The Relationship Between Vitamin D and the Development and Treatment of Attention-Deficit Hyperactivity Disorder: An Overview of Systematic Reviews

Abstract

Purpose of Review

This review explores the role of vitamin D in the pathophysiology and management of attention-deficit/hyperactivity disorder (ADHD). Given the localization of Vitamin D receptors in brain regions implicated in ADHD and vitamin D’s role in neurotransmitter regulation, this review synthesizes research that examines vitamin D’s relationship to the development and therapeutic outcomes of ADHD.

Recent Findings

A systematic literature search resulted in the selection of seven reviews meeting the inclusion criteria. These reviews summarize original studies that are focused on: 1. The association between prenatal Vitamin D levels and ADHD in offspring, with meta-analyses suggesting that higher maternal serum Vitamin D levels reduce the likelihood and severity of ADHD symptoms in children. 2. Comparative analyses of Vitamin D levels in children with ADHD versus those without, showing lower Vitamin D levels in affected children. 3. Intervention studies where Vitamin D supplementation was linked to improvements in ADHD symptoms.

Results

Seven reviews met the inclusion criteria, from which the main results were: 1. Meta-analyses suggested a decreased risk of offspring with ADHD and fewer or less severe ADHD-related features later in life with higher maternal serum Vitamin D levels. 2. Children with ADHD were found to have lower serum Vitamin D levels than children without ADHD across the original literature. 3. Vitamin D supplementation was associated with improvements in ADHD symptoms.

Summary

The literature supports relationships between Vitamin D levels and ADHD, both in its emergence and clinical management. Despite these findings, further research is indicated. There remains a need for additional well-powered randomized clinical trials to provide evidence and guide clinical practice regarding the use of Vitamin D in ADHD and to ensure that interventions are efficacious, well tolerated and tailored to individual patients.

Introduction

Attention-deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by inattention, hyperactivity, and impulsivity-related symptoms, often starting in early childhood [1]. ADHD often persists through adulthood, with inattention as a primary component [2, 3]. The global prevalence of ADHD is estimated to range from 5% to 7.2% in children and 2.5% to 6.7% in adults [4]. ADHD may be underdiagnosed among adults, perhaps as diagnostic criteria were initially developed for children [5–7]. Untreated ADHD is associated with poor quality of life in adulthood, ranging from unemployment to difficulties in interpersonal relationships [7, 8]. ADHD often co-occurs with other psychiatric conditions such as oppositional defiant disorder, depression, anxiety) [9–13], drug use [14], driving-related accidents [15], and criminal behaviors [16, 17]. Altogether, ADHD exerts enormous costs on individuals, families, and communities [18, 19].

While the exact etiology of ADHD is unknown, multiple implicated factors include genetics, traumatic brain injuries, pregnancy complications, nutrition, and other environmental variables [9, 20, 21]. These factors may lead to varying dopamine, norepinephrine, and serotonin levels in the brain, which could contribute to the dysregulation of catecholamines in striatal structures and frontal cortical circuits, which have been implicated in ADHD [22, 23]. Pharmacological and psychosocial interventions have empirical support for treating ADHD [24–26]. Generally, stimulants are the first-line of approved pharmacological intervention for treating ADHD [27]. While effective, adverse effects and stigma are noteworthy, indicating the importance of developing alternate approaches [28]. Significant adverse effects of stimulant medications may include cardiovascular and growth effects and the potential for misuse, after both shorter-term and prolonged courses of treatment [27, 29, 30]. These concerns may influence parental hesitation and reluctance to initiate stimulant treatment for their children and, thus, limit the treatment’s utility. Therefore, there is considerable interest in interventions that boost treatment effectiveness while minimizing adverse effects [31, 32].

There is expanding evidence supporting the role of micronutrients in the pathophysiology and management of ADHD [33, 34]. One specific nutrient that has garnered increasing attention is Vitamin D, in part due to the localization of Vitamin D receptors and Vitamin D conversion enzymes in key brain regions, including the prefrontal cortex, striatum, and cerebellum [35]. Collectively, these regions are important for executive functioning, working memory, impulse inhibition, reward processing, and motor coordination, and have been implicated in the development of ADHD [35–37]. In addition, Vitamin D has demonstrated a multifaceted role in regulating neurotransmitters involved in ADHD by influencing gene expression of neurotransmitter receptors, transporters, and rate-limiting enzymes in the production of neurotransmitters [38–42].

