Evaluation of the Relationship Between Vitamin Levels and Symptom Severity in Adults With Attention-Deficit/Hyperactivity Disorder

Evaluation of the Relationship Between Vitamin Levels and Symptom Severity in Adults With Attention-Deficit/Hyperactivity Disorder | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Evaluation of the Relationship Between Vitamin Levels and Symptom Severity in Adults With Attention-Deficit/Hyperactivity Disorder Demiryürek Esra, Kocayiğit Havva This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8339197/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 25 Feb, 2026 Read the published version in Scientific Reports → Version 1 posted 12 You are reading this latest preprint version Abstract Objective: This study aimed to compare serum vitamin B12, 25-hydroxyvitamin D, ferritin, and iron levels between adults diagnosed with attention deficit hyperactivity disorder (ADHD) and healthy controls, and to evaluate the relationship between these biochemical markers and the severity of ADHD symptoms. Methods: A total of 35 adults with ADHD and 36 age- and sex-matched healthy controls who presented to a psychiatry outpatient clinic in Sakarya in 2024 were included. Participants' demographic data and clinical characteristics were collected through interviews, while laboratory findings were examined using blood samples taken at the time of inclusion in the study. The severity of ADHD symptoms was assessed using the Adult ADHD Self-Report Scale (ASRS) and the Wender–Utah Rating Scale (WURS). Results: Serum vitamin B12 and 25-hydroxyvitamin D levels were significantly lower in the ADHD group compared with controls (p 0.05). Furthermore, both vitamin B12 and vitamin D levels showed a negative correlation with total ASRS and WURS scores (p < 0.001). Conclusion: These findings suggest that vitamin B12 and vitamin D deficiencies may be associated with greater symptom severity in adult ADHD. The results highlight the potential contribution of biochemical factors to the neurobiological basis of ADHD and indicate that routine assessment of vitamin levels may be beneficial in clinical practice. Health sciences/Biomarkers Health sciences/Diseases Health sciences/Medical research Health sciences/Neurology Biological sciences/Neuroscience ADHD vitamin B12 vitamin D ferritin iron Introduction Attention-Deficit/Hyperactivity Disorder (ADHD) is a neurodevelopmental condition that begins in childhood and may persist into adulthood. Adult ADHD can lead to a marked reduction in quality of life due to symptoms of inattention, impulsivity, and hyperactivity. The prevalence of adult ADHD in the general population has been reported to range between 2–5%. While neurotransmitter systems such as dopamine and norepinephrine are central to its pathophysiology, nutritional and biochemical factors involved in the synthesis and metabolism of these neurotransmitters may also play a contributory role. Recent studies have demonstrated that vitamin D, vitamin B12, ferritin, and iron levels play important roles in neurodevelopmental processes and cognitive functioning. Accordingly, deficiencies in these micronutrients have been proposed as potential contributors to ADHD pathogenesis. Meta-analyses conducted in child and adolescent populations have shown significantly lower serum 25-hydroxyvitamin D (25-OHD) levels in patients with ADHD compared with healthy controls (1). Randomized controlled trials have also reported that vitamin D supplementation may lead to partial improvement in attention and hyperactivity symptoms (2,3). Similarly, there is robust evidence indicating reduced ferritin levels in individuals with ADHD. A meta-analysis found that ferritin levels were significantly lower in ADHD patients compared with controls (SMD = − 0.40; 95% CI = − 0.66 to − 0.14), whereas findings for serum iron levels have been inconsistent (4,5). Studies on vitamin B12 have likewise suggested that B12 levels may be lower in children and adolescents with ADHD (6). However, the number of large-sample or prospective studies examining these parameters in adult ADHD populations remains limited. In light of these considerations, comparing serum vitamin B12, 25-OH vitamin D, ferritin, and iron levels between adults with ADHD and healthy controls, as well as examining the relationship between these biomarkers and symptom severity, is clinically relevant and addresses an important gap in the current literature. Materials and Methods This cross-sectional study aimed to compare serum vitamin B12, vitamin D, ferritin, and iron levels in adults diagnosed with attention-deficit/hyperactivity disorder (ADHD) with those of a healthy control group, and to evaluate the associations between these biochemical markers and the severity of ADHD symptoms. Participants were recruited between January and December 2024 from a private psychiatry outpatient clinic in Sakarya, Türkiye. Thirty-five adults diagnosed with ADHD by a psychiatrist according to DSM-5 criteria and 36 age- and sex-matched healthy controls were included in the study. Individuals aged 18–65 years with normal cognitive functioning and