV hyperactivity/impulsivity (ES = 0.20, p < .01). PUFA + MG and PUFA groups were not different from each other. CTRS did not have between-group differences
Emotional dysregulation
Johnstone 2022	Oppositional Defiant Disorder (ODD) and Disruptive Mood Dysregulation Disorder (DMDD) subscales from the parent-reported CASI-5; Peer Conflict subscale from the other-adult/teacher-rated CASI-5	In ITT analyses (n = 126), ODD and DMDD subscales improved in both groups with no between-group differences; Peer Conflict subscale improved in the micronutrient group compared to placebo (ES = 0.16; p = .04)
Rucklidge 2018	Clinician-report CGI-I (Mood); Strengths & Difficulties Questionnaire-Conduct Problems subscale, parent-report; Behavior Rating Inventory of Executive Function-Emotional Control subscale, teacher-report	In ITT analyses (n = 93), participants who received micronutrients showed greater improvements in mood via the CGI-Mood (ES = 0.51; p = .02) aggression via the SDQ (ES = 0.52, p = .02) and emotional dysregulation via the BRIEF (ES = 0.66, p < .01) than the placebo group
Schoenthaler 1997	Frequency of violent rule infarctions and non-violent rule infarctions	In the micronutrient group, non-violent rule infarctions were significantly reduced (F = 7.6; p < .01) as were violent rule infarctions (F = 4.2; p = .04) compared to the placebo group
Sinn & Bryan 2007	Conners’ Parent Rating Scale- Long Version (CPRS-L)	For the micronutrient group, CPRS-L improved significantly in 1 of 2 domains that assessed emotional dysregulation: oppositional (ES = 0.43; p < .01), but not global emotional lability

^aThe CASI-5 composite score was a combination of the 6 subscales which assessed symptoms of, and impairment from, ADHD and emotional dysregulation (composite score developed in the previous study (Johnstone et al., 2020).

^bSinn & Bryan: exact p-value not reported.

Autism spectrum disorders

One of the earliest studies using micronutrient supplementation for the treatment of ASD was a small pilot RCT involving 20 children diagnosed with ASD. Those receiving a micronutrient supplement exhibited improvements in sleep patterns and gastrointestinal issues. Additionally, there were suggestive trends indicating enhanced behaviour, eye contact and receptive language skills (Adams & Holloway, 2004). Subsequently, a larger RCT conducted with 141 children and adults diagnosed with ASD reported positive effects from a modified version of the formula over a placebo. The intervention demonstrated significant reductions in tantrums (effect size [ES] = 0.51) and hyperactivity (ES = 0.37), along with improvements in receptive language (ES = 0.40) and overall functioning (ES = 0.46). However, it did not significantly impact expressive language, play, sociability, cognition, sleep and eye contact (Adams et al., 2011). Both studies utilized formulas containing 29 nutrients and monitored participants for a 3-month period.

Following these trials, researchers conducted an effectiveness study comparing micronutrients in combination with various other therapies (including essential fatty acids, Epsom salts, carnitine, digestive enzymes and a gluten-free/dairy-free diet) versus no treatment over a 12-month period. The comprehensive treatment approach led to significant improvements, including enhanced non-verbal IQ, reduced ASD symptoms, improved social responsiveness, favourable changes in sensory profiles and decreased aberrant behaviour (Adams et al., 2018).

Although not an RCT, a case–control study that systematically followed 44 children and adults ranging from 2 to 28 years old undergoing micronutrient treatment for ASD, some for up to 2 years, illustrates the potential advantage of this intervention over other conventional options. The participants were matched by age, gender and symptom severity to 44 individuals from the same clinic using conventional medications. The clinician, blinded to the treatment group, evaluated participants. The micronutrient formula demonstrated superiority over medications overall, particularly in the areas of irritability and hyperactivity, displaying significant benefits with a between-group effect size of about 0.6. Moreover, the clinician-rated Yale-Paris Self-Injurious Behavior Scale indicated a notable advantage of the micronutrients: post-treatment, the intensity of self-injurious behaviour reduced significantly, whereas there was no change in the medication group. This approximately 50% decrease in self-injurious behaviour intensity in the micronutrient group, unexpected and compelling, warrants further rigorous clinical investigations, given the distressing nature of these behaviours for families (Mehl-Madrona, Leung, Kennedy, Paul, & Kaplan, 2010).