Several existing systematic reviews have explored the connection between prenatal Vitamin D levels and ADHD in offspring [43, 44], the link between Vitamin D levels assessed in umbilical cord blood at birth and the emergence of ADHD [45–47], the prevalence of Vitamin D deficiency in individuals with ADHD [48, 49], and the efficacy of Vitamin D as a supplementary treatment for ADHD [50–54]. However, most of these reviews either explored a role for Vitamin D in ADHD in the context of other micronutrients or a role for Vitamin D in several neurodevelopmental disorders. However, there was a lack of a focus on the specific connection between Vitamin D and ADHD and on insights into the optimal dosage, treatment duration, and long-term effects associated with its use in ADHD treatment based on existing data. The current overview aimed to analyze and consolidate information derived from systematic reviews, meta-analyses, and rapid reviews that considered the role of Vitamin D in the development, progression, and treatment of ADHD.

Methods

We followed current guidelines for conducting overviews of systematic reviews, including recommendations from the Joanna Briggs Institute for evidence synthesis in umbrella reviews [55]. The protocol for this overview was registered and retrievable from the Open Science Framework [56].

Search Strategy

Searches were undertaken on Ovid MEDLINE, Embase (Ovid), APA PsycInfo (Ovid), Cochrane Library, Web of Science (Core Collection), and Scopus (Elsevier). A medical subject heading (MeSH) analysis of known key articles provided by the research team captured subject heading terms or keywords for the primary concepts of “Vitamin D” and “ADHD”. Using the PRESS standard, the search strategy was then peer-reviewed by a second librarian not otherwise associated with the project [57]. The initial literature search was conducted on March 8, 2023, and was repeated on October 16, 2023, for further systematic reviews that met inclusion criteria. Finally, reviewers checked for additional relevant articles in the included studies. A summarized flowchart of how the search was conducted can be found in Fig. 1. The search strategies for each database are shown in Supplement 1.

Fig. 1.

PRISMA diagram of search results

Eligibility Criteria

The inclusion criteria for this overview were as follows. For study design, we included review articles, including meta-analyses, that summarized and synthesized primary studies exploring the effect of different Vitamin D levels (assessed through blood levels either prenatally from maternal/cord blood or in children diagnosed with ADHD) or the effect of Vitamin D supplementation/augmentation on ADHD-related outcomes. Reviews had to describe at least one electronic database that was searched, present at least one eligibility criterion, and provide a systematic narration of the characteristics and findings of the included studies presented. Studies were not excluded based on language. There was no limitation of date imposed on the search. We did not include gray literature or abstracts.

For participants, individuals with ADHD with measured Vitamin D levels or receipt of Vitamin D as a supplement for treatment and offspring of mothers with measured Vitamin D levels were included. Studies exploring measured Vitamin D levels in cord or neonatal dried blood samples were included. ADHD diagnosis needed to have been defined based on one of the following: the 3rd, 4th, or 5th editions and revision of the Diagnostic and Statistical Manual of Mental Disorders [58–63], the International Classification of Diseases ninth or tenth revisions (ICD-9 or ICD-10 codes) [64, 65], or assessment by a clinician.

For interventions, systematic reviews were included if they evaluated pharmacological interventions using Vitamin D supplementation only or as an adjunct therapy for treating ADHD and Vitamin D supplementation for maternal Vitamin D deficiency. As for comparators, they could include placebo, stimulant treatment, other ADHD treatments, psychological treatment (without pharmacological treatment), or no intervention.

Finally, for outcomes, ADHD diagnosis and symptom severity were considered. ADHD diagnosis outcomes included ADHD diagnosis of offspring and individuals based on registry diagnoses, diagnostic interviews, or symptoms. Adverse effects of Vitamin D supplementation for ADHD and Vitamin D status after supplementation for ADHD were also considered.

Screening, Data Extraction, and Analysis

Titles and abstracts of articles established were screened independently by at least two reviewers (LJK, BBY, and RK) and classified as included, unclear, or excluded. Disagreements were discussed with the senior author (GAA) until a consensus was reached. The full reports of all articles classified as included or unclear at this stage were then obtained and screened by two independent reviewers (LJK, BBY, and RK). The rationale behind assessments was recorded. A data extraction sheet was designed based on the following general characteristics: publication characteristics, study objectives, and description of results. Two reviewers independently extracted the data from the included studies (LJK and BBY). Missing data in studies were noted and considered when interpreting the results. Evidence synthesis was conducted qualitatively using a narrative approach. No additional statistical analysis was performed.

Assessment of Methodological Quality

We used A Measurement Tool to Assess Systematic Reviews-2 (AMSTAR-2), a validated scale to assess the quality of the systematic reviews [42]. The tool classified reviews as critically low (more than one critical flaw with or without non-critical weaknesses), low (one critical flaw with or without non-critical weaknesses), moderate (more than one non-critical weakness), and high (no or one non-critical weakness). The quality of reviews was scored by two reviewers (LJK and BBY) and reviewed with the corresponding author (GAA).

Results

Through primary database screening and removal of duplicates, 255 articles were identified for full-text screening, of which seven met the inclusion criteria. An additional manual search was conducted during which the literature contained in the selected articles was analyzed. Figure 1 illustrates the stages of the study screening process.

