Omega  3 fatty acid and ADHD: Blood level analysis and meta-analytic extension of supplementation trials

https://doi.org/10.1016/j.cpr.2014.05.005Get rights and content

Highlights

  • Meta-analysis found lower blood levels of n-3 fatty acids in ADHD versus controls.

  • Study verified efficacy with small effect of n-3 supplementation for improving ADHD symptoms.

  • Evidence may justify n-3 as a potential supplementary treatment for ADHD.

Abstract

Interest in the value of omega  3 (n  3) fatty acid supplementation for treatment of ADHD remains high. No prior meta-analysis has examined whether ADHD is associated with alterations in blood lipid levels and meta-analyses of supplementation have reached conflicting conclusions.

Methods

We report two new meta-analyses. Study 1 examined blood levels of omega  3 fatty acids in relation to ADHD. Study 2 examined a larger sample of randomized intervention trials than previously reported.

Results

Study 1 included 9 studies (n = 586) and found lower overall blood levels of n  3 in individuals with ADHD versus controls (g = 0.42, 95% CI = 0.26–0.59; p < .001). Study 2 included 16 studies (n = 1408) and found that n  3 supplementation improved ADHD composite symptoms; using the best available rating and reporter (g = 0.26, 95% CI = 0.15–0.37; p < .001). Supplementation showed reliable effects on hyperactivity by parent and teacher report, but reliable effects for inattention only by parent report.

Conclusions

Omega  3 levels are reduced in children with ADHD. Dietary supplementation appears to create modest improvements in symptoms. There is sufficient evidence to consider omega  3 fatty acids as a possible supplement to established therapies. However it remains unclear whether such intervention should be confined to children with below normal blood levels.

Introduction

Whether ADHD may be related to inadequate bioavailability of omega  3 fatty acids, and whether it may be improved by dietary supplementation, has drawn increasing interest in part due to the growing awareness of the role of nutrition in neural development (Janssen & Kiliaan, 2013) and, potentially, in ADHD (Arnold et al., 2012, Bloch and Qawasmi, 2011, Nigg et al., 2012, Stevenson et al., 2014). Furthermore, the importance of long chain polyunsaturated fatty acids (LC-PUFAs), in particular omega  3 long chain fatty acids, has been highlighted as a promising area of research interest to physical as well as mental health (Milte et al., 2009, Sinn and Bryan, 2007, Vaisman et al., 2008, Voigt et al., 2001). It is increasingly recognized that like other mental disorders, ADHD, while heritable, is probably a product of interplay of genetic liability and environmental stressors (Nigg, Nikolas, & Burt, 2010), of which nutrition may be a component. However, recent reviews and meta-analyses have reached conflicting conclusions with regard to omega  3 supplementation, as detailed below.

Polyunsaturated fatty acids (PUFAs) exist in two classes: Omega  3 (n  3) and omega  6 (n  6) and humans cannot synthesize them. Once ingested, short chain PUFAs are converted to long-chain fatty acids (LC-PUFAs); their conversion chains are summarized in Fig. 1. Optimal health and development require a balanced ratio of n  3 to n  6 but the typical western diet provides a much larger share of n  6 as compared to n  3, often resulting in an imbalance and in an insufficient n  3 (Schuchardt, Huss, Stauss-Grabo, & Hahn, 2009). Therefore the n  3 status is of most interest in the present report. In that domain, as Fig. 1 shows, ALA (which must be ingested) is converted to EPA and then DHA through enzymatic elongation, resulting in their designation as LC-PUFA. (Decsi & Kennedy, 2011) Genetically mediated differences in conversion and metabolism may be present if children with ADHD have low blood levels of EPA and DHA despite adequate dietary intake and absorption. A first question, therefore, is whether ADHD is characterized by lower blood levels of these compounds.

EPA and DHA are the most well studied and accordingly are the most commonly supplemented fatty acids in over-the-counter fish oils; DHA has been added to many pre-natal vitamins and to infant formula. Breast milk also naturally contains LC-PUFAs, which may be related to better cognitive outcomes in children who were breastfed (Drane & Logemann, 2000), compared to formulas prior to their supplementation with LC-PUFAs (Belfort et al., 2013).