Attention deficit/hyperactivity disorder

Historical evidence regarding micronutrient use in the treatment of ADHD has been clouded by early studies, marked by either minute doses showing no efficacy or mega-doses resulting in toxicity (Heilskov Rytter et al., 2015). In the past two decades, studies utilizing micronutrients within or above Recommended Dietary Allowances (RDA) but typically below Upper Tolerable Intake Level (UL) for most components have shown substantial improvements in behavioural functioning, encompassing core ADHD symptoms and emotion regulation. The earlier studies highlighted proof of concept, safety and efficacy in both children and adults with ADHD (Gordon, Rucklidge, Blampied, & Johnstone, 2015; Kaplan, Fisher, Crawford, Field, & Kolb, 2004; Rucklidge, Frampton, Gorman, & Boggis, 2014; Rucklidge, Taylor, & Whitehead, 2011). Three RCTs have been conducted with children.

Sinn and Bryan (2007) compared the effects of two groups combined (a polyunsaturated fatty acids (PUFAs) plus micronutrient group and a PUFA-alone group) to placebo amongst 87 children with ADHD, conducting completers’ analyses. The micronutrient formula used was an over-the-counter one-a-day supplement. Based on the Connors’ Parent and Teacher Rating Scales, the combined PUFA groups demonstrated significant improvements compared to placebo on parent, but not teacher ratings of inattention and hyperactivity/impulsivity. However, there were no group differences between the PUFA + micronutrients group compared with PUFA alone. Micronutrients alone were not compared to placebo.

The second RCT involved 93 medication-free children aged 7–12 from New Zealand, randomly assigned to micronutrients or placebo capsules for 10 weeks, assessed using the Clinical Global Impression-Improvement (CGI-I) scale, with domains of ADHD symptoms and overall functioning (Rucklidge, Eggleston, Johnstone, Darling, & Frampton, 2018). Micronutrients significantly improved ADHD symptoms (ES = 0.53; p = .01) as rated by blinded clinicians, and overall functioning (ES = 0.46; p = .029). Whilst parent and teacher-rated ADHD symptoms and clinician-rated hyperactivity/impulsivity improved in both groups, there were no significant between-group differences. A meta-analysis affirmed these findings, indicating consistent effects on clinician-rated inattention, global functioning, CGI-I and CGI-I for ADHD (Johnstone et al., 2020; Johnstone, Hughes, Goldenberg, Romijn, & Rucklidge, 2020).

Participants from this RCT were followed for 1 year, revealing that approximately 80% of those consistently using micronutrients achieved remission from ADHD symptoms (>30% reduction in ADHD symptoms), compared to around 40% of those who switched from micronutrients to medications post-trial and 20% of those discontinuing all treatments (Darling, Eggleston, Retallick-Brown, & Rucklidge, 2019). The main reasons for micronutrient discontinuation were cost and number of capsules to be taken daily. Sustained symptom improvement was reported for those adhering to the micronutrient regimen, indicating the time-dependent nature of micronutrient treatment efficacy. Participants switching from micronutrients to stimulant medications exhibited higher rates of mood or anxiety issues than those maintaining micronutrient treatments at the one-year follow-up; however, it is important to note that these children were less likely to have responded to the micronutrient treatment during the open-label phase (Darling et al., 2019).

The third RCT was a multi-site RCT across the United States and Canada (Johnstone et al., 2022) yielded similar results to the New Zealand trial (Rucklidge et al., 2018). Amongst 126 children aged 6–12 in the intention-to-treat cohort, 54% in the micronutrient group versus 18% in the placebo group were identified as responders based on the CGI-I (risk ratio = 2.97, p < .001). Whilst both groups demonstrated significant ADHD symptom improvements via the parent-rated Child & Adolescent Symptom Inventory 5, no significant differences emerged between groups on this measure. However, secondary analyses of the Parent Target Problems found that micronutrients, compared with placebo, were associated with greater improvements in two specific parental concerns: inattention and internalizing symptoms (anxiety/depression), with medium to large between-group difference effect sizes (0.55–0.80; Tost et al., 2024). Also, the micronutrient group exhibited a 6 mm greater height increase compared to the placebo group (ES = 1.15). During an 8-week open-label extension, CGI-I responders increased from 18% for participants initially assigned to placebo during the RCT to 64% during open-label. In participants who received 16 weeks of micronutrients, the response rate increased from 54% to 63% (Leung et al., 2024).