Among the seven included reviews [33, 43, 66–70], all were systematic reviews, of which five included meta-analyses [33, 43, 66, 68, 69]. Four reviews covered prenatal Vitamin D levels, using either maternal levels or newborn cord blood [43, 66, 69, 70]. Three reviews covered Vitamin D levels in children with an ADHD diagnosis [66–68] Lastly, one review of randomized controlled trials was included, with a focus on exploring the efficacy of Vitamin D supplementation as an adjunct to methylphenidate in individuals with ADHD [33]. Further details are displayed in the table of included reviews (Table 1).

Table 1.

Characteristics and main findings of the reviews included: AMSTAR-2 quality, study design, population type, number of studies, review objective, primary findings

	Author, Year	Quality (AMSTAR-2)	Study design	Population	Included Studies (N)	Objective	Primary Findings
1	M. Föcker, 2017	Critically low quality (Four critical flaws: 7, 9, 11, and 15)*	Systematic review	Children and adolescents with reported mental problems in the context of a Vitamin D status assessment at least at one time point	8 ADHD-related studies: 6 case–control 2 cohort	To identify the potential benefits and limitations of Vitamin D for mental health, including ADHD	1. The largest study on ADHD showed a statistically significant difference between mean 25(OH)D levels of ADHD cases and controls 2. Two other studies found negative associations of 25(OH)D levels and autism-spectrum disorder/ADHD in offspring
2	E. Kotsi, 2018	Critically low quality (Two critical flaws: 4 and 9)*	Systematic review and meta-analysis	5–18 year-old children and adolescents with ADHD	8 total studies: 7 case-controls and 1 cross-sectional	To investigate whether children and adolescents with ADHD have lower levels of Vitamin D compared to healthy controls	3. All eight studies reported significantly lower 25(OH)D concentrations in ADHD patients compared with healthy controls 4. Pooled data showed a significant difference between the ADHD and control groups 5. Meta-regression analysis on latitude gradient of each study country showed a statistically significant correlation
3	Y. Khoshbakht, 2018	High quality (One non-critical flaw: question 10)*	Systematic review and meta-analysis	Children and adolescents aged < 18 years	13 total studies (9 in meta-analysis): 8 case-controls 3 cohorts 1 cross-sectional 1 prospective case–control	To summarize the relevant observation studies describing the connection between Vitamin D status and ADHD and perform meta-analysis to provide overall estimates	6. Nine studies indicated that children diagnosed with ADHD had lower serum Vitamin D concentrations compared to healthy controls 7. Five studies showed a significant association between Vitamin D deficiency or insufficiency and an increased likelihood of developing ADHD in children and adolescents 8. Four prospective studies revealed a correlation between reduced maternal or cord serum Vitamin D levels and an escalated risk of ADHD development in childhood or adolescence. Notably, medium- and high-quality studies demonstrated more prominent findings in terms of significant associations between Vitamin D deficiency and ADHD risk
4	A. M. García-Serna, 2019	Low quality (One critical flaw: 7)*	Systematic review and meta-analysis	Offspring with measured Vitamin D at birth or of mothers with measured prenatal Vitamin D	5 studies related to ADHD: 4 cohorts 1 case–control	To investigate relationship between prenatal Vitamin D status and neuro-developmental outcomes, including ADHD	9. Two studies reported no association between prenatal 25(OH)D levels and an ADHD diagnosis 10. Three studies showed an inverse relationship between prenatal 25(OH)D concentrations and ADHD-like symptoms 11. Meta-analysis revealed overall inverse relationship between prenatal 25(OH)D and ADHD
5	J. Gan, 2019	High quality (one non-critical flaw: question 10)*	Systematic review and meta-analysis	Children with ADHD treated with methylphenidate	4 RCTs	To examine the Vitamin D supplementation in patients with ADHD	12. Vitamin D as an adjunctive treatment to methylphenidate may improve most measured ADHD symptoms, except those pertaining to oppositional scores 13. A clinically meaningful but small effect of Vitamin D supplementation as an adjunct to methylphenidate on ADHD total scores was observed
6	S. Upadhyaya, 2022	Critically low quality (Three critical flaws: 7, 11, and 15)*	Systematic review	Offspring with measured Vitamin D at birth or of mothers with measured prenatal Vitamin D	9 studies related to ADHD: 1 nested sample RCT 1 nested case–control 6 cohorts 1 case–control	To examine the relationship between maternal Vitamin D levels and offspring psychiatric outcomes, including ADHD	14. Two studies reported significant links between maternal Vitamin D levels and increased odds of offspring with ADHD 15. Two studies did not find significant associations between ADHD and Vitamin D levels from umbilical cord sample or maternal sera from 3rd trimester 16. Three of 5 studies on symptom-level outcomes presented associations between prenatal or perinatal Vitamin D and increased likelihoods of ADHD symptoms
7	Sh. A. Tirani, 2023	Low quality (One critical flaw: Question 9)*	Systematic review and meta-analysis	Offspring of mothers with measured prenatal Vitamin D	5 studies related to ADHD: 4 cohort studies and 1 nested case–control	To explore associations between serum Vitamin D levels during pregnancy and ADHD in offspring	16. The highest maternal serum Vitamin D levels were significantly associated with less ADHD in the offspring 17. Linear dose–response analysis: each 25 nmol/L increase in maternal serum Vitamin D levels was associated with an 18% reduced likelihood of offspring with ADHD 18. Nonlinear dose–response analysis: significant U-shaped association, 62 nmol/L maternal Vitamin D level related to the lowest offspring ADHD likelihood, with lowest and highest levels associated with increased likelihoods of offspring with ADHD