no history of anemia were eligible for inclusion. Those with comorbid neurological disorders, chronic systemic illnesses, psychotropic medication use, pregnancy, obesity, or active infection were excluded. Demographic characteristics (age, sex, years of education), socioeconomic variables (marital status, living conditions, occupation), and psychiatric history (childhood ADHD or other psychiatric diagnoses, past stimulant or other psychotropic medication use, family history) were recorded for all participants. Clinical reasons for referral and current psychiatric medications were also assessed. Symptom severity was evaluated using the Wender–Utah Rating Scale (WURS) and the Adult ADHD Self-Report Scale (ASRS). Venous blood samples were collected on the same day as the clinical assessment. Serum vitamin B12, 25-hydroxyvitamin D, ferritin, and iron levels were analyzed using standardized laboratory procedures. Biochemical measurements were performed at the Sakarya University Training and Research Hospital Biochemistry Laboratory. Ferritin and B12 levels were assessed using chemiluminescent immunoassay on the ABBOTT ARCHITECT i2000SR analyzer; 25-OH D levels were measured using the ChromSystems-based Architect 25-OH Vitamin D kit on the same platform; serum iron was evaluated photometrically on the ABBOTT ARCHITECT c16000 device. The study was conducted in accordance with the principles of the Declaration of Helsinki, and informed consent was obtained from all participants. The study protocol was approved by the Ethics Committee of Sakarya University School of Medicine. Statistical Analysis Data were analyzed using IBM SPSS Statistics version 27.0. The distribution of continuous variables was assessed using the Kolmogorov–Smirnov test. Normally distributed variables were expressed as mean ± standard deviation (SD), and categorical variables as frequencies and percentages. Between-group comparisons were performed using independent-samples t-tests for continuous variables and chi-square tests for categorical variables. Correlations between variables were analyzed using Spearman’s correlation coefficient. A p-value of < 0.05 was considered statistically significant. Results Comparison of demographic characteristics between the 35 adult ADHD patients and 36 healthy controls revealed no significant differences in age, sex, marital status, employment status, or years of education (all p > 0.05). All ASRS subscale and total scores were significantly higher in the ADHD group compared with controls (p < 0.001). Specifically, ADHD patients had significantly elevated ASRS inattention (31.37 ± 3.19), hyperactivity/impulsivity (24.57 ± 6.29), and total scores (55.94 ± 8.72) relative to controls (13.78 ± 3.37; 5.75 ± 3.67; 19.53 ± 6.20, respectively). WURS subscale and total scores, including irritability, depression, school problems, behavior/impulsivity, and inattention, were also significantly higher in the ADHD group (all p < 0.001). These findings confirm that both childhood-related symptoms and current attentional and behavioral impairments are substantially more pronounced in adults with ADHD than in controls. No significant between-group differences were found in serum iron (67.17 ± 31.76 µg/dL vs. 69.38 ± 24.36 µg/dL; p = 0.745) or ferritin levels (41.34 ± 23.72 ng/mL vs. 41.71 ± 14.94 ng/mL; p = 0.939). In contrast, vitamin B12 levels were significantly lower in the ADHD group (194.83 ± 21.05 pg/mL vs. 299.94 ± 126.99 pg/mL; p < 0.001). Similarly, 25-OH vitamin D levels were markedly reduced in ADHD patients (22.73 ± 7.21 ng/mL vs. 28.74 ± 5.67 ng/mL; p < 0.001). These results indicate that vitamin B12 and vitamin D deficiencies are more common in adults with ADHD, whereas iron and ferritin levels do not differ significantly. Correlation analyses demonstrated significant negative associations between vitamin B12 and 25-OH vitamin D levels and both ASRS and WURS subscale and total scores (p < 0.001). Lower serum levels of these vitamins were associated with increased severity of inattention, hyperactivity/impulsivity, and behavioral symptoms. Strong negative correlations were observed particularly with ASRS inattention (r = − 0.54, p < 0.001), ASRS hyperactivity/impulsivity (r = − 0.44, p < 0.001), and WURS inattention scores (r = − 0.56, p < 0.001). WURS irritability (r = − 0.30, p = 0.011), depression (r = − 0.43, p < 0.001), and behavior/impulsivity (r = − 0.36, p = 0.002) also showed similar inverse relationships. No significant correlations were found between iron or ferritin levels and any symptom scores (all p > 0.05). These findings suggest that neurobiochemical deficiencies may be related to symptom severity in ADHD. Discussion This study investigated serum vitamin B12, 25-OH vitamin D, ferritin, and iron levels in adults with ADHD compared with healthy controls, and examined the associations between these biomarkers and ADHD symptom severity. Our findings revealed significantly lower levels of vitamin B12 and vitamin D in the ADHD group, whereas iron and ferritin did not differ between groups. Furthermore, significant negative correlations were identified