Bridging ADHD and Metabolic Disorders: Insights into Shared Mechanisms and Clinical Implications

Abstract

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by inattention, impulsivity and/or hyperactivity. In recent years, metabolic alterations, primarily obesity, insulin resistance, and diabetes, have emerged as frequent comorbidities in individuals with ADHD, suggesting a bidirectional relationship between neurodevelopmental and metabolic dysfunctions. Emerging evidence indicates that dysregulation of dopaminergic signaling, disturbances in the hypothalamic-pituitary-adrenal (HPA) axis, and chronic low-grade inflammation are central to both ADHD symptomatology and metabolic impairments. For instance, alterations in dopamine-related genes (e.g., DRD4, DAT1) not only affect cognitive and behavioral functions but also play a role in appetite regulation and glucose homeostasis. Epidemiological studies further demonstrate that individuals with ADHD exhibit poorer glycemic control and a higher prevalence of both type 1 and type 2 diabetes, while early-life metabolic challenges such as maternal diabetes may predispose offspring to ADHD. This review aims to comprehensively synthesize the epidemiological, genetic, and pathogenetic evidence linking ADHD to metabolic alterations. We discuss key pathophysiological pathways—including dopaminergic dysregulation, HPA axis disturbances, inflammation, and oxidative stress—and evaluate their contributions to the co-occurrence of ADHD and metabolic disorders. In addition, we explore the clinical implications and integrated treatment approaches that encompass lifestyle modifications, pharmacological therapies, and multidisciplinary care. Finally, we outline future research directions to develop personalized and holistic interventions.

1. Introduction

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental condition that is frequently comorbid with other psychiatric disorders and creates a substantial burden for the individual, their family, and the community [1]. ADHD is characterized by core symptoms of age-inappropriate inattention, impulsivity, and/or hyperactivity, with its clinical manifestations evolving across the lifespan. While inattention often persists from childhood into adulthood, hyperactivity in adults might instead present as an inability to relax or internal restlessness, and impulsivity may manifest as impatience, inappropriate risk-taking or emotional lability [2,3,4,5].

The global prevalence of ADHD in childhood is estimated at approximately 5%, based on meta-regression analyses [6]. Interestingly, the prevalence in adults appears higher than would be expected by the persistence rates from children, suggesting the emergence of new diagnoses during adulthood. This trend is likely influenced by evolving diagnostic criteria, as defined in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), as well as increased awareness of the disorder, partly driven by social media [7]. Despite this change, ADHD remains an underdiagnosed and undertreated condition in adults, often resulting in significant impairment [8]. Beyond its clinical manifestations, ADHD is increasingly understood as a disorder of disrupted neurotransmitter systems, particularly involving dopamine pathways in the prefrontal cortex. These abnormalities affect executive functions such as attention, behavioral inhibition, and emotional regulation, which are central to ADHD pathophysiology [1]. Emerging evidence also suggests that neuroinflammation and oxidative stress may contribute to these neurochemical imbalances, linking ADHD to broader systemic alterations, including metabolic dysfunction [1,9].

The association between ADHD and obesity has been documented in the literature, with various proposed mechanisms linking the two conditions such as abnormal eating patterns, decreased physical activity and sleep disruption. Preliminary evidence has also revealed possible common genetic underpinnings [9]. Obesity itself can be considered as a real pandemic as its global prevalence nearly tripled between 1975 and 2016, affecting both high-income and low-to-middle-income countries [10]. Its prevalence has also increased in the last decade in pediatric populations. In particular, one in five children or adolescents have experienced excess weight [11]. Since 2000, childhood obesity has continued to rise, particularly in economically disadvantaged countries [12]. This widespread phenomenon has contributed to the increasing prevalence of metabolic disorders, including non-alcoholic fatty liver disease and type 2 diabetes (T2D) [13,14].

Throughout history, the clash of different pandemics has led to unexpected and often deleterious effects. A recent example is the interplay between obesity and COVID-19, where their overlap resulted in severe clinical consequences for affected individuals [15]. Given the rising global prevalence of both ADHD and obesity, it is necessary to investigate their interconnection and the potential implications of their convergence. This review aims to synthesize the current evidence about ADHD and metabolism, their interrelationships starting from the pathophysiological mechanisms and common risk factors, and then moving toward management and treatment concerns. Among the metabolic impairments, we will specifically focus on obesity and diabetes.