^*Refer to supplementary Table 1 for the detailed description of the AMSTAR-2 rating of the included literature

Prenatal Vitamin D Levels and the Development of ADHD in children and adolescents

Four systematic reviews addressed prenatal Vitamin D levels, measured by maternal serum or umbilical cord blood, and their correlations with the development of ADHD or ADHD-related symptoms in offspring children and adolescents [43, 66, 69, 70].

Tirani et al. included 5 articles, published between 2014 and 2022, with sample sizes ranging from 487 to 2134 subjects [71–75]. The combination of all five included 5451 subjects, 1267 of which were diagnosed with ADHD, through several screening tools including ICD-10, ICD-8, DSM-IV, ADHD Test and parental report. They investigated the association between maternal serum Vitamin D levels and offspring ADHD. The review included cohort and nested case–control studies, and the age range of the children involved in the included investigations was from 0 to 23 years. The assessment of maternal serum Vitamin D levels was conducted during different trimesters of pregnancy, and various laboratory techniques to measure Vitamin D levels were used, including chemiluminescence immunoassay (CLIA), chemiluminescence micro-particle immunoassay (CMIA), high-performance liquid chromatography (HPLC), and liquid chromatography tandem mass spectrometry (LC–MS/MS) [69].

The findings suggested that higher maternal serum Vitamin D levels were significantly associated with a reduced risk of ADHD in the offspring. There was a 41% drop in the odds of developing ADHD in the offspring of mothers with the highest serum levels of Vitamin D, compared to the offspring of mothers with the lowest levels. To eliminate heterogeneity, they repeated the analysis excluding the USA-based study and found a 32% reduction of offspring ADHD. Specifically, the meta-analysis showed that each 10 ng/mL increase in maternal serum Vitamin D level was associated with an 18% reduced risk of offspring ADHD. The approximate level associated with the lowest odds of offspring ADHD in this meta-analysis was 62 nmol/L [69].

Garcia et al. analyzed 25 studies on the association between prenatal Vitamin D levels and neurodevelopmental outcomes, including cognition, psychomotor performance, language development, behavioral difficulties, ADHD, and symptoms of autism [76]. The years of publication of the articles included in this review ranged from 1959 to 2015. Among the included literature, 5 studies (4 cohorts and one case–control) were specific to ADHD and were subject to the meta-analysis [45, 47, [73–75]. The sample sizes in the studies that covered ADHD ranged from 404 to 1650 participants. The review found that higher prenatal exposure to Vitamin D was associated with less severe scores on ADHD-related measures later in life based on DSM-IV and the Child Behavior Checklist (CBCL). Although two included studies [47, 75] reported no associations between Vitamin D levels and ADHD-like symptoms, their meta-analysis revealed that the pooled relative risk comparing the highest with the lowest circulating levels of 25(OH)D was 0.72 (95% CI, 0.59, 0.89, p = 0.002). The analysis did not detect any heterogeneity or publication bias in the studies included [76].

The systematic review and meta-analysis by Khoshbakht et al. [66] included 13 relevant investigations that assessed the relationship between maternal Vitamin D levels and ADHD in children and adolescents [44, 45, 47, 75, 77–85]. The years of publication of the included articles in this review range from 2014 to 2017. The sample sizes in the studies included in the review ranged from 30 to 10,334 participants. These investigations consisted of 9 retrospective case–control and cross-sectional studies that compared serum Vitamin D concentrations between children with ADHD and healthy controls [77–85] and 4 prospective studies that assessed the relationship between maternal or offspring’s Vitamin D levels and ADHD later in life [44, 45, 47, 75]. It is worth mentioning that the prospective studies were also included in the Upadhyaya et al. and Garcia et al. reviews. The studies included a total of 3484 patients with ADHD, with 2183 from the case–control and cross-sectional studies and 1301 from the prospective studies. The studies varied in terms of study design, research location, participants’ age and gender, study sample size, and outcome assessment methods.