between B12 and vitamin D levels and ASRS and WURS scores. These results suggest that deficiencies in vitamins B12 and D may be associated with attentional and behavioral symptoms observed in ADHD. The significantly reduced vitamin B12 and 25-OH vitamin D levels in adults with ADHD align with previous literature. Meta-analyses and systematic reviews by Khoshbakht et al. (1) and Mazahery et al. (7,11) have consistently reported lower vitamin D levels in individuals with ADHD, as well as an association between reduced vitamin D status and increased risk of the disorder. Randomized controlled trials have shown partial improvements in attention and hyperactivity symptoms following vitamin D supplementation (2). Vitamin D plays roles in the regulation of genes involved in dopaminergic neurotransmission and in the modulation of neuronal growth factors (2,8). These mechanisms may explain how vitamin D deficiency contributes to impairments in executive functioning and cognitive slowing (9,11). Although fewer studies have examined vitamin B12 in ADHD, evidence suggests that low B12 levels may negatively affect attention, dopaminergic function, and cognitive performance. Reviews by Bryan et al. (12) and Malhi et al. (13) indicate that B12 deficiency is associated with reduced dopamine and serotonin synthesis, impaired methylation pathways, and diminished neurocognitive functioning. Oner et al. (6) have demonstrated links between B12 levels and attentional processes in children and adolescents. Additionally, meta-analytic findings by Rucklidge et al. (14) indicate that micronutrient supplementation may improve ADHD symptoms. Taken together, these findings support the possibility that similar neurobiochemical mechanisms may also be relevant in adults with ADHD. In contrast to findings in children, our study did not detect significant differences in iron or ferritin levels between adults with ADHD and controls. Meta-analytic evidence by Wang et al. (4) has demonstrated reduced ferritin levels in children with ADHD. Beard et al. (15) reported that iron deficiency affects dopamine receptor density and dopamine transporter expression, thereby impairing neurotransmission. Neuroimaging studies such as that of Cortese et al. (16) have shown reduced brain iron levels in ADHD. The discrepancy between child and adult findings may be due to stabilization of iron metabolism in adulthood or diminished relevance of brain iron stores in later life. Additionally, exclusion of individuals with anemia or iron deficiency in our sample may have contributed to the absence of group differences. This study is among the few to evaluate vitamin B12, vitamin D, iron, and ferritin levels simultaneously in an adult ADHD population. While most literature focuses on pediatric samples, our findings highlight the potential relevance of nutritional and biochemical factors in adult ADHD symptomatology. Furthermore, the use of two well-validated symptom scales—ASRS and WURS—increases the reliability of the results. Nevertheless, the cross-sectional design limits causal inference. For example, it remains unclear whether low vitamin levels contribute to ADHD or whether ADHD-related behaviors (inattention, impulsivity) reduce dietary quality and sun exposure, thereby lowering vitamin levels. Additionally, variables such as diet, sunlight exposure, and physical activity were not fully controlled. Despite the modest sample size, the results underline the potential clinical relevance of assessing biochemical markers in adults with ADHD. Overall, this study suggests that considering nutritional factors may enhance understanding of the biochemical and neurometabolic underpinnings of adult ADHD. In clinical practice, routine assessment of vitamin B12 and vitamin D levels in adults diagnosed with ADHD and appropriate supplementation where deficiencies exist may contribute to improved symptom control. Future prospective, large-scale, and intervention-based studies are warranted to further clarify the roles and therapeutic potential of these vitamins in ADHD pathophysiology. Declarations Competing interests statement: The authors declare no competing interests. Funding: Not applicable. Author Contribution E.D and H.K: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Writing - original draft, Visualization, Resources, Software, Validation. Data Availability The datasets generated and/or analysed during the current study are not publicly available due to ethical restrictions and patient confidentiality, but are available from the corresponding author on reasonable request. References Khoshbakht Y, Bidaki R, Salehi-Abargouei A. Vitamin D status and attention deficit hyperactivity disorder: a systematic review and meta-analysis of observational studies. Nutr Neurosci. 2018;21(8):614–24. Mohammadpour N, Jazayeri S, Tehrani-Doost M, Djalali M, Hosseini S, Keshavarz SA. Effect of vitamin D supplementation as adjunctive therapy to methylphenidate on ADHD symptoms: A randomized, double-blind, placebo-controlled trial. Nutr Neurosci. 