Emotional dysregulation

In addition to the hallmark symptoms associated with ASD (social communication challenges and restricted or repetitive behaviours) and ADHD (e.g. hyperactivity, inattention), emotional dysregulation is a common and often function-impairing feature in ASD and ADHD. Defined broadly, emotional dysregulation refers to difficulties in managing or regulating emotions effectively and includes behaviour such as aggression, moodiness, irritability and anger.

Emotional dysregulation in ASD.

In the 4 ASD studies described above, outcomes that relate to emotional dysregulation included tantrums and self-injurious behaviour, both of which were significantly improved with the micronutrient interventions.

Emotional dysregulation in ADHD.

All three of the aforementioned RCTs in children with ADHD assessed changes in emotional dysregulation following micronutrient supplementation, and all three reported significant improvement in at least some of the emotional dysregulation measures in the micronutrient group compared to placebo.

The first RCT in 104 children with ADHD compared PUFA+micronutrients, PUFA-alone and placebo. For the PUFA+micronutrients and PUFA groups combined, there were significant improvements in one of two measures of emotional dysregulation on the Conners’ Parent Rating Scale-Revised Long compared to the placebo group (Oppositional subscale: ES = 0.43; p < .01), but the PUFA+micronutrient and PUFA-alone groups were not different from each other (Sinn & Bryan, 2007).

The second RCT in 93 children reported that children in the micronutrient group had greater improvement in mood (via the CGI-Mood: ES = 0.51; p = .017), aggression (via the Conduct Problems subscale of the Strengths & Difficulty Questionnaire; ES = 0.52; p = .015) and emotion regulation (via the Behavior Rating Inventory of Executive Function-Emotional Control subscale; ES = 0.66; p = .009) than the placebo group. Additionally, children were followed up 1 year after baseline assessments (Darling et al., 2019). Amongst the participants, 62 were initially categorized as mood dysregulated (≥20 on the Child Mania Rating Scale (CMRS)), with 10 meeting the full criteria for Disruptive Mood Dysregulation Disorder (DMDD) based on DSM-5 criteria. At the one-year follow-up, the participants who continued micronutrient supplementation exhibited significantly lower levels of mood dysregulation (assessed using CMRS) compared to those who switched to stimulant medication and those who discontinued all treatment. Large between-group effect sizes were observed (ES = 1.5–1.7; Rucklidge, 2019). When analyzing participants based on remission of dysregulated mood (<20 on CMRS), all of those on nutrients achieved remission, contrasting with 38% on medications and 48% receiving no treatment. In terms of responder status (defined as ‘much’ or ‘very much’ improved on the CGI-I), 85% of those on nutrients were responders, compared to 62% on medications and 22% with no treatment.

The third RCT of micronutrients in 126 children with ADHD reported that the micronutrient group had significant improvements in emotional dysregulation compared to placebo in one of three subscales of the Child & Adolescent Symptom Inventory, version 5 (Peer Conflict subscale: ES = 0.16; p = .04) as rated by another adult (teacher or family member; Johnstone et al., 2022).

A pilot waitlist-controlled study investigated the effect of a micronutrient powder absorbed by the oral mucosa on emotion dysregulation in 5-to-10-year-old children (n = 48; Katta, Blampied, Eggleston, & Rucklidge, 2024). At the end of the RCT phase, there were large group differences in clinician-rated emotional dysregulation (ES = 1.25, p < .001), and 67% in the micronutrient group and 8% in the waitlist condition were ‘much’ or ‘very much’ improved (CGI-I). Further, the micronutrient group displayed a clinically meaningful reduction in ADHD and ODD symptoms compared to the waitlist. The treatment effect regressed when participants stopped taking the micronutrients and was reinstated when participants were taking the micronutrients. The observed benefits were maintained over a sustained time period (3 months). To verify whether these effects hold compared to placebo, an RCT has just been launched to explore the additive effect of mindfulness with micronutrients in treating emotional dysregulation and aggression in children 6–10 years compared to active monitoring and placebo. Also, an RCT has just been completed in teens with emotional dysregulation being treated with micronutrients or a placebo (Rucklidge et al., 2022), with results expected by 2025.

Aggression.