2. Pathophysiological Mechanisms Linking ADHD Neurobiological Factors and Metabolism

ADHD is a highly heritable disorder, but not all of its risk is genetic. Estimates suggest that environmental factors may account for between 10% and 40% of the variance associated with ADHD [16]. Although the etiology is still uncertain, hypo-efficient dopamine systems, and the subsequent neurochemical imbalances, have been linked to ADHD onset and its features, such as sustained attention deficits, overactivity and impulsiveness [17]. Reduced postsynaptic activation in the prefrontal and striatal regions has been observed in several MRI studies [18,19]. In the striatum, dopamine activates postsynaptic neurons but ADHD patients experience a delayed dopamine signal, rather than the immediate anticipatory dopamine signal, that normal subjects experience [20]. Furthermore, a number of other neuroendocrine imbalances may be present in ADHD: a higher cumulative diurnal cortisol level has been found, with increased morning and afternoon cortisol, after controlling for symptoms of anxiety, depression and conduct disorder [21], with a reduced bedtime salivary cortisol [22], reflecting a different circadian cortisol profile. Leptin levels may be normal or increased in ADHD [23,24], while ghrelin and neuropeptide Y remain normal [24,25]. Based on these data, individuals with ADHD may also exhibit altered energetic metabolism. The interlinks between ADHD behavioral patterns and metabolism could be bidirectional. Recently, mice fed a high-fat diet were observed to have developed behavioral deficits resembling ADHD phenotypes, such as decreased wakefulness, increased REM (rapid eye movement) sleep with fragmented patterns, and impaired visuospatial memory, suggesting that dietary patterns can affect the dopaminergic system [26].

Emerging evidence underscores a shared genetic architecture underlying ADHD and metabolic dysfunction, including obesity and type 2 diabetes [27]. Genome-wide association studies have revealed that multiple genetic loci implicated in ADHD also overlap with those associated with metabolic disorders, reflecting common biological pathways [28,29] (Figure 1).

This figure illustrates the complex interplay between ADHD, obesity, and diabetes, driven by genetic, environmental, and neurobiological factors. Altered dopamine signaling contributes to sleep disorders, which in turn lead to dysregulated eating behaviors. HPA axis dysfunction exacerbates ADHD core symptoms—inattention, impulsivity, and hyperactivity—fostering sedentary behavior and obesity. Chronic inflammation and oxidative stress further reinforce emotional dysregulation, internalized stigma, and metabolic disturbances, ultimately increasing the risk of type 2 diabetes.

2.1. Dopaminergic System and Its Role in ADHD and Metabolism

Polymorphisms in dopamine-related genes, such as DRD4 and DRD5 (dopamine receptor genes) and DAT1 (dopamine transporter gene), are well-established contributors to ADHD pathophysiology [30,31]. These genes regulate dopaminergic signaling, which is crucial for attention, reward processing, and impulse control [32,33]. However, their effects extend beyond the central nervous system to metabolic regulation. Dysregulation in dopaminergic pathways can impair reward sensitivity, leading to altered eating behaviors such as hyperphagia [34,35]. This disruption in reward systems may explain the higher prevalence of obesity observed in individuals with ADHD [35]. Additionally, dopamine plays a role in modulating insulin secretion and glucose homeostasis, linking these polymorphisms to an increased risk of insulin resistance [36].

2.2. HPA Axis Dysregulation and Genetic Variants

The hypothalamic–pituitary–adrenal (HPA) axis, a key regulator of stress responses and energy balance, is frequently disrupted in ADHD [37]. Genetic variations in NR3C1, which encodes the glucocorticoid receptor, have been associated with dysregulated cortisol secretion in individuals with ADHD [38]. These alterations may contribute to heightened stress reactivity, promoting abdominal fat deposition and insulin resistance through prolonged exposure to elevated cortisol levels [39]. Dysfunctional HPA axis activity also influences neurodevelopment and behavior, further intertwining ADHD symptoms with metabolic derangements [40].

2.3. Genetic Links to Inflammatory Pathways

Chronic low-grade inflammation is a hallmark of metabolic disorders and has been increasingly recognized in ADHD [41,42]. Polymorphisms in pro-inflammatory cytokine genes, such as IL-6 and TNF-α, have demonstrated dual associations with ADHD and metabolic dysfunction [43,44]. Elevated levels of these cytokines are observed in both conditions and may exacerbate neuroinflammation, impair neuroplasticity, and contribute to the systemic inflammation observed in obesity and type 2 diabetes [45,46].

2.4. Epigenetic Modifications and Environmental Interactions

Epigenetic mechanisms provide a dynamic link between genetic predisposition and environmental exposures, influencing both ADHD and metabolic dysfunction [47,48]. Prenatal stress, maternal obesity, poor maternal nutrition, and exposure to environmental toxins (e.g., tobacco smoke, heavy metals) are known risk factors for ADHD [49,50]. These exposures can lead to epigenetic changes, such as DNA methylation or histone modification, in genes regulating neurodevelopment and metabolic processes [51,52]. For example, maternal stress during pregnancy has been associated with altered methylation of genes involved in HPA axis regulation and energy homeostasis, potentially predisposing offspring to ADHD and obesity later in life [53].

2.5. Shared Polygenic Risk Scores and Heritability

Studies using polygenic risk scores (PRS) suggest that ADHD and metabolic disorders share common genetic determinants, contributing to their co-occurrence [54]. Twin studies further support this, with heritability estimates for ADHD and obesity ranging between 70–80%, indicating significant genetic contributions to both conditions [55,56]. Interestingly, the co-heritability of ADHD and increased body mass index (BMI) has also been observed, suggesting a partially overlapping genetic etiology [57].