Additionally, recent research has shown inverse correlations between levels of DHA in cord blood and offspring inattention and hyperactivity at age ten years (Kohlboeck et al., 2011).

Links to ADHD are plausible because fatty acids are essential to neural development and signaling. For example, levels of available PUFA and LC-PUFA influence cell membrane fluidity, affecting absorption or release of neurotransmitters (Janssen & Kiliaan, 2013). and contribute to cortical organization and connectivity (Grayson, Kroenke, Neuringer & Fair, 2014). Adding to the importance of the current study is that consumers may in fact frequently be supplementing children's diets in an effort to control ADHD symptoms (Millichap & Yee, 2012). This makes evidence as to their effectiveness—or not—quite timely.

Multiple studies, reviews and three prior meta-analyses have examined the efficacy of fatty acid supplementation on ADHD symptoms. The following summary of their findings notes relevant limitations of each study's methodology. Bloch and Qawasmi (2011) examined 10 intervention studies of ADHD and fish oil (a major source of PUFAs) or omega  3 supplementation, selected either a parent or a teacher rating from each study but did not compare them, and concluded that there was a benefit, with a standardized mean effect size (SMD) of 0.31 (95% CI = 0.16 to 0.47, p < 0.001). Gillies, Sinn, Lad, Leach, and Ross (2012) included studies using any combination of omega  3 and omega  6 acids but pooled results separately for different study designs, leading to small sample sizes for particular comparisons. Although they noted a higher likelihood of improvement in the omega  3/6 group compared to placebo (risk ratio = 2.19, 95% CI = 1.04–4.62), this pertained only to two studies. Their primary conclusion was that when they pooled 5 studies of ADHD symptoms (n = 413) there was no difference in ADHD symptoms by parent-rating (SMD (standard mean difference) = 0.17, 95% CI = 0.03–0.38) or teacher rating (SMD = 0.05, 95% CI =  0.18–0.27). Sonuga-Barke et al. (2013) examined 11 intervention studies (7 studies included in Bloch & Qawasmi, 2011 and 2 studies supplementing with only n  6) and selected the “most proximal rater.” They found a reliable but modest effect of SMD = 0.21 (95% CI = 0.05–0.36, p = 0.007), which weakened to SMD = 0.16 (95% CI = 0.01–0.31, p = 0.04) when only “probably blinded” trials were included. Stevenson et al. (2014) reviewed and critiqued these meta-analyses as well as newer studies, and concluded that LCPUFA's have a modest effect on ADHD symptoms. We sought to expand and clarify the previous work in three ways.

First, it is unclear whether children with ADHD have inadequate baseline omega  3 levels. This is relevant to theories of etiology and to directing future work to determine whether all or only some children with ADHD may be appropriate clinical targets for supplementation. No prior meta-analysis had addressed this critical point, to the best of our knowledge, although some studies have shown reduced levels in participants with ADHD in comparison to the reference samples (Antalis et al., 2006, Stevens et al., 2003).

Second, with regard to results of supplementation trials, it is unclear whether ADHD symptom domains of (a) inattention/disorganization versus (b) hyperactivity/impulsivity respond differentially to supplementation, which will be important to interpreting future studies as well as aiming toward individualized clinical application of dietary supplementation. Gillies et al. (2012) looked at this but only across 5 studies, and we sought here to do so more comprehensively.

Third, previous meta-analyses have been inconsistent when examining the potential effects the rater may have on the results. We were interested in rater effects as a sign of replication or non-replication of results across rater and setting, important to fully evaluating the strength and generalizability of effects—particularly in light of questions about adequacy of observer blinding in these studies. No prior meta-analysis directly examined this.