The efficacy of supplementary nutrients in mitigating antisocial and aggressive behaviours has been demonstrated through case studies, open-label trials and multiple RCTs. A comprehensive spectrum of minerals and vitamins, occasionally combined with omega-3 fatty acids, has shown the capacity to diminish aggression and violent incidents across diverse populations, ranging from aggressive children to incarcerated adults (Gesch, Hammond, Hampson, Eves, & Crowder, 2002; Hambly et al., 2017; Kaplan et al., 2004; Kaplan, Hilbert, & Tsatsko, 2015; Rucklidge et al., 2018; Schoenthaler et al., 1997; Tammam, Steinsaltz, Bester, Semb-Andenaes, & Stein, 2016; Zaalberg, Nijman, Bulten, Stroosma, & van der Staak, 2010). One of the earliest randomized trials, conducted almost three decades ago, involved a fully blinded three-month RCT with 62 incarcerated youths aged 13–17. Participants receiving a comprehensive array of minerals and vitamins exhibited a 28% greater reduction in rule violations, including both violent (ES = 0.52; p = .04) and non-violent (ES = 0.70; p = .008) offenses, compared to those in the placebo group (Schoenthaler et al., 1997).

In another RCT, school children aged 6–12 who received a broad spectrum of micronutrients for an entire school year also demonstrated improvement (Schoenthaler & Bier, 2000). The experimental group of 40 children receiving the micronutrient supplement exhibited 47% fewer antisocial behaviours necessitating disciplinary action compared to the 40 children in the placebo group. Monitored antisocial behaviours included threats, fighting, vandalism, defiance, endangering others and disorderly conduct.

Raine et al. (2016) conducted a randomized, single-blind, stratified, factorial trial with a high-risk community sample of 290 children aged 11–12 years. They were randomized into Nutrition only, cognitive behavioural therapy (CBT) only, Nutrition + CBT and Control groups. The nutritional supplementation consisted of omega-3 fatty acids, multivitamins and calcium. The daily dose of multivitamins consisted of 12 vitamins and seven minerals administered as one chewable tablet together with one fruit-flavoured chewable tablet containing calcium (600 mg) and vitamin D (400 μm). The nutrition intervention led to reduced externalizing behaviour compared to the controls at 3 months, with amplification of the intervention effect with CBT occurring by the 6-month mark, with between-group effect sizes ranging from 0.33 to 0.37.

Importantly, these findings have also been observed in studies involving incarcerated adults (Gesch et al., 2002; Zaalberg et al., 2010), as well as in children with explosive rage, irritability and conduct disorder (Hambly et al., 2017; Kaplan et al., 2004; Rucklidge et al., 2018). These human studies align with existing literature on laboratory animals, reinforcing the link between inadequate nutrition and aggressive behaviour (Valzelli, 1984).

In summary, abundant evidence suggests that supplementation with a comprehensive spectrum of micronutrients can effectively reduce aggression. A recent systematic review confirms that broad-spectrum micronutrients are more effective and consistent at reducing aggression than single nutrient supplements (Qamar et al., 2023).

Addressing dysregulated mood in ADHD is notoriously challenging (Carlson, 2020), and conventional medications can exacerbate ADHD symptoms in the presence of emotion dysregulation (Masi et al., 2020). Conversely, these studies using micronutrients identify the potential effectiveness of broad-spectrum micronutrient interventions, especially concerning mood dysregulation and explosive rage, underscoring an underexplored avenue for further investigation to address this rising psychiatric problem in children, not currently well controlled by conventional treatments (Leibenluft et al., 2024).

Bipolar disorder.

Numerous clinical observations, open-label trials, case studies and database analyses have been conducted involving broad-spectrum micronutrients in individuals with bipolar disorder, both in adults and children, demonstrating significant symptom improvement and reduced medication dependency (Frazier et al., 2013; Gately & Kaplan, 2009; Kaplan et al., 2001; Kaplan, Crawford, Gardner, & Farrelly, 2002; Kaplan, Hilbert, & Tsatsko, 2015; Popper, 2001; Rucklidge et al., 2010). However, no RCTs have examined broad-spectrum micronutrients in bipolar disorder, to date.