The researchers conducted a meta-analysis of all 4 of the prospective studies examining maternal or cord serum Vitamin D concentrations [44, 45, 47, 75]. They found a significant association between reduced maternal or cord serum Vitamin D levels and an increased risk of ADHD development in childhood or adolescence (RR: 1.40; 95% CI: 1.09, 1.81; p = 0.009). There was minimal between-study heterogeneity (Cochran’s Q test, p = 0.538; I2 = 0.0%). Subgroup analysis based on the origin of Vitamin D samples (maternal serum levels, cord levels) suggested an association with maternal serum Vitamin D concentration (RR: 1.46; 95% CI: 0.97, 2.21; p = 0.070) with low heterogeneity amongst studies (Cochran’s Q test, p = 0.435; I2 = 0.0%). An association was also suggested regarding cord blood Vitamin D concentrations (RR: 1.37; 95% CI: 0.98, 1.91; p = 0.067), accompanied by minimal heterogeneity (Cochran’s Q test, p = 0.301; I2 = 6.7%). Sensitivity analysis revealed that excluding a particular study [45], notable for having the youngest study population (2.7 ± 0.6 years), rendered the previously observed significant correlation between reduced levels of Vitamin D and heightened risk of ADHD during childhood or adolescence statistically non-significant (RR: 1.31; 95% CI: 0.96, 1.80; p = 0.089). As such, multiple findings were suggestive but not statistically significant.

Upadhyaya et al. included 9 studies that explored the relationship between maternal Vitamin D levels and ADHD [44–47, 71–73, 75, 86]. The years of publication of the articles included in this review ranged from 2014 to 2022. The number of ADHD cases in the samples of these studies ranged from 24 to 1067. Four of the included studies had ADHD as a diagnostic outcome [47, 71, 72, 75], and five studies specifically assessed ADHD symptoms [44–46, 73, 86]. Regarding ADHD as a diagnostic outcome, only two studies reported significant links between maternal Vitamin D levels and elevated odds of offspring diagnosed with ADHD [71, 72]. The study with the largest sample size, which extensively explored ADHD outcomes, showed significant associations between decreased Vitamin D levels and offspring ADHD (aOR: 1.45, 95% CI: 1.15–1.81) [72]. Another study demonstrating significant associations found that Vitamin D levels during the third trimester were linked to lower odds of offspring with ADHD (aOR: 0.34, 95% CI: 0.12–0.94), whereas no association was found for levels measured during early pregnancy [71]. The two other studies [47, 75], which were included in the meta-analyses done by the Garcia and Khoshbakht groups, did not reveal significant associations between Vitamin D deficiency and ADHD. Notably, the first study might have been limited by considering a small group of covariates [47], and the second study had a very small number (n = 24) of ADHD cases and defined Vitamin D deficiency as below < 50 nmol/L [75], which might be considered relatively high compared to other studies.

Regarding ADHD symptoms, three studies displayed a significant association between low prenatal or perinatal Vitamin D levels and increased risk for offspring ADHD symptoms [44, 45, 73]. The fourth study displayed no difference in ADHD symptoms based on Vitamin D categories [46]. However, it also investigated how maternal depression influenced offspring ADHD symptoms and discovered an interaction concerning Vitamin D deficiency in the correlation between maternal depression and offspring ADHD symptoms. The fifth and final study was the only study to assess ADHD symptoms in children 5 to 18 years old [86], as the other four assessed the symptoms only in toddlers or preschool-aged children. The study did not find any significant associations between prenatal Vitamin D levels and symptoms of ADHD in children aged 5 to 18 years old. It is worth mentioning, however, that there was a high attrition rate among children aged 14–18 years old. Notably, their work demonstrated a positive association between prenatal Vitamin D levels and social competence in 5-year-old children. Throughout the five studies, ADHD symptoms were assessed by the Strengths and Difficulties Questionnaire and Attention-Deficit/Hyperactivity Disorder Test, parent version of Conners’ Hyperactivity Index, teacher report of ADHD symptoms, and parent-reported CBCL. Three of the studies measured Vitamin D from maternal serum in early pregnancy [44, 73, 86] and the other two from cord blood [45, 46].

Vitamin D Levels in Children with ADHD

Three studies [66–68] addressed serum Vitamin D levels in children diagnosed with ADHD or exhibiting ADHD-like symptoms in comparison to controls.

The meta-analysis conducted by Kotsi et al. included a total of 8 case–control studies with a cumulative sample size of 11,324 children [48, 49, 77–79, 81, 82, 84], of which 2,655 were diagnosed with ADHD and the remaining 8,669 were healthy controls. The years of publication for the included articles in this review ranged from 2014 to 2017. All eight studies included reported significantly lower serum concentrations of Vitamin D in children and adolescents diagnosed with ADHD.