2019;22(9):659–67. Elshorbagy HH, Barseem NF, Abdelghani WE, et al. Vitamin D status in children with attention-deficit hyperactivity disorder. Egypt J Neurol Psychiatr Neurosurg. 2018;54:26. Wang Y, Huang L, Zhang L, Qu Y, Mu D. Iron status in attention-deficit/hyperactivity disorder: a systematic review and meta-analysis. PLoS One. 2017;12(1):e0169145. Konofal E, Lecendreux M, Arnulf I, Mouren MC. Iron deficiency in children with attention-deficit/hyperactivity disorder. Arch Pediatr Adolesc Med. 2004;158(12):1113–5. Oner P, Oner O, Bozkurt OH, et al. The relations between vitamin B12, folate and ferritin levels and clinical features of Turkish children and adolescents with ADHD. Psychiatry Clin Psychopharmacol. 2010;20(2):131–6. Mazahery H, Conlon CA, Beck KL, Kruger MC, Stonehouse W. Vitamin D and the brain: Mechanisms and neuropsychiatric implications. Nutrients. 2018;10(10):1455. Jorde R, Kubiak J, Svartberg J, Grimnes G. Vitamin D and cognitive function: A prospective study among middle-aged and older adults. Psychoneuroendocrinology. 2019;104:104–12. Cortese S. Nutrition, micronutrients, and ADHD: What the evidence says. Neurosci Biobehav Rev. 2020;118:209–25. Lozoff B, Beard J, Connor J, Barbara F, Georgieff M, Schallert T. Long-lasting neural and behavioral effects of iron deficiency in infancy. Am J Clin Nutr. 2016;104(Suppl 3):931S–39S. Mazahery H, Conlon CA, Kruger MC, Beck KL, Stonehouse W. Vitamin D supplementation improves cognitive performance and behavior: A review of trials. Nutr Rev. 2021;79(9):1012–28. Bryan J, Calvaresi E, Hughes D. Micronutrient status and cognitive function: A systematic review. Nutrients. 2021;13(9):3115. Malhi GS, Coulston CM, Fritz K. The role of nutrition and nutritional supplements in psychiatry: A review of evidence-based recommendations. CNS Drugs. 2020;34(9):921–45. Rucklidge JJ, Johnstone JM, Harrison R, Boggis A. Broad-spectrum micronutrient treatment for ADHD: A systematic review. Psychiatry Clin Neurosci. 2017;71(2):87–100. Beard JL, Connor JR, Jones BC. Iron deficiency alters brain development and neurotransmitter function. Nutr Rev. 2003;61(3):S45–8. Cortese S, Imperati D, Zhou J, Proal E, Klein RG, Mannuzza S, Castellanos FX. Brain iron levels in attention-deficit/hyperactivity disorder: A magnetic resonance spectroscopy study. Biol Psychiatry. 2012;72(12):893–8. Tables Tables are available in the Supplementary Files section. Additional Declarations No competing interests reported. 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Adult ADHD can lead to a marked reduction in quality of life due to symptoms of inattention, impulsivity, and hyperactivity. The prevalence of adult ADHD in the general population has been reported to range between 2\u0026ndash;5%. While neurotransmitter systems such as dopamine and norepinephrine are central to its pathophysiology, nutritional and biochemical factors involved in the synthesis and metabolism of these neurotransmitters may also play a contributory role.\u003c/p\u003e \u003cp\u003eRecent studies have demonstrated that vitamin D, vitamin B12, ferritin, and iron levels play important roles in neurodevelopmental processes and cognitive functioning. Accordingly, deficiencies in these micronutrients have been proposed as potential contributors to ADHD pathogenesis. Meta-analyses conducted in child and adolescent populations have shown significantly lower serum 25-hydroxyvitamin D (25-OHD) levels in patients with ADHD compared with healthy controls (1). Randomized controlled trials have also reported that vitamin D supplementation may lead to partial improvement in attention and hyperactivity symptoms (2,3).\u003c/p\u003e \u003cp\u003eSimilarly, there is robust evidence indicating reduced ferritin levels in individuals with ADHD. A meta-analysis found that ferritin levels were significantly lower in ADHD patients compared with controls (SMD = \u0026minus;\u0026thinsp;0.40; 95% CI = \u0026minus;\u0026thinsp;0.66 to \u0026minus;\u0026thinsp;0.14), whereas findings for serum iron levels have been inconsistent (4,5). Studies on vitamin B12 have likewise suggested that B12 levels may be lower in children and adolescents with ADHD (6). However, the number of large-sample or prospective studies examining these parameters in adult ADHD populations remains limited.\u003c/p\u003e \u003cp\u003eIn light of these considerations, comparing serum vitamin B12, 25-OH vitamin D, ferritin, and iron levels between adults with ADHD and healthy controls, as well as examining the relationship between these biomarkers and symptom severity, is clinically relevant and addresses an important gap in the current literature.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cp\u003eThis cross-sectional study aimed to compare serum vitamin B12, vitamin D, ferritin, and iron levels in adults diagnosed with attention-deficit/hyperactivity disorder (ADHD) with those of a healthy control group, and to evaluate the associations between these biochemical markers and the severity of ADHD symptoms.\u003c/p\u003e \u003cp\u003eParticipants were recruited between January and December 2024 from a private psychiatry outpatient clinic in Sakarya, T\u0026uuml;rkiye. Thirty-five adults diagnosed with ADHD by a psychiatrist according to DSM-5 criteria and 36 age- and sex-matched healthy controls were included in the study.