Supplementation during pregnancy and its impact on infant outcomes

Research has shown that mothers who used multivitamins during pregnancy had infants with a lower risk of developing psychiatric disorders such as autism and ADHD at 3 and 7 years, respectively (Schmidt, Iosif, Guerrero Angel, & Ozonoff, 2019; Virk et al., 2018). The NUTRIMUM study, conducted in Aotearoa New Zealand, conducted with 88 women with moderate symptoms of antenatal depression, showed improved maternal mental health outcomes following micronutrient supplementation compared with placebo and also led to reassuring birth outcomes and neonatal competencies post-birth (Bradley et al., 2020, 2024; Heaton et al., 2024). Specifically, micronutrient-exposed infants performed better than antidepressant-exposed and a reference group on habituation, motor and autonomic stability (p < .05), with between group effect sizes ranging from 1.0 to 1.7 and 0.5 to 1.0, respectively. In-utero micronutrient exposure appeared to mitigate risks of antenatal depression on infant outcomes by showing positive effects on infant behaviour on par with or better than pregnancies of mothers who were not depressed and superior to antidepressants. There was also an association between micronutrient exposure length and better habituation (r = .41, p = .028), suggesting that longer exposure to the micronutrients during pregnancy was associated with better infant regulation. Micronutrient exposure was also identified as a stronger predictor of neonatal performance over maternal depression, social adversity, gestational age and infant sex (Campbell et al., 2024). The NUTRIMUM study highlights the potential protective effect of micronutrients in improving outcomes for infants, especially for those born to mothers who experienced depression; however, longer follow-ups and more controlled studies are required to confirm these preliminary but reassuring findings. The challenge will be in conducting such research given the ethical concerns associated with studying individuals during pregnancy.

Safety and side effects of broad-spectrum micronutrients

To date, comprehensive investigations into the safety of broad-spectrum micronutrient formulations have not revealed any serious adverse effects. Numerous studies have meticulously collected safety data, employing various parameters such as blood tests, heart rate and blood pressure assessments before and after micronutrient supplementation, spanning from several months to several years. Cumulatively, these studies, which encompassed several hundred blood tests before and after micronutrient administration, have not shown any evidence indicating clinically significant short-term adverse effects (Adams et al., 2018; Johnstone et al., 2022; Rucklidge et al., 2018; Rucklidge, Eggleston, Ealam, Beaglehole, & Mulder, 2019; Rucklidge, Frampton, et al., 2014; Simpson et al., 2011). Further, concerns have been raised about consuming some nutrients at high doses, such as manganese; however, these doses have been appropriately justified (Johnstone et al., 2023).

The most frequently reported side effects have been mild and transient, primarily manifesting as headaches, stomach aches and some transient gastrointestinal upsets. These effects can often be mitigated by ingesting the capsules with a full stomach and plenty of water. In a minority of cases, participants have reported heightened agitation, which often subsides upon dosage reduction.

It is important to acknowledge that these safety results come from studies conducted with individuals not using concurrent psychiatric medication. When micronutrients are taken alongside medications, close monitoring by the prescriber is essential, and dosage adjustments may be necessary (Popper, Kaplan, & Rucklidge, 2017; Rucklidge, Johnstone, Villagomez, Ranjbar, & Kaplan, 2023).

In terms of comparative safety, study participants have reported fewer adverse effects from micronutrient treatments in contrast to conventional medications. For instance, in the study comparing nutrients to medications for autism-related symptoms, individuals with autism taking prescription medications experienced 6.5 times as many adverse events as those taking micronutrients (Mehl-Madrona et al., 2010). In the NUTRIMUM study, all measured birth indicators (e.g., infant gestational age, infant length, prematurity, infant resuscitation and maternal blood loss) favoured micronutrients over antidepressants, although these post-observation results were from a naturalistic follow-up in which the mothers had chosen the treatment they received in pregnancy (Heaton et al., 2024).