3. Inflammation and Oxidative Stress as Neurobiological Bridges Between ADHD and Metabolic Dysfunction

Chronic inflammation and oxidative stress are key mechanisms linking ADHD and metabolic dysfunction, creating a complex interplay of neuroimmune and metabolic pathways that exacerbate both conditions [58,59,60]. These shared pathophysiological processes highlight the profound connections between systemic inflammation, oxidative damage, and their cumulative impact on neurodevelopment and metabolism [58,59]. Notably, oxidative stress directly affects neurotransmitter systems by altering the synthesis, release, and reuptake of key monoamines such as dopamine and serotonin, neurotransmitters that are central to ADHD pathophysiology and are also involved in appetite, mood regulation, and energy homeostasis [46,59]. This interference further contributes to the overlapping cognitive, behavioral, and metabolic dysfunctions observed in ADHD and related disorders.

ADHD has been consistently associated with elevated levels of pro-inflammatory cytokines, including interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and C-reactive protein (CRP), which are similarly upregulated in metabolic disorders such as obesity and type 2 diabetes [60,61]. This inflammatory milieu is not only a hallmark of systemic immune dysregulation but also a driver of neurodevelopmental impairments and metabolic disturbances [46]. IL-6, for instance, influences synaptic plasticity and neurotransmitter signaling, critical for cognitive and behavioral regulation in ADHD, while also playing a role in hepatic glucose production and lipid metabolism, thereby contributing to insulin resistance and obesity [62,63,64]. Similarly, TNF-α exacerbates insulin resistance by impairing insulin receptor signaling, while simultaneously promoting neuroinflammatory processes that worsen core ADHD symptoms like attention deficits and impulsivity [65,66,67]. Elevated CRP, a marker of systemic inflammation, bridges these disorders by linking them to vascular dysfunction and heightened cardiometabolic risk [68,69].

Inflammation further disrupts the HPA axis, a key regulator of stress responses and energy homeostasis [70]. Chronic inflammation-induced dysregulation of cortisol secretion amplifies the pathophysiology of both ADHD and metabolic disorders [71,72]. Altered cortisol rhythms in ADHD impair attention and emotional regulation, while excess cortisol in metabolic disorders promotes visceral fat accumulation, insulin resistance, and dyslipidemia [71,72,73]. Furthermore, inflammatory signals disrupt the regulation of dopamine and serotonin pathways, indirectly influencing neurotransmitter homeostasis and exacerbating core ADHD symptoms. These disturbances also contribute to metabolic dysfunction by impairing mechanisms involved in appetite regulation, glucose metabolism, and mood [59,74].

Oxidative stress adds another layer to this interplay, characterized by an imbalance between reactive oxygen species (ROS) production and antioxidant defenses [46]. Excessive ROS levels cause oxidative damage to lipids, proteins, and DNA, particularly in dopamine-rich brain regions such as the prefrontal cortex, impairing synaptic function and contributing to cognitive and behavioral symptoms of ADHD [46]. In metabolic disorders, oxidative stress impairs insulin signaling pathways and promotes pancreatic beta-cell dysfunction, accelerating the progression of insulin resistance and hyperglycemia [75]. Mitochondrial dysfunction emerges as a central mechanism in this context, as mitochondria, being primary energy producers and sources of ROS, amplify oxidative damage and reduce ATP availability [76]. In ADHD, this dysfunction limits neuronal energy resources, affecting processes like attention and memory, while in metabolic disorders, it hampers fatty acid oxidation and glucose metabolism, exacerbating insulin resistance and promoting weight gain [77].

The bidirectional relationship between inflammation and oxidative stress creates a self-perpetuating loop, where inflammation drives ROS production and oxidative stress exacerbates inflammatory responses through pathways like nuclear factor-kappa B (NF-κB) activation [46]. This synergistic interaction not only deepens the neurodevelopmental and metabolic impairments seen in ADHD and metabolic dysfunction but also influences behaviors such as appetite regulation and energy expenditure, leading to overeating, obesity, and poor glycemic control, which in turn exacerbate ADHD symptoms [78,79].

Addressing these shared mechanisms offers promising avenues for therapeutic interventions. Anti-inflammatory strategies, including selective cytokine inhibitors and anti-inflammatory diets rich in omega-3 fatty acids and polyphenols, hold potential to mitigate systemic and neuroinflammation [80]. Similarly, antioxidant therapies, whether through nutrient-rich diets or pharmacological agents targeting mitochondrial function, such as coenzyme Q10 and N-acetylcysteine, may reduce oxidative damage and restore cellular energy balance [81,82]. An integrated approach that combines pharmacological treatments with lifestyle modifications and dietary interventions may provide synergistic benefits, as we will discuss in the next paragraphs [75].

4. Obesity, Metabolic Syndrome, Diabetes, and ADHD: Shared Risk Factors

Diet plays a fundamental role in the relationship between ADHD and metabolic disorders such as obesity, metabolic syndrome, and diabetes, as high consumption of ultra-processed foods, excessive sugar intake, and unhealthy dietary patterns have been linked to both. Diets rich in refined carbohydrates and saturated fats can contribute to inflammation, oxidative stress, and dysregulation of dopamine signaling, all of which are implicated in ADHD and obesity [83,84]. Lower adherence to a Mediterranean diet has been linked to ADHD diagnosis, with lower intake of fruits, vegetables, whole grains, and fatty fish, alongside a higher frequency of skipping breakfast and consuming fast food [85]. Furthermore, micronutrient deficiencies, particularly in iron, zinc, and omega-3 fatty acids, have been associated with both ADHD severity and metabolic disturbances, emphasizing the importance of a balanced diet in managing these conditions [86]. Beyond lifestyle, socioeconomic disparities influence access to nutritious food, opportunities for physical activity, and healthcare, exacerbating both conditions [87,88]. Additionally, sedentary behavior and physical inactivity, which are more common in individuals with ADHD, further contribute to metabolic dysregulation and obesity risk [89,90].