\u003c/p\u003e \u003cp\u003eIndividuals aged 18\u0026ndash;65 years with normal cognitive functioning and no history of anemia were eligible for inclusion. Those with comorbid neurological disorders, chronic systemic illnesses, psychotropic medication use, pregnancy, obesity, or active infection were excluded.\u003c/p\u003e \u003cp\u003eDemographic characteristics (age, sex, years of education), socioeconomic variables (marital status, living conditions, occupation), and psychiatric history (childhood ADHD or other psychiatric diagnoses, past stimulant or other psychotropic medication use, family history) were recorded for all participants. Clinical reasons for referral and current psychiatric medications were also assessed.\u003c/p\u003e \u003cp\u003eSymptom severity was evaluated using the Wender\u0026ndash;Utah Rating Scale (WURS) and the Adult ADHD Self-Report Scale (ASRS).\u003c/p\u003e \u003cp\u003eVenous blood samples were collected on the same day as the clinical assessment. Serum vitamin B12, 25-hydroxyvitamin D, ferritin, and iron levels were analyzed using standardized laboratory procedures. Biochemical measurements were performed at the Sakarya University Training and Research Hospital Biochemistry Laboratory. Ferritin and B12 levels were assessed using chemiluminescent immunoassay on the ABBOTT ARCHITECT i2000SR analyzer; 25-OH D levels were measured using the ChromSystems-based Architect 25-OH Vitamin D kit on the same platform; serum iron was evaluated photometrically on the ABBOTT ARCHITECT c16000 device.\u003c/p\u003e \u003cp\u003e The study was conducted in accordance with the principles of the Declaration of Helsinki, and informed consent was obtained from all participants. The study protocol was approved by the Ethics Committee of Sakarya University School of Medicine.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eData were analyzed using IBM SPSS Statistics version 27.0. The distribution of continuous variables was assessed using the Kolmogorov\u0026ndash;Smirnov test. Normally distributed variables were expressed as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (SD), and categorical variables as frequencies and percentages. Between-group comparisons were performed using independent-samples t-tests for continuous variables and chi-square tests for categorical variables. Correlations between variables were analyzed using Spearman\u0026rsquo;s correlation coefficient. A p-value of \u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eComparison of demographic characteristics between the 35 adult ADHD patients and 36 healthy controls revealed no significant differences in age, sex, marital status, employment status, or years of education (all p\u0026thinsp;\u0026gt;\u0026thinsp;0.05).\u003c/p\u003e \u003cp\u003eAll ASRS subscale and total scores were significantly higher in the ADHD group compared with controls (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Specifically, ADHD patients had significantly elevated ASRS inattention (31.37\u0026thinsp;\u0026plusmn;\u0026thinsp;3.19), hyperactivity/impulsivity (24.57\u0026thinsp;\u0026plusmn;\u0026thinsp;6.29), and total scores (55.94\u0026thinsp;\u0026plusmn;\u0026thinsp;8.72) relative to controls (13.78\u0026thinsp;\u0026plusmn;\u0026thinsp;3.37; 5.75\u0026thinsp;\u0026plusmn;\u0026thinsp;3.67; 19.53\u0026thinsp;\u0026plusmn;\u0026thinsp;6.20, respectively). WURS subscale and total scores, including irritability, depression, school problems, behavior/impulsivity, and inattention, were also significantly higher in the ADHD group (all p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). These findings confirm that both childhood-related symptoms and current attentional and behavioral impairments are substantially more pronounced in adults with ADHD than in controls.\u003c/p\u003e \u003cp\u003eNo significant between-group differences were found in serum iron (67.17\u0026thinsp;\u0026plusmn;\u0026thinsp;31.76 \u0026micro;g/dL vs. 69.38\u0026thinsp;\u0026plusmn;\u0026thinsp;24.36 \u0026micro;g/dL; p\u0026thinsp;=\u0026thinsp;0.745) or ferritin levels (41.34\u0026thinsp;\u0026plusmn;\u0026thinsp;23.72 ng/mL vs. 41.71\u0026thinsp;\u0026plusmn;\u0026thinsp;14.94 ng/mL; p\u0026thinsp;=\u0026thinsp;0.939).\u003c/p\u003e \u003cp\u003eIn contrast, vitamin B12 levels were significantly lower in the ADHD group (194.83\u0026thinsp;\u0026plusmn;\u0026thinsp;21.05 pg/mL vs. 299.94\u0026thinsp;\u0026plusmn;\u0026thinsp;126.99 pg/mL; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Similarly, 25-OH vitamin D levels were markedly reduced in ADHD patients (22.73\u0026thinsp;\u0026plusmn;\u0026thinsp;7.21 ng/mL vs. 28.74\u0026thinsp;\u0026plusmn;\u0026thinsp;5.67 ng/mL; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). These results indicate that vitamin B12 and vitamin D deficiencies are more common in adults with ADHD, whereas iron and ferritin levels do not differ significantly.