Additionally, clinicians often think micronutrient interventions are solely for individuals with identified deficiencies, such as zinc or vitamin D. Numerous studies have explored this aspect and found that a deficiency, as determined by participants’ blood nutrient levels, has not identified candidates who would benefit from supplementation. Specifically, in the context of ADHD, two RCTs have examined predictors of response to nutrient treatment (Rucklidge, Eggleston, et al., 2021; Rucklidge, Eggleston, Ealam, et al., 2019; Rucklidge, Johnstone, Gorman, Boggis, & Frampton, 2014). The key findings included: (1) the majority of nutrient levels fell within the normal range across both studies (72% of the samples exhibited nutrient levels in the ‘normal’ range), with pre-treatment nutrient levels not correlating with any ADHD symptoms; (2) pre-treatment nutrient levels failed to reliably predict treatment response, indicating that individuals with ‘normal’ nutrient levels exhibited a response rate similar to those with ‘abnormal’ levels and (3) changes in nutrient biomarkers did not correlate with mental health improvement (Rucklidge, Eggleston, Darling, et al., 2019). Similar conclusions have been drawn in studies examining serum levels of specific micronutrients (e.g., vitamin D, folate and B12) as predictors of response to nutrient interventions in individuals with mood and psychotic disorders (van der Burg, Cribb, Firth, Karmacoska, & Sarris, 2021).

The term ‘nutrient deficiency’ might be misleading, as it implies a deviation from the average population. If an individual’s nutritional requirements exceed what is considered the average nutrient range, micronutrient levels may not identify deficiencies relative to the individual’s unique metabolic needs. Consequently, the evidence leans towards micronutrient testing with observation of deficiencies not being a prerequisite for considering this treatment.

Future directions for research in nutrition and child mental illness

Vitamin and mineral supplementation for children with psychiatric disorders offers families a new evidence-based option, as demonstrated by the reported studies. Micronutrient supplementation has shown effectiveness for a variety of psychological problems, including ADHD, ASD, aggression and emotional dysregulation. Some childhood conditions, such as eating disorders, psychotic disorders and sleep disorders, have not been adequately investigated. Nevertheless, the breadth and consistency of the research show the benefit of receiving a broad foundation of micronutrients for reducing some psychiatric problems. Documented safety and lack of evidence of toxicity reassure this treatment approach is safe with no significant adverse effects.

There is growing evidence suggesting that humans are exposed to more environmental pollution over time and this exposure is contributing to poor health outcomes (Fuller et al., 2022). This trend is coupled with an evidenced decrease in the nutritional benefits associated with our food. Poorer soil conditions and high-yield farm practices contribute to significantly fewer micronutrients in even ‘healthy’ foods such as fruits and vegetables (Mayer, 1997). Regardless, whilst for the general population consuming vitamins and minerals from a balanced diet may help avoid deficiency syndromes such as rickets or scurvy; for individuals and families with psychiatric disorders, such a balanced diet may not be sufficient to meet their metabolic needs. It may be that in the future, we begin to view some of these disorders as ‘deficiency’ syndromes in which there is an on-going proportionally higher need for micro and macronutrients. Nutritional modification and supplementation may be seen to increasingly ameliorate at least some of the biological susceptibility to disability.

This review demonstrates the complexity of research with these diverse populations. Despite significant group differences being observed, favouring micronutrients over placebo, there was still variability in the results of reviewed studies, both in terms of replicated evidence as well as methodological robustness. As such, this review highlights the need for further design standardization. Uncontrolled studies with small sample sizes, varied intervention methodology (e.g., nutritional supplementation, measurement and assessment variability), inadequate treatment length, lack of physiological rationale and a general lack of independent replication, have contributed to the erosion of the acceptability and integrity of this field of research. Ensuring adequate blinds are maintained will be essential for nutrient studies given the high likelihood of expectancy bias being evident in future trials. A focus on prevention will also be welcomed although conducting these types of studies over extended periods of time with adequate controls presents significant challenges. Further, results should be reported within the context of treatment costs, treatment burden, treatment-related adverse effects and clinically meaningful differences to determine if the findings are not only statistically robust but also practically significant in a real-world setting. Generalizability to under-researched populations (e.g., indigenous cultures, non-binary, socially disadvantaged, remote and regional communities) also needs addressing in future studies.

A factor that has hampered the scientific exploration of the effects of supplementation has been the historically low nutrient doses (often below RDA) used in research. This is unsurprising given the previous adverse effects of mega doses amongst these populations (Haslam, Dalby, & Rademaker, 1984). However, likely confusion between RDA and UL of supplements has resulted in the trialing of inadequate doses of many promising micronutrients. This research should open renewed discussions on the adequacy of the current RDI levels for optimal brain health.