Beyond these lifestyle factors, psychosocial challenges associated with ADHD, such as stigma, low self-esteem, and emotional distress, may also contribute to metabolic dysfunction. Individuals with ADHD often experience social rejection, academic difficulties, and impaired self-regulation, which can lead to emotional eating, stress-related metabolic changes, and poorer adherence to healthy behaviors [91]. Internalized stigma and shame, commonly observed in individuals with ADHD and obesity, have been linked to lower self-esteem, negative body image, and reduced quality of life, which may further exacerbate the risk of metabolic disorders [92,93]. Additionally, emotional dysregulation and maladaptive coping strategies, such as excessive daydreaming and social withdrawal, may reinforce unhealthy eating patterns and sedentary behaviors [94]. Chronic stress and altered serotonin signaling, which have been linked to both ADHD and metabolic disturbances, may further increase vulnerability to obesity and insulin resistance [95].

Poor sleep quality has also been identified as a common factor affecting both ADHD and metabolic health [96]. Sleep disturbances, including shorter sleep duration, irregular sleep patterns, and insomnia, are frequently reported in individuals with ADHD and have been associated with increased risk of obesity and insulin resistance. Disruptions in the sleep–wake cycle may impair glucose metabolism, exacerbate impulsivity and emotional dysregulation, and reduce motivation for physical activity, further compounding metabolic risk [96,97]. Additionally, ADHD-related hyperactivity and difficulties in sleep onset may create a feedback loop in which poor sleep contributes to further dysregulation of energy balance and eating behaviors [8].

These findings underscore the complex interplay between lifestyle, socioeconomic factors, and psychosocial factors, highlighting the need for holistic intervention strategies that address both ADHD-related challenges and metabolic risk factors.

4.1. ADHD and Obesity

The higher prevalence of obesity in individuals with ADHD compared to the general population pertains to both children and adults, as demonstrated in a meta-analysis by Cortese et al., with odds ratios ranging from 1.2 to 1.7 [98]. This association persists across different populations and remains robust after adjusting for confounding factors, including socioeconomic status and psychiatric comorbidities. Importantly, this bidirectional relationship suggests that ADHD may predispose individuals to obesity, while obesity may exacerbate ADHD symptoms through shared biological and behavioral mechanisms [98].

Behavioral characteristics intrinsic to ADHD, such as impulsivity, hyperactivity, and inattention, significantly contribute to the increased obesity risk. Impulsivity can manifest as disinhibited eating behaviors, including binge eating and a preference for high-calorie, palatable foods [99]. Many patients with ADHD display heightened sensitivity to immediate rewards, which can predispose them to preferentially select calorie-dense foods that offer rapid gratification [100]. Hyperactivity, while theoretically associated with higher energy expenditure, is often insufficient to counteract the caloric excess driven by poor dietary choices. Inattention further impairs meal planning and adherence to structured dietary regimens, compounding the risk of weight gain [101,102]. Moreover, ADHD-related difficulties in executive function, such as poor self-regulation and planning, contribute to sedentary behavior [103]. Screen time, often used as a coping mechanism for hyperactivity or boredom, replaces physical activity, further promoting weight gain [104]. Addressing these behavioral factors through targeted interventions, such as cognitive-behavioral therapy and structured lifestyle programs, is essential in mitigating obesity risk in ADHD patients [105,106]. While limited, existing literature highlights potential neurobiological links between ADHD and obesity [107]. Beyond dopamine dysregulation, several additional neurobiological and pharmacological factors may contribute to altered eating behaviors and metabolic outcomes in individuals with ADHD [108]. Emerging evidence points to potential disruptions in hypothalamic pathways that regulate energy homeostasis [109]. Although direct evidence linking these pathways to ADHD is still limited, their involvement may further explain the propensity for hedonic overeating observed in this population [110]. Another factor warranting attention is the potential alteration in autonomic nervous system activity associated with ADHD [111]. Reduced sympathetic tone in these individuals could lead to decreased energy expenditure, thereby compounding the risk of weight gain [112]. The impact of pharmacological treatments further complicates the picture. Stimulant medications, such as methylphenidate, are known for their short-term appetite-suppressing effects and subsequent weight loss [113,114]. However, the long-term metabolic consequences remain less clear; some studies suggest that these initial effects may plateau or even reverse, potentially leading to weight gain over time [112]. Additionally, medications used to manage psychiatric comorbidities, such as lisdexamfetamine for binge eating disorder or selective serotonin reuptake inhibitors (SSRIs), can independently influence weight and metabolic outcomes [115,116].

Given these multifaceted influences, a deeper understanding of how hypothalamic regulation, autonomic nervous system alterations, and pharmacotherapy interact is essential. This knowledge will be critical for tailoring ADHD management strategies, especially for patients who are at an increased risk of obesity.