The systematic review by Focker et al. included 8 studies that examined the association between ADHD and Vitamin D levels [44, 47, 49, 77, 79–81, 87], six of which were cross-sectional [49, 77, 79–81, 87]. All six reported significant associations between low Vitamin D levels and the presence of ADHD. It is important to highlight that three of the six utilized the same sample [49, 80, 87]. The largest included a cross-sectional study on ADHD in this review (N = 6922; age range 11–17 years). This study was based on a German population and found lower mean 25(OH)D levels among cases compared to controls, which was also confirmed in logistic regression models adjusting for age, sex, body mass index (BMI) and psychotropic medication use, with ADHD diagnosis as a dependent variable in the model (p = 0.035). The remaining two studies were longitudinal [44, 47], one of which reported an inverse association between Vitamin D and ADHD [44] while the other specifically examined prenatal Vitamin D deficiency and revealed no significant associations [47]. Noteworthily, these two studies were also included in the Khoshbakht et al. review.

Khoshbakht et al. conducted a review of nine studies comparing serum Vitamin D levels in children with and without ADHD [77–85]. The analysis revealed that children diagnosed with ADHD exhibited an average serum Vitamin D concentration 6.93 ng/mL lower than their healthy counterparts (95% CI: −9.34, −4.51 ng/mL; p < 0.001). Subgroup analyses adjusting for potentially confounding variables consistently demonstrated lower Vitamin D levels in children with ADHD. Despite variability between studies, both unadjusted (Weighted Mean Difference (WMD): −6.3 ng/mL; 95% CI: −10.11, −2.49 ng/mL; p = 0.001) and adjusted analyses (WMD: −7.05 ng/mL; 95% CI: −8.55, −5.54 ng/mL; p < 0.001) exhibited the same pattern. Analysis based on study quality yielded consistent findings across low-, middle-, and high-quality studies. Sensitivity analysis indicated a notable reduction in heterogeneity of the analysis upon excluding a specific study [81], yet the overall effect remained significant. No evidence of publication bias was detected.

The authors also analyzed data from five of the retrospective studies to investigate the relationship between Vitamin D deficiency or insufficiency and ADHD risk in children and adolescents [77, 78, 80, 83, 85]. The analysis indicated a significant association, with an overall OR of 2.57 (95% CI: 1.09, 6.04; p = 0.03). However, considerable heterogeneity was observed across studies (I2 = 84.3%). Subgroup analyses, stratified adjusting for potentially confounding variables (e.g., age, sex, race, and dietary habits) yielded varied results. Studies lacking adjustment for potential confounders showed no significant association (OR: 1.51; 95% CI: 0.22, 10.12; p = 0.647), with substantial heterogeneity (I2 = 84.6%). Conversely, studies considering potential confounders demonstrated a significant association (OR: 3.24; 95% CI: 1.05, 10.03; p < 0.041), with considerable heterogeneity (I2 = 91.4%). Further analysis by study quality displayed varying findings. Analysis of studies rated to be of low quality revealed no significant association (OR: 0.55; 95% CI: 0.1, 25.77; p = 0.758), while the analysis of medium- and high-quality studies suggested significant associations (OR: 6.05; 95% CI: 2.2, 16.63; p < 0.001 and OR: 3.24; 95% CI: 1.05, 10.03; p = 0.03, respectively), with substantial heterogeneity. Sensitivity analysis demonstrated that the removal of a specific study [85] mitigated heterogeneity but did not significantly alter the overall effect (OR: 3.70; 95% CI: 1.76, 7.75).

Vitamin D Interventions in Randomized Control Trials (RCTs)

One systematic review and meta-analysis included four RCTs that examined Vitamin D supplementation as an adjunctive treatment to methylphenidate, a commonly used medication for treating ADHD [33]. The primary outcomes included the following five aspects of ADHD symptoms: ADHD total scores, inattention scores, hyperactivity scores, behavior scores, and oppositional scores. The forest plots presented in the study demonstrated that Vitamin D supplementation showed a small but statistically significant improvement in ADHD symptoms for total scores, inattention scores, hyperactivity scores, and behavior scores. However, there was no statistically significant improvement in oppositional scores. Adverse events reported in the Vitamin D group were mild and not significantly different from the control group, suggesting that Vitamin D supplementation was well-tolerated. Furthermore, Vitamin D supplementation increased serum Vitamin D levels and the proportion of sufficient Vitamin D levels among participants. The study concluded that Vitamin D supplementation as an adjunctive therapy to methylphenidate reduced ADHD symptoms without serious adverse events and was associated with improved Vitamin D status. However, considering the generally low strength of evidence, the study emphasized the need for more well-designed RCTs to assess the efficacy, tolerability and safety of Vitamin D supplementation for both children and adults with ADHD, especially when combined with other ADHD treatments.