\u003c/p\u003e \u003cp\u003eCorrelation analyses demonstrated significant negative associations between vitamin B12 and 25-OH vitamin D levels and both ASRS and WURS subscale and total scores (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Lower serum levels of these vitamins were associated with increased severity of inattention, hyperactivity/impulsivity, and behavioral symptoms. Strong negative correlations were observed particularly with ASRS inattention (r = \u0026minus;\u0026thinsp;0.54, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), ASRS hyperactivity/impulsivity (r = \u0026minus;\u0026thinsp;0.44, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and WURS inattention scores (r = \u0026minus;\u0026thinsp;0.56, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). WURS irritability (r = \u0026minus;\u0026thinsp;0.30, p\u0026thinsp;=\u0026thinsp;0.011), depression (r = \u0026minus;\u0026thinsp;0.43, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and behavior/impulsivity (r = \u0026minus;\u0026thinsp;0.36, p\u0026thinsp;=\u0026thinsp;0.002) also showed similar inverse relationships.\u003c/p\u003e \u003cp\u003eNo significant correlations were found between iron or ferritin levels and any symptom scores (all p\u0026thinsp;\u0026gt;\u0026thinsp;0.05). These findings suggest that neurobiochemical deficiencies may be related to symptom severity in ADHD.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study investigated serum vitamin B12, 25-OH vitamin D, ferritin, and iron levels in adults with ADHD compared with healthy controls, and examined the associations between these biomarkers and ADHD symptom severity.\u003c/p\u003e \u003cp\u003eOur findings revealed significantly lower levels of vitamin B12 and vitamin D in the ADHD group, whereas iron and ferritin did not differ between groups. Furthermore, significant negative correlations were identified between B12 and vitamin D levels and ASRS and WURS scores. These results suggest that deficiencies in vitamins B12 and D may be associated with attentional and behavioral symptoms observed in ADHD.\u003c/p\u003e \u003cp\u003eThe significantly reduced vitamin B12 and 25-OH vitamin D levels in adults with ADHD align with previous literature. Meta-analyses and systematic reviews by Khoshbakht et al. (1) and Mazahery et al. (7,11) have consistently reported lower vitamin D levels in individuals with ADHD, as well as an association between reduced vitamin D status and increased risk of the disorder. Randomized controlled trials have shown partial improvements in attention and hyperactivity symptoms following vitamin D supplementation (2). Vitamin D plays roles in the regulation of genes involved in dopaminergic neurotransmission and in the modulation of neuronal growth factors (2,8). These mechanisms may explain how vitamin D deficiency contributes to impairments in executive functioning and cognitive slowing (9,11).\u003c/p\u003e \u003cp\u003eAlthough fewer studies have examined vitamin B12 in ADHD, evidence suggests that low B12 levels may negatively affect attention, dopaminergic function, and cognitive performance. Reviews by Bryan et al. (12) and Malhi et al. (13) indicate that B12 deficiency is associated with reduced dopamine and serotonin synthesis, impaired methylation pathways, and diminished neurocognitive functioning. Oner et al. (6) have demonstrated links between B12 levels and attentional processes in children and adolescents. Additionally, meta-analytic findings by Rucklidge et al. (14) indicate that micronutrient supplementation may improve ADHD symptoms. Taken together, these findings support the possibility that similar neurobiochemical mechanisms may also be relevant in adults with ADHD.\u003c/p\u003e \u003cp\u003eIn contrast to findings in children, our study did not detect significant differences in iron or ferritin levels between adults with ADHD and controls. Meta-analytic evidence by Wang et al. (4) has demonstrated reduced ferritin levels in children with ADHD. Beard et al. (15) reported that iron deficiency affects dopamine receptor density and dopamine transporter expression, thereby impairing neurotransmission. Neuroimaging studies such as that of Cortese et al. (16) have shown reduced brain iron levels in ADHD. The discrepancy between child and adult findings may be due to stabilization of iron metabolism in adulthood or diminished relevance of brain iron stores in later life. Additionally, exclusion of individuals with anemia or iron deficiency in our sample may have contributed to the absence of group differences.\u003c/p\u003e \u003cp\u003eThis study is among the few to evaluate vitamin B12, vitamin D, iron, and ferritin levels simultaneously in an adult ADHD population. While most literature focuses on pediatric samples, our findings highlight the potential relevance of nutritional and biochemical factors in adult ADHD symptomatology. Furthermore, the use of two well-validated symptom scales\u0026mdash;ASRS and WURS\u0026mdash;increases the reliability of the results.