ADHD and Metabolic Syndrome

Metabolic Syndrome describes a constellation of metabolic abnormalities (central obesity, insulin resistance, hypertension, hypertriglyceridemia, and low levels of high-density lipoprotein cholesterol) that are strongly associated with visceral adiposity. The diagnosis of MetS requires the co-occurrence of at least three of these five components [117]. It is highly prevalent and rising globally, with current estimates indicating that approximately 25% of adults in the United States meet the diagnostic criteria. MetS also affects pediatric populations, with a median prevalence of 3% in the general pediatric population, increasing to 12% in overweight and up to 29% in obese children. Given its established association with cardiovascular risk and type 2 diabetes, MetS represents a critical clinical concern across the lifespan [118].

In the context of ADHD, its relationship with MetS remains a subject of ongoing investigation. A large-scale study from the Netherlands involving over 2300 adults with varying stages of affective disorders found no significant association between ADHD symptoms and MetS or obesity-related parameters after adjusting for sociodemographic and lifestyle factors [118]. Conversely, a cross-sectional study of adult ADHD outpatients reported a 10.8% prevalence of MetS, with elevated triglyceride levels, increased diastolic blood pressure, and waist circumference identified as significant predictors [119]. Furthermore, surrogate markers of insulin resistance, including the lipid accumulation product and the triglyceride-waist circumference index, showed strong predictive value for MetS in this population. These mixed findings highlight the need for routine metabolic screening in adults with ADHD, especially considering the overlapping risk factors and the potential impact of stimulant treatment and lifestyle behaviors [119]. Further longitudinal research is warranted to disentangle the contributions of ADHD symptoms, psychiatric comorbidities, and pharmacologic interventions to the development of MetS.

4.2. ADHD and Diabetes

The connection between altered glucose metabolism and ADHD may originate during fetal development. A retrospective birth cohort study evaluated 333,182 singletons born from 1995–2012, with an average follow-up of 4.9 years starting at age 4, and documented that the severity of maternal diabetes influenced ADHD risk in offspring. Compared to children unexposed to maternal diabetes, the adjusted hazard ratios (HRs) for ADHD were highest in those exposed to type 1 diabetes (T1D), followed by T2D, with a lower risk for gestational diabetes mellitus (GDM) requiring medication and an even lower risk for GDM not requiring medication. Given that insulin cannot cross the placenta unless bound to antibodies, these findings suggest that the intrauterine glycemic environment plays a crucial role in the development of ADHD [120]. The authors speculate that maternal hyperglycemia may expose the fetus to stress, chronic inflammation, hypoxia, and fetal hyperinsulinemia, all of which could disrupt fetal brain development during critical prenatal periods, potentially leading to neurobehavioral disorders later in life. A recent meta-analysis supports this hypothesis, identifying maternal pregestational diabetes as a potential risk factor for ADHD in offspring [121]. Another study with a follow-up of up to 29 years further confirmed these findings [122].

The causal link between poor glycemic control and ADHD extends beyond the prenatal period into childhood. A Swedish population study found that children with T1D had a higher risk of being diagnosed with developmental disorders than the general population, with the risk particularly elevated in those with uncontrolled diabetes [123]. A meta-analysis further demonstrated that the ADHD prevalence in the T1D population increased with age [124]. Additionally, recurrent hypoglycemia, especially episodes involving hypoglycemic coma, has been implicated in the development of ADHD [125]. Managing diabetes in childhood poses significant challenges, with implications for both physical growth and neurodevelopment [126]. The coexistence of diabetes and ADHD exacerbates these challenges, leading to worse health outcomes. T1D patients with comorbid ADHD are more likely to experience suboptimal HbA1c levels, higher hospitalization rates, diabetic ketoacidosis, and hypoglycemia compared to T1D patients without ADHD [127,128,129]. Moreover, ADHD is a predictor of poor long-term glycemic control [128,130] and may increase the likelihood of withdrawal from insulin pump therapy [131].

Interestingly, a higher ADHD prevalence is also notable among adults with T2D, where both insulin secretion and insulin resistance are present, reaching nearly half of the participants in one study [132].

While hyperglycemic states are linked to ADHD, the reverse is also true: ADHD patients have double the risk of developing T2D compared to controls. Psychiatric comorbidities such as substance use disorder, depression, and anxiety are the main drivers of the association between these diseases [133] alongside traditional risk factors like increased waist circumference and obesity [134]. The underlying biochemical pathways remain unclear, though alterations in the dopaminergic system may play a role. Dopamine receptors on beta cells influence insulin secretion and ADHD-related dopaminergic dysfunction could negatively impact this process [36]. Sleep disturbances, another common issue in ADHD, have been linked to diabetes onset, as difficulty with initiating or maintaining sleep may increase sympathetic nervous activity [135]. Additionally, stimulant medications such as methylphenidate have been shown to reduce insulin secretion as discussed before [136].