Discussion

In summary, the investigation into the relationship between prenatal Vitamin D levels and the development of ADHD in children and adolescents suggests a complex landscape with both consistencies and possible discrepancies across the literature. Tirani et al. reported a significant association between higher maternal serum Vitamin D levels and lower ADHD propensities in offspring, highlighting the potential importance of optimal Vitamin D levels during pregnancy for neurodevelopmental outcomes. Garcia et al. supported this by reporting that higherprenatal exposure to 25-hydroxyVitamin D was associated with improved cognitive development and fewer or less severe ADHD-related measures. However, Upadhyaya et al. presented more inconclusive results, with some studies showing a significant association between low maternal Vitamin D levels and ADHD and others finding no significant associations. Turning to the examination of serum Vitamin D levels in children with ADHD, the three systematic reviews with meta-analyses consistently demonstrated lower serum concentrations of Vitamin D in children diagnosed with ADHD or exhibiting ADHD-like symptoms compared to controls. The meta-analyses by Kotsi et al. and Khoshbakht et al. and the systematic review by Focker et al. all supported a significant association between lower Vitamin D status and the likelihood of ADHD. Khoshbakht et al. provided further evidence, reporting that children and adolescents with ADHD had lower mean concentrations of serum 25-hydroxyVitamin D compared to healthy controls. Regarding Vitamin D interventions in RCTs, Gan et al. provided valuable insights. While Vitamin D supplementation as an adjunctive therapy to methylphenidate showed a small but statistically significant improvement in ADHD symptoms, the limited quality of evidence emphasizes the need for more well-designed RCTs to examine the efficacy, tolerability, and safety of Vitamin D supplementation for individuals with ADHD.

Overall, actively monitoring and correcting low Vitamin D levels in pregnant women through promoting safe sun exposure and Vitamin D intake may carry substantial clinical and preventive significance [88–93]. However, there is no consensus on the ideal serum Vitamin D levels for pregnant women. Certain studies have proposed a cutoff point of 20 ng/mL for serum Vitamin D levels to prevent adverse pregnancy outcomes [94], whereas others, including the findings by Tirani et al., suggest a threshold of 15 ng/mL. Moreover, there is a lack of agreement on the specific stage of pregnancy when the protective effects of Vitamin D may be most pronounced. Certain studies suggest that such effects may be more robust during early to mid-gestation (the first and second trimesters), coinciding with early neurodevelopment, as opposed to later gestational stages or at birth [43, 95, 96].

All systematic reviews covering children and adolescents with ADHD, including two large-scale meta-analyses, consistently reported an inverse association between serum Vitamin D levels and ADHD symptoms [66–68]. However, this association was derived from observational studies, introducing uncertainty regarding potential cause-and-effect relationships. Various potential confounding factors, such as genetic influences, socioeconomic status, dietary habits, physical activity levels, maternal influences during pregnancy, exposures to environmental toxins, co-occurring conditions, and medication use, may impact the observed relationship [93, 97–99]. From a neurobiological standpoint, the existing literature suggests associations between decreased serotonin synthesis [100, 101], increased neuronal oxidative stress [102, 103], and ADHD development. Vitamin D contributes to nerve cell development and functioning, including the modulation of enzymes involved in serotonin synthesis and the prevention of oxidative damage to neurons [104–108]. In conclusion, despite the promising potential protective role of Vitamin D in ADHD, clinical trials are needed. These trials will aid in identifying and controlling for potential confounding factors, establishing appropriate Vitamin D supplementation doses for both healthy children and those with ADHD, and determining the optimal timing for interventions.

Regarding Vitamin D as an intervention in RCTs, the review performed by Gan et al. reported significant improvements in inattention, hyperactivity, and behavior with Vitamin D supplementation as an adjunctive therapy to methylphenidate but did not report significant improvement in oppositional scores. The improved scores suggest that sufficient Vitamin D levels may help manage certain ADHD symptoms [33]. These results are consistent with more recent studies, ones not included in Gan’s review, that have reported similar findings of lower Vitamin D levels [66, 77] and that some ADHD symptoms improved following Vitamin D supplementation [51, 109, 111]. Therefore, it may be helpful to monitor individuals with ADHD who may be at elevated risk for Vitamin D deficiency and routinely provide them with supplements, similar to the potential benefit of providing supplements to pregnant women. Regarding safety and tolerability, adverse effects related to Vitamin D supplementation were mild and insignificant. These results have been replicated in another more recent RCT, even with higher doses of Vitamin D [112]. On the contrary, Vitamin D deficiency has been associated with many adverse health effects such as bone and cardiovascular diseases [112, 113], Thus, Vitamin D has significant clinical relevance considering its potential to reduce ADHD symptoms and prevent certain co-occurring medical conditions while having relatively low costs and few adverse effects.