\u003c/p\u003e \u003cp\u003eNevertheless, the cross-sectional design limits causal inference. For example, it remains unclear whether low vitamin levels contribute to ADHD or whether ADHD-related behaviors (inattention, impulsivity) reduce dietary quality and sun exposure, thereby lowering vitamin levels. Additionally, variables such as diet, sunlight exposure, and physical activity were not fully controlled. Despite the modest sample size, the results underline the potential clinical relevance of assessing biochemical markers in adults with ADHD.\u003c/p\u003e \u003cp\u003eOverall, this study suggests that considering nutritional factors may enhance understanding of the biochemical and neurometabolic underpinnings of adult ADHD. In clinical practice, routine assessment of vitamin B12 and vitamin D levels in adults diagnosed with ADHD and appropriate supplementation where deficiencies exist may contribute to improved symptom control. Future prospective, large-scale, and intervention-based studies are warranted to further clarify the roles and therapeutic potential of these vitamins in ADHD pathophysiology.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eCompeting interests statement:\u003c/h2\u003e \u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e \u003c/p\u003e \u003ch2\u003eFunding:\u003c/h2\u003e \u003cp\u003eNot applicable.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eE.D and H.K: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Writing - original draft, Visualization, Resources, Software, Validation.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe datasets generated and/or analysed during the current study are not publicly available due to ethical restrictions and patient confidentiality, but are available from the corresponding author on reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003e\u003cb\u003eKhoshbakht Y, Bidaki R, Salehi-Abargouei A.\u003c/b\u003e Vitamin D status and attention deficit hyperactivity disorder: a systematic review and meta-analysis of observational studies. \u003cem\u003eNutr Neurosci.\u003c/em\u003e 2018;21(8):614–24.\u003c/li\u003e\n\u003cli\u003e\u003cb\u003eMohammadpour N, Jazayeri S, Tehrani-Doost M, Djalali M, Hosseini S, Keshavarz SA.\u003c/b\u003e Effect of vitamin D supplementation as adjunctive therapy to methylphenidate on ADHD symptoms: A randomized, double-blind, placebo-controlled trial. \u003cem\u003eNutr Neurosci.\u003c/em\u003e 2019;22(9):659–67.\u003c/li\u003e\n\u003cli\u003e\u003cb\u003eElshorbagy HH, Barseem NF, Abdelghani WE, et al.\u003c/b\u003e Vitamin D status in children with attention-deficit hyperactivity disorder. \u003cem\u003eEgypt J Neurol Psychiatr Neurosurg.\u003c/em\u003e 2018;54:26.\u003c/li\u003e\n\u003cli\u003e\u003cb\u003eWang Y, Huang L, Zhang L, Qu Y, Mu D.\u003c/b\u003e Iron status in attention-deficit/hyperactivity disorder: a systematic review and meta-analysis. \u003cem\u003ePLoS One.\u003c/em\u003e 2017;12(1):e0169145.\u003c/li\u003e\n\u003cli\u003e\u003cb\u003eKonofal E, Lecendreux M, Arnulf I, Mouren MC.\u003c/b\u003e Iron deficiency in children with attention-deficit/hyperactivity disorder. \u003cem\u003eArch Pediatr Adolesc Med.\u003c/em\u003e 2004;158(12):1113–5.\u003c/li\u003e\n\u003cli\u003e\u003cb\u003eOner P, Oner O, Bozkurt OH, et al.\u003c/b\u003e The relations between vitamin B12, folate and ferritin levels and clinical features of Turkish children and adolescents with ADHD. \u003cem\u003ePsychiatry Clin Psychopharmacol.\u003c/em\u003e 2010;20(2):131–6.\u003c/li\u003e\n\u003cli\u003e\u003cb\u003eMazahery H, Conlon CA, Beck KL, Kruger MC, Stonehouse W.\u003c/b\u003e Vitamin D and the brain: Mechanisms and neuropsychiatric implications. \u003cem\u003eNutrients.\u003c/em\u003e 2018;10(10):1455.\u003c/li\u003e\n\u003cli\u003e\u003cb\u003eJorde R, Kubiak J, Svartberg J, Grimnes G.\u003c/b\u003e Vitamin D and cognitive function: A prospective study among middle-aged and older adults. \u003cem\u003ePsychoneuroendocrinology.\u003c/em\u003e 2019;104:104–12.\u003c/li\u003e\n\u003cli\u003e\u003cb\u003eCortese S.\u003c/b\u003e Nutrition, micronutrients, and ADHD: What the evidence says. \u003cem\u003eNeurosci Biobehav Rev.\u003c/em\u003e 2020;118:209–25.\u003c/li\u003e\n\u003cli\u003e\u003cb\u003eLozoff B, Beard J, Connor J, Barbara F, Georgieff M, Schallert T.\u003c/b\u003e Long-lasting neural and behavioral effects of iron deficiency in infancy. \u003cem\u003eAm J Clin Nutr.\u003c/em\u003e 2016;104(Suppl 3):931S–39S.\u003c/li\u003e\n\u003cli\u003e\u003cb\u003eMazahery H, Conlon CA, Kruger MC, Beck KL, Stonehouse W.\u003c/b\u003e Vitamin D supplementation improves cognitive performance and behavior: A review of trials. \u003cem\u003eNutr Rev.\u003c/em\u003e 2021;79(9):1012–28.\u003c/li\u003e\n\u003cli\u003e\u003cb\u003eBryan J, Calvaresi E, Hughes D.\u003c/b\u003e Micronutrient status and cognitive function: A systematic review. \u003cem\u003eNutrients.\u003c/em\u003e 2021;13(9):3115.\u003c/li\u003e\n\u003cli\u003e\u003cb\u003eMalhi GS, Coulston CM, Fritz K.\u003c/b\u003e The role of nutrition and nutritional supplements in psychiatry: A review of evidence-based recommendations. \u003cem\u003eCNS Drugs.\u003c/em\u003e 2020;34(9):921–45.\u003c/li\u003e\n\u003cli\u003e\u003cb\u003eRucklidge JJ, Johnstone JM, Harrison R, Boggis A.