Beyond these environmental factors, genetics also contributes to the connection between diabetes and ADHD. A genome-wide association study found a positive genetic correlation between the conditions, probably mediated by the pleiotropic effects from genes such as: AMKV, MST1R, MON1A, RBM6, RBM5 (3p21.31), ARHGAP39 (8q24.3), and NKX2-2 (20p11) [137]. Thus, substantial insights were gained about etiology and risk factors for diabetes onset in ADHD. Conversely the pathogenesis needs to be better defined, in particular for type 2 diabetes where insulin deficiency coexists with insulin resistance in different grades [138].

Insulin resistance is a key feature of type 2 diabetes pathogenesis [139] and often develops years before diabetes onset. It is commonly observed in obese nondiabetic adolescents when assessed using insulin-resistance indices [140]. However, the gold standard for insulin resistance assessment is the euglycemic clamp technique [141]. Given the increased inflammation and the neurotransmitter imbalances previously mentioned, it would be reasonable to expect a higher prevalence of insulin resistance in this population. However, to our knowledge, studies evaluating insulin sensitivity with gold standard methods are still missing.

In conclusion, the relationship between diabetes and ADHD is bidirectional, yet the study of their pathophysiological connections remains in its early stages. We have gained substantial insights into the harmful effects of hyperglycemia on fetal and childhood brain development, but the precise mechanisms remain unclear. Similarly, in ADHD, metabolic impairments related to obesity and dopaminergic dysfunction may contribute to diabetes risk, but it is still uncertain whether ADHD influences diabetes onset through effects on insulin secretion, insulin resistance, or both. Further research is needed to clarify these complex interactions, as we will discuss in the next paragraphs.

5. Clinical Implications and Treatment Considerations

In the era of precision medicine and multiple drug choices, comorbidities play a crucial role in shaping treatment strategies, guiding clinicians toward therapies that address both neurological and metabolic concerns. We have previously discussed that the interconnections between ADHD and metabolism are primarily epidemiological and, at times, clinical, but the underlying biochemical mechanisms linking obesity and diabetes to ADHD remain largely unexplored. Preclinical research on the intersection of ADHD-related neuronal circuit dysfunction and metabolic parameters is still in its early stages. However, some longitudinal studies suggest that hyperglycemia may play a causal role in the onset of ADHD, although the exact pathophysiological mechanisms and additional etiological factors remain unclear [142]. One key piece of evidence supporting this connection is the neurological impact of diabetic ketoacidosis (DKA), an acute complication arising from severe insulin deficiency, leading to hyperglycemia and ketone body production. DKA has been associated with neurological complications as morphological and functional brain changes, particularly affecting the frontal white matter [143]. We have discussed how reduced postsynaptic activation in prefrontal region is a possible finding in ADHD. This suggests a potential link between metabolic dysregulation and cognitive function. However, while the impact of metabolic disorders on ADHD risk has been explored to some extent, the reverse relationship—how ADHD may contribute to metabolic disease—remains insufficiently studied. Longitudinal research on this subject is still lacking, making it difficult to establish management recommendations for ADHD patients with metabolic comorbidities. Nonetheless, existing therapeutic strategies for both conditions offer valuable insights to help guide clinical decision-making.

ADHD has been shown to worsen glycemic and metabolic outcomes in children and adolescents. Given this, a more intensive and closely monitored treatment approach is warranted to prevent acute complications such as DKA, which is particularly common in adolescents and in individuals with psychiatric comorbidities [144]. Continuous glucose monitoring (CGM) should be preferred over traditional self-monitoring of blood glucose, as CGM provides real-time data and can help to prevent glycemic fluctuations [145].

In adults, treatment priorities should focus on reducing both acute and chronic complications [146]. Cardiovascular risk is a major concern, as it increases with age and is closely linked to cumulative LDL cholesterol exposure [147,148,149]. A recent meta-analysis confirmed that ADHD itself is associated with an increased risk of cardiovascular diseases, regardless of the presence of metabolic comorbidities [150]. Therefore, a comprehensive cardiovascular risk management in ADHD patients, incorporating lipid control, blood pressure management, and lifestyle modifications, is encouraged. Given the interplay between psychiatric and metabolic factors, a multidisciplinary approach is recommended. For example, therapeutic choices would benefit from this shared approach. Some general considerations are provided that could serve as a common ground among the clinicians:

5.1. Lifestyle Modifications and Nutritional Approaches

Physical activity should be strongly encouraged in ADHD patients, as it not only improves focus and executive functioning but also reduces obesity risk [151]. Notably, moderate to vigorous activity has been associated with a lower incidence of sleep disorders in men but not in women, highlighting the importance of gender-specific considerations in ADHD management [152]. Dietary interventions may also play a role. An omega-3 enriched diet should be encouraged, as these nutrients not only confer cardiovascular benefits [153] but may also reduce impulsive behavior in ADHD patients [154] (Table 1).

5.2. Pharmacological Considerations

While methylphenidate remains the main therapeutic strategy for ADHD treatment [155], combining it with psychosocial interventions—such as home-based behavioral therapy, school-based programs, and summer treatment programs—has been shown to improve functional outcomes beyond pharmacotherapy alone, including academic performance, parent–child relationships, and social skills [156]. However, the metabolic effects of these interventions remain unclear and warrant further study.