Regarding clinical guidelines, current recommendations for Vitamin D supplementation exhibit significant heterogeneity and lack a consensus among clinicians [114–116]. The current nutritional guidelines are largely based on research examining beneficial dosages for preventing rickets and osteomalacia symptoms [112]. Moreover, in reference to other health outcomes, data suggest that moderate dosages (defined to be around 800 to 1000 IU a day) may achieve greater benefits than very high dosages that could potentially induce harm [112]. Vitamin D supplementation should be controlled within optimal physiological ranges to accurately explore relationships between dosages and outcomes [117]. Establishing optimal dosing will likely necessitate further extensive research using RCTs in which doses are varied randomly. This approach will enable a more comprehensive assessment of dose–response relationships and how individual differences may influence responses to supplementation.

Moreover, dosages of Vitamin D supplementation may vary based on individual responses, and these may be influenced by genetic and metabolic differences across populations [112, 118]. Genetic polymorphisms in the functioning of the Vitamin D receptor that vary across different races [119, 120] and variations in response to Vitamin D supplementation and its metabolism in individuals with different body weights [121] may contribute to this variability. Examining the interactions between genetics, body weight, and Vitamin D would be important to understand what factors might predict responses to Vitamin D supplementation. Thus, there is a need for RCTs with larger sample sizes to establish guidelines for accurate and representative physiological Vitamin D thresholds and levels.

Despite considerable evidence suggesting an association between low Vitamin D levels and ADHD in children and adolescents, limitations are present in the existing studies. The heterogeneity across studies, including variations in study designs, sample sizes, assessment methods, and thresholds used to measure Vitamin D status, introduces complexity and potential sources of bias. For instance, Upadhyaya et al. reported inconclusive results, underscoring the variability in findings within the existing literature. The retrospective and prospective nature of the investigations further complicates the interpretation of results, as retrospective studies are susceptible to recall bias, and prospective studies may not fully capture the dynamic nature of Vitamin D levels during critical developmental periods. The discrepancies in the literature included in Upadhyaya’s review may be attributed to several factors. Differences in study design, sample sizes, measurement methodologies, and outcome assessments of the included literature could contribute to the variability observed across studies. Moreover, concerns raised during the quality assessment of included studies, such as high attrition rates, inadequate strategies to address attrition, small sample sizes, and varying definitions of deficient Vitamin D levels, may further complicate the interpretation and consistency of results concerning ADHD outcomes.

Another limitation involves the low quality of the reviews assessed using the AMSTAR tool (refer to Supplementary Table 1, supplementary material). Five of the seven included reviews were assessed to be of low or critically low quality. The remaining two were assessed to be of high quality. The main reasons found for an assessment of low or critically low quality were not providing a list of excluded studies with reasons for exclusion and not assessing the risk of bias in the included studies. These were both critical factors in the rating scale of AMSTAR-2. Of the 7 included studies, 4 included a detailed list of excluded studies, and 4 properly assessed risk of bias. None of the reviews reported sources of funding from the individual primary papers.

Overall, the consistent findings across multiple studies suggest a potential link between Vitamin D levels, both prenatal and in children, and the risk of ADHD. However, discrepancies in some studies highlight the complexity of this relationship, underscoring the need for further high-quality research to better understand the precise role of Vitamin D in ADHD development and the potential of Vitamin D as an intervention, including possibly as an augmentation strategy alongside stimulant treatment. In conclusion, while the existing literature offers valuable insights, the limitations underscore the need for caution in drawing causal inferences. Future research efforts should prioritize methodological rigor, incorporating well-designed RCTs and addressing potential confounding factors, to understand better the relationships between Vitamin D and ADHD and advance prevention and treatment efforts.

Conclusion

In conclusion, the relationship between Vitamin D and ADHD presents a complex landscape, with prenatal levels showing varied associations with ADHD and its severity. Lower Vitamin D levels in children with ADHD appear more consistently observed, suggesting a potential role in pathophysiology. Promisingly, Vitamin D supplementation as an adjunct to methylphenidate has demonstrated improvements in ADHD symptoms. However, uncertainties remain regarding optimal levels, timing, and supplementation guidelines. The existing evidence underscores the need for further high-quality RCTs to determine therapeutic efficacy and guide clinical recommendations. As the research progresses, a clearer understanding of the nuanced interplay between Vitamin D and ADHD could offer valuable insights for both prevention and intervention strategies.

Supplementary Material

Supplementary Information The online version contains supplementary material available at https://doi.org/10.1007/s40473-024-00278-7.

Data Availability

No datasets were generated or analysed during the current study.