Polyunsaturated Fatty Acids

Polyunsaturated fatty acids (PUFAs) are a well-studied complementary treatment for ADHD. Omega-3 fatty acids cannot be synthesized by humans and are required in our diet. In the Western diet, omega-6 fatty acids or their precursors (e.g. linoleic acid) are much more abundant than omega-3 fatty acids or their precursors (e.g. alpha-linolenic acid).25 A high omega-6 to omega-3 ratio can alter cell membrane properties and increase production of inflammatory mediators because arachidonic acid, an omega 6 fatty acid found in cell membranes, is the precursor of inflammatory eicosanoids, such as prostaglandins and thromboxanes.26 By contrast, omega-3 fatty acids are anti-inflammatory.26 Therefore, a high dietary omega-6 to omega-3 fatty ratio could promote neuroinflammation. Increased omega-3 fatty acid concentration in the diet may also act by altering central nervous system cell membrane fluidity and phospholipid composition which may alter the structure and function of the proteins embedded in it.27 By this mechanism, increased omega-3 fatty acid concentrations in cell membranes have been shown to affect serotonin and dopamine neurotransmission especially in the frontal cortex and may be of importance in ADHD pathogenesis.28 Omega-3 fatty acids may also potentially act in reducing oxidative stress, which has been demonstrated to be elevated in ADHD.29

An initial meta-analysis involving ten trials including 699 children with ADHD demonstrated a significant benefit of PUFA supplementation compared to placebo. The benefits of PUFA supplementation were small (compared to the effect sizes observed for conventional pharmacological treatments for ADHD) but statistically significant.17 Additionally, meta-regression demonstrated a significant relationship between eicosapentaenoic acid (EPA) dose within supplements and measured efficacy.17 Two update systematic reviews using similar methodology have since confirmed the efficacy of PUFA supplementation for ADHD symptoms.30, 31 One of these meta-analyses also confirmed the significant association between EPA dose and measured benefit in the treatment of ADHD. 31

However, two recent systematic reviews have raised questions regarding the benefits of omega-3 supplementation of ADHD.19, 32 The divergent results of these meta-analyses are attributable to methodological differences from the other systematic reviews. A recent Cochrane review in the area failed to demonstrate a significant benefit of omega-3 supplementation on most but not all outcome measures for ADHD.19 As is traditional for Cochrane reviews, the authors did not pool results across different study designs (e.g. crossover vs. parallel-group trials) and this difference in methodology led to comparatively underpowered meta-analyses for many outcomes. Another recent systematic review, by contrast, added additional trials which examined the effects of omega-3 fatty acid supplementation on ADHD symptoms in other clinical populations (e.g. children with reading difficulties, developmental coordination disorders and dyslexia).32 This meta-analysis found a significant benefit of PUFA supplementation but also noted evidence of publication bias in the literature that might be inflating effect estimates. Publication bias was detected through asymmetry in the funnel plot. However, the addition of trials involving subjects with primary diagnoses other than ADHD (included only in this meta-analysis) was likely responsible for asymmetry in the funnel plot (as none of the previous ADHD-only meta-analyses detected funnel plot asymmetry). One particular trial examining ADHD symptoms in children with reading disabilities included a larger number of participants (comprised 24% of the total weight of the meta-analysis) and demonstrated a minimal effect of PUFA supplementation in improving ADHD.33 Inclusion of this large trial is responsible for the funnel plot asymmetry in the meta-analysis. However, it is quite plausible that children with primary reading