In managing diabetes, therapeutic agents with pleiotropic effects may offer promise for patients with comorbid ADHD. While insulin remains the standard treatment for type 1 diabetes, the role of adjunctive therapies in this population is still debated [157]. For T2D, recent advancements in treatment—particularly sodium–glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs)—offer beneficial metabolic effects beyond glycemic control [158,159,160,161]. For instance, GLP-1 receptor agonists have shown promise in combating obesity while potentially enhancing cognitive function [162,163]. Further, given the role of gut peptides in the brain’s reward system, GLP1-RA may have a positive influence [164]. Further research is needed to clarify the impact of these drugs on the central nervous system.

Table 1. Summary of pathophysiological mechanisms and therapeutic implications in ADHD and metabolic dysfunction.

Mechanism	Clinical Effect	Associated Metabolic Outcomes	Therapeutic Implications	References
Dopaminergic Dysregulation	Altered dopamine signaling affects attention, impulsivity, and reward sensitivity.	Impaired appetite regulation, altered insulin secretion, increased obesity risk.	Dopamine modulators, nutritional interventions (e.g., omega-3 supplementation).	[17,20,36]
HPA Axis Dysregulation	Dysregulated cortisol secretion and increased stress reactivity.	Visceral fat accumulation, insulin resistance, and heightened diabetes risk.	Stress management strategies, HPA-targeted therapies, lifestyle modifications.	[21,22,23]
Inflammation and Oxidative Stress	Chronic low-grade inflammation and increased ROS contribute to neuroinflammation.	Insulin resistance, dyslipidemia, obesity, and type 2 diabetes.	Anti-inflammatory diets, antioxidant therapies, and interventions targeting ROS production.	[125,126,145]
Genetic and Epigenetic Factors	Shared genetic loci and epigenetic modifications create a common predisposition for both ADHD and metabolic dysfunction.	Predisposition to metabolic syndrome, obesity, and diabetes.	Personalized medicine approaches, early screening, and targeted lifestyle modifications.	[122,139,140]
Integrated Clinical Approaches	Comorbid ADHD and metabolic disorders require holistic, multidisciplinary management.	Improved glycemic control, weight management, and overall cognitive function.	Combined pharmacological treatments (e.g., CGM, SGLT2 inhibitors, GLP-1 RAs), behavioral therapies, and lifestyle programs.	[147,152,159]

HPA: Hypothalamic–pituitary–adrenal; ROS: Reactive oxygen species; ADHD: Attention deficit hyperactivity disorder; CGM: Continuous glucose monitoring; SGLT2: Sodium–glucose cotransporter-2; GLP-1 RA: Glucagon-like peptide-1 receptor agonist.

Table 1. Summary of pathophysiological mechanisms and therapeutic implications in ADHD and metabolic dysfunction.

Mechanism	Clinical Effect	Associated Metabolic Outcomes	Therapeutic Implications	References
Dopaminergic Dysregulation	Altered dopamine signaling affects attention, impulsivity, and reward sensitivity.	Impaired appetite regulation, altered insulin secretion, increased obesity risk.	Dopamine modulators, nutritional interventions (e.g., omega-3 supplementation).	[17,20,36]
HPA Axis Dysregulation	Dysregulated cortisol secretion and increased stress reactivity.	Visceral fat accumulation, insulin resistance, and heightened diabetes risk.	Stress management strategies, HPA-targeted therapies, lifestyle modifications.	[21,22,23]
Inflammation and Oxidative Stress	Chronic low-grade inflammation and increased ROS contribute to neuroinflammation.	Insulin resistance, dyslipidemia, obesity, and type 2 diabetes.	Anti-inflammatory diets, antioxidant therapies, and interventions targeting ROS production.	[125,126,145]
Genetic and Epigenetic Factors	Shared genetic loci and epigenetic modifications create a common predisposition for both ADHD and metabolic dysfunction.	Predisposition to metabolic syndrome, obesity, and diabetes.	Personalized medicine approaches, early screening, and targeted lifestyle modifications.	[122,139,140]
Integrated Clinical Approaches	Comorbid ADHD and metabolic disorders require holistic, multidisciplinary management.	Improved glycemic control, weight management, and overall cognitive function.	Combined pharmacological treatments (e.g., CGM, SGLT2 inhibitors, GLP-1 RAs), behavioral therapies, and lifestyle programs.	[147,152,159]

HPA: Hypothalamic–pituitary–adrenal; ROS: Reactive oxygen species; ADHD: Attention deficit hyperactivity disorder; CGM: Continuous glucose monitoring; SGLT2: Sodium–glucose cotransporter-2; GLP-1 RA: Glucagon-like peptide-1 receptor agonist.

Similarly, insulin-sensitizing agents like metformin may offer adjunctive benefits in ADHD treatment due to their neuroprotective properties and positive effects on metabolism [165]. Metformin, widely used for treating insulin resistance and T2D, has demonstrated potential benefits in managing weight gain associated with psychotropic medications, particularly in children treated with mixed serotonin and dopamine receptor antagonists [166]. Given its favorable safety profile, metformin may be a valuable option for young, obese, insulin-resistant ADHD patients, although specific data on its effects in this population are currently lacking. Interactions of these drugs with methylphenidate and other psychiatric medications have not yet been fully investigated.