Finally, each prior meta-analysis excluded some available studies for various reasons. We added 5 studies that none of the other meta-analyses used. Three of these are relatively new reports that met our criteria for inclusion (Milte et al., 2012, Perara et al., 2012, Richardson et al., 2012). As far as we can tell, should they have been published at the time, they would have met the inclusion criteria for one or more of the prior meta-analyses. We also included Kirby, Woodward, Jackson, Wang, and Crawford (2010). It was not mentioned by the prior reviews but it appeared to us that it would have met the inclusion criteria for one or more of them because it was a randomized controlled trial using a validated ADHD rating scale. We added one another study: Itomura et al. (2005). It was considered only by Bloch and Qawasmi (2011), who excluded the study because it was not clear what parent-rating scale of DSM symptoms was used or whether it was done with a validated rating scale. We did not consider this a reason to exclude the study, because counts of ADHD symptoms by parent rating tend to be highly correlated across types of measures, and number of DSM symptoms (albeit assessed with a known rating scale) has been used in other important ADHD treatment studies including the MTA study. We excluded 4 studies that were used in at least one previous analysis. Aman, Mitchell, and Turbott (1987) and Arnold et al. (1989) were excluded for using only omega  6 as the intervention. Although Hirayama, Hamazaki, and Terasawa (2004) met our inclusion criteria, insufficient data were published in the paper to enable an effect size to be computed and attempts to reach the author were unsuccessful. Finally, Brue, Oakland, and Evans (2001) study was excluded for using a supplement with various active compounds so that effects could not be attributed to n  3. All of these resulted in an updated and larger data base than any prior meta-analysis with which to estimate population effects, focused specifically on n  3.

We organize this report into two distinct meta-analyses. Study 1 aims to examine blood lipid profiles of children with and without ADHD. Study 2 aims to replicate and extend meta-analytic results for intervention studies of omega  3 fatty acids and fish oil.

Both meta-analyses included studies that reported n  3 data; report of n  6 data was not used herein. We made this decision because n  6 PUFA levels are typically higher than n  3 levels; therefore increases in dietary intake produce only modest increases in the linoleic acid (LA) and arachidonic acid (AA) content of the plasma. However, even small increases in dietary n  3 PUFA intake can produce relatively large increases in plasma n  3 PUFA. Additionally, n  6 acids have pro-inflammatory properties while n  3 acids have anti-inflammatory properties; the latter are more heavily theorized to be beneficial for ADHD and brain development under Western diets (Schuchardt et al., 2009).

Section snippets

Search methods

Pubmed and Pyschinfo were used for the article search from January 2001 through March 2013. Search terms included: ADHD, attention deficit hyperactivity disorder, fatty acid, n  3, omega−3, polyunsaturated fatty acids, PUFA, blood levels, plasma and RBC. In addition we searched reference sections of prior meta-analyses and reviews.

Inclusion criteria

Inclusion in Study 1 required (a) an operationally defined ADHD group, (b) a control group exhibiting typical development, and (c) reported data of red blood cells

Search methods

Pubmed and Psychinfo were used for the article search from January 2001 through March 2013. Search terms included: ADHD, attention deficit hyperactivity disorder, fatty acid, n  3, omega−3, polyunsaturated fatty acids, PUFAs, supplementation and intervention. Prior reviews were examined to ensure all studies cited by them were considered. When insufficient data were reported attempts were made to contact authors to acquire the data. Fig. 2 shows the flow diagram of study selection and exclusion

Discussion

Ongoing public and scholarly interest in the relevance of omega  3 fatty acid supplementation for ADHD mandates further study. Here, we followed up recent meta-analyses of supplementation trials with (a) a first meta-analysis of blood levels and (b) a refined and updated meta-analysis of intervention trials with a larger pool of studies and participants than previously examined. Study 1 found that children with ADHD, in fact, do exhibit lower blood levels of omega  3 fatty acids. This is

Author contributions

Elizabeth Hawkey and Joel Nigg contributed equally to all aspects of this manuscript.

Funding/support

The OHSU internal institutional funds.

Acknowledgments

The OHSU internal institutional funds provided financial support for this study.

Financial disclosure There are no financial interests to disclose for either author.

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