Micronutrient supplementation should not be viewed as a substitute for eating a healthy diet, but instead, a complement to diet. However, there have been no studies to date that have investigated whether diet manipulation alone is sufficient or whether additional micronutrients in pill form are necessary for significant improvement to occur. It is hypothesized that a whole food diet would contain all the micronutrients, as well as many other essential compounds, such as phytochemicals and may, therefore, outperform supplementation. However, to the best of our knowledge, there have been no direct comparisons between a dietary intervention and a micronutrient supplementation intervention to determine the equivalency or superiority of one over the other. There is the obvious appeal of the supplementation approach in terms of ease of implementation, especially in rural communities.

The effect of dietary patterns within micronutrient studies has also not been adequately captured, although secondary analyses suggest that baseline diet quality did not moderate response to micronutrient intervention (Robinette et al., 2024). In other words, even those who entered the study with a relatively healthy diet benefitted from the micronutrient intervention to a similar degree as children who entered the trial with a diet higher in ultra-processed foods. As such, diet quality should not be used as an exclusion criterion for micronutrient supplementation studies. Individual factors influence response to supplementation and dietary changes, including gut microbiome diversity, nutrient absorption, stress and stage of life (Rucklidge, Johnstone, & Kaplan, 2021). Identifying the role of these factors in outcome is in the early stages of research.

It is important to highlight that the studies reviewed were conducted on either medication-naïve participants or ones who chose to stop medications to participate in the research. There are well-documented challenges of combining these micronutrient interventions with psychiatric medications that need to be adequately considered, with guidelines suggested by integrative psychiatrists being carefully implemented (Rucklidge et al., 2023; Villagomez, Cross, & Ranjbar, 2023). The most commonly identified risk is that the nutrients result in over-medication, often necessitating a reduction in the medication through a careful cross-tapering procedure. The interested reader is referred to guidelines written by physicians to guide this approach (Popper et al., 2017; Rucklidge et al., 2023; Villagomez et al., 2023).

The field of nutritional psychiatry is rapidly expanding with investigators around the world examining diet and nutrient supplementation in relation to understanding the development of mental disorders, as well as offering new avenues for treatment (Firth, Gangwisch, Borisini, Wootton, & Mayer, 2020; Lane et al., 2022, 2024; Rucklidge et al., 2023; Villagomez et al., 2023). Several studies are underway or planned that will further investigate mechanisms of action and others that will attempt to replicate previous studies whilst adding methodological rigor to previous designs. A focus on moderators of treatment will also be important to determine if there are subgroups, such as those with more severe pathology or certain clusters of symptoms that respond more robustly to nutrient supplementation than others. In addition, future RCTs exploring the efficacy of micronutrient supplementation as a treatment for various psychiatric disorders in children are expected to increase over the coming decade.

Conclusion

Vitamin and mineral supplementation show evidence for addressing some psychiatric disorders in children, demonstrating efficacy and effectiveness, and documenting safety. However, the complexity of research with diverse psychiatric populations reveals variability in results, urging the need for replication with well-defined populations with greater representation across different ethnicities and geography. Environmental toxicants and nutritional deficiencies underscore the inadequacy of relying solely on a balanced diet, particularly for individuals with psychiatric disorders. The scientific exploration of supplementation is hindered by historic studies using high ‘mega doses’ or low doses (Heilskov Rytter et al., 2015) and misunderstanding regarding recommended levels (Johnstone et al., 2023). Micronutrient supplementation, whilst not a diet substitute, presents an easily implementable approach, yet challenges in combining interventions with psychiatric medications need careful consideration. The expanding field of nutritional psychiatry anticipates increased research, focusing on mechanisms, methodological rigour and subgroup responses in future studies.

Key points.

• Whilst diet change can be effective, diet alone may not meet nutritional needs due to factors such as individual differences including stress levels, medication use and gut health, as well as depleted soil minerals and climate change affecting the nutritional content of food, raising concerns about dietary sufficiency.

• Micronutrient supplementation has shown effectiveness for a variety of psychiatric problems, including ADHD, autism, aggression and emotional dysregulation, whilst some childhood mental health conditions, such as eating disorders, psychotic disorders and sleep disorders, have not been adequately investigated.

• The breadth and consistency of the research show the benefit of receiving a broad foundation of micronutrients for reducing some psychiatric problems, highlighting the vital role these nutrients play in optimizing brain health.

• Documented safety and lack of evidence of toxicity reassure this treatment approach is safe in the short term with no serious adverse effects.

Data availability statement

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.