5.3. Bariatric Surgery

For severely obese ADHD patients, bariatric surgery remains a viable treatment option, demonstrating comparable efficacy to its outcomes in non-ADHD individuals. Studies suggest that surgical interventions may be superior to pharmacotherapy in achieving sustained weight loss and metabolic improvements [167,168]. However, the long-term effects of bariatric surgery on ADHD symptoms and cognitive function require further exploration. Given the complex interplay between ADHD and metabolic disorders, treatment strategies must adopt a holistic, patient-centered approach, integrating psychiatric and metabolic care to optimize outcomes [169,170,171].

6. Future Directions and Research Needs

Despite growing evidence linking ADHD to metabolic dysfunction, several critical knowledge gaps remain that must be addressed to develop targeted interventions mitigating both ADHD symptoms and metabolic complications. A more comprehensive understanding of the interplay between ADHD and metabolism is essential, and current research must evolve beyond predominantly cross-sectional designs. Longitudinal studies tracking metabolic health from childhood through adulthood in individuals with ADHD are needed to establish causal relationships, identify early predictive markers, and elucidate disease trajectories. Additionally, standardized metabolic biomarkers for assessing risk remain elusive. However, emerging candidates such as adiponectin, leptin, and inflammatory markers like CRP may offer insight into early metabolic alterations in ADHD [24,172,173]. Future investigations should focus on identifying specific metabolic signatures that could enhance diagnostic precision and inform treatment monitoring.

The relationship between ADHD and metabolic disorders is further complicated by shared genetic and epigenetic mechanisms [174]. Variants in dopamine signaling pathways, appetite regulation genes such as FTO and MC4R, and circadian rhythm regulators suggest a biological overlap that warrants closer examination [175]. Understanding how these genetic predispositions interact with environmental factors like diet and physical activity will be key to unraveling their collective impact on metabolic health. Moreover, emerging research on the gut–brain axis points to the composition of gut microbiota as a potential mediator of both neurodevelopmental and metabolic outcomes [176]. Investigating microbiome-targeted therapies, including probiotics and specific dietary interventions, could reveal new strategies for modulating ADHD symptoms while improving metabolic profiles. In parallel, the long-term metabolic effects of ADHD medications require careful scrutiny; while stimulant medications often lead to appetite suppression and potential weight loss, some non-stimulant treatments have been associated with increased risks of insulin resistance and obesity. Addressing these challenges calls for innovative therapeutic strategies that integrate neurodevelopmental and metabolic perspectives. Novel pharmacological approaches are being explored, including medications that modulate both dopamine and metabolic pathways. The development of multi-target drugs that address both executive dysfunction and metabolic abnormalities represents another promising avenue. Beyond pharmacotherapy, non-pharmacological interventions that promote neuroplasticity and healthy lifestyles are critical. Cognitive training combined with exercise regimens could simultaneously boost executive function and improve insulin sensitivity and cardiovascular health [177,178]. The link between sleep duration, obesity, and type 2 diabetes suggests that interventions targeting sleep hygiene may help mitigate metabolic risks in individuals with ADHD [179,180]. In addition, implementing school-based programs focused on early metabolic health could help prevent obesity and type 2 diabetes in high-risk populations.

The metabolic aspects of ADHD also carry significant public health implications, particularly as the prevalence of both ADHD and obesity continues to rise [181]. Incorporating routine metabolic screening into ADHD clinical guidelines, especially for children and adolescents at heightened risk, is imperative for early detection and prevention. The establishment of interdisciplinary care models that bring together pediatricians, psychiatrists, endocrinologists, and nutritionists will be crucial for delivering comprehensive management of ADHD and its metabolic comorbidities. Furthermore, public health initiatives must work to raise awareness about the interconnected nature of ADHD and metabolic dysfunction, ensuring broader access to integrative treatment strategies and preventive measures [182,183]. Finally, given the influence of socioeconomic and environmental factors on both conditions, future research should prioritize the examination of health disparities and the development of targeted interventions for high-risk populations [184,185].

This review offers a comprehensive synthesis of current knowledge on the interplay between ADHD and metabolic dysfunction. However, several limitations should be acknowledged. As a narrative review, it is inherently subject to selection and publication bias and lacks the methodological rigor of a systematic review. The heterogeneity of the studies included, in terms of design, diagnostic criteria, and population characteristics, limits the ability to draw definitive conclusions. Moreover, given the rapid pace of research in both neurodevelopmental and metabolic fields, some emerging findings may not have been captured. These limitations underscore the need for continued research and periodic reassessment of the evolving evidence base.

7. Conclusions

There is a robust, bidirectional link between ADHD and metabolic disorders, driven by shared mechanisms such as dopaminergic dysregulation, HPA axis disruption, and chronic inflammation. These overlapping pathways suggest that therapeutic strategies targeting both neurodevelopmental and metabolic dysfunctions may yield significant clinical benefits. However, further research is necessary to clarify the genetic, epigenetic, and environmental factors at play, and to refine personalized treatment approaches that integrate metabolic and psychiatric care. Addressing these challenges is critical for reducing the long-term burden of these comorbid conditions.