\u003c/b\u003e Broad-spectrum micronutrient treatment for ADHD: A systematic review. \u003cem\u003ePsychiatry Clin Neurosci.\u003c/em\u003e 2017;71(2):87–100.\u003c/li\u003e\n\u003cli\u003e\u003cb\u003eBeard JL, Connor JR, Jones BC.\u003c/b\u003e Iron deficiency alters brain development and neurotransmitter function. \u003cem\u003eNutr Rev.\u003c/em\u003e 2003;61(3):S45–8.\u003c/li\u003e\n\u003cli\u003e\u003cb\u003eCortese S, Imperati D, Zhou J, Proal E, Klein RG, Mannuzza S, Castellanos FX.\u003c/b\u003e Brain iron levels in attention-deficit/hyperactivity disorder: A magnetic resonance spectroscopy study. \u003cem\u003eBiol Psychiatry.\u003c/em\u003e 2012;72(12):893–8.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"ADHD, vitamin B12, vitamin D, ferritin, iron","lastPublishedDoi":"10.21203/rs.3.rs-8339197/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8339197/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjective:\u003c/h2\u003e \u003cp\u003eThis study aimed to compare serum vitamin B12, 25-hydroxyvitamin D, ferritin, and iron levels between adults diagnosed with attention deficit hyperactivity disorder (ADHD) and healthy controls, and to evaluate the relationship between these biochemical markers and the severity of ADHD symptoms.\u003c/p\u003e\u003ch2\u003eMethods:\u003c/h2\u003e \u003cp\u003eA total of 35 adults with ADHD and 36 age- and sex-matched healthy controls who presented to a psychiatry outpatient clinic in Sakarya in 2024 were included. Participants' demographic data and clinical characteristics were collected through interviews, while laboratory findings were examined using blood samples taken at the time of inclusion in the study. The severity of ADHD symptoms was assessed using the Adult ADHD Self-Report Scale (ASRS) and the Wender\u0026ndash;Utah Rating Scale (WURS).\u003c/p\u003e\u003ch2\u003eResults:\u003c/h2\u003e \u003cp\u003eSerum vitamin B12 and 25-hydroxyvitamin D levels were significantly lower in the ADHD group compared with controls (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). No significant differences were observed in ferritin and iron levels (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05). Furthermore, both vitamin B12 and vitamin D levels showed a negative correlation with total ASRS and WURS scores (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e\u003ch2\u003eConclusion:\u003c/h2\u003e \u003cp\u003eThese findings suggest that vitamin B12 and vitamin D deficiencies may be associated with greater symptom severity in adult ADHD. The results highlight the potential contribution of biochemical factors to the neurobiological basis of ADHD and indicate that routine assessment of vitamin levels may be beneficial in clinical practice.\u003c/p\u003e","manuscriptTitle":"Evaluation of the Relationship Between Vitamin Levels and Symptom Severity in Adults With Attention-Deficit/Hyperactivity Disorder","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-25 19:51:51","doi":"10.21203/rs.3.rs-8339197/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-01-19T10:09:24+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-01-12T09:27:08+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-01-07T04:14:13+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"188499616437885922549623119467356697451","date":"2025-12-30T08:06:00+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"42370540306827816984506368910579123182","date":"2025-12-30T03:01:57+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"162333194915601537609051733284337216356","date":"2025-12-26T19:16:06+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"18599933504741743137965641928065123865","date":"2025-12-25T08:43:45+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-12-24T07:37:01+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-12-19T12:33:24+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-12-18T06:49:13+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-12-16T19:38:07+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2025-12-16T17:00:34+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"7a0b2568-eeda-457f-a0ea-99cb45fcc32c","owner":[],"postedDate":"December 25th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":60170141,"name":"Health sciences/Biomarkers"},{"id":60170142,"name":"Health sciences/Diseases"},{"id":60170143,"name":"Health sciences/Medical research"},{"id":60170144,"name":"Health sciences/Neurology"},{"id":60170145,"name":"Biological sciences/Neuroscience"}],"tags":[],"updatedAt":"2026-03-02T16:07:48+00:00","versionOfRecord":{"articleIdentity":"rs-8339197","link":"https://doi.org/10.1038/s41598-026-41493-4","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2026-02-25 15:59:07","publishedOnDateReadable":"February 25th, 2026"},"versionCreatedAt":"2025-12-25 19:51:51","video":"","vorDoi":"10.1038/s41598-026-41493-4","vorDoiUrl":"https://doi.org/10.1038/s41598-026-41493-4","workflowStages":[]},"version":"v1","identity":"rs-8339197","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8339197","identity":"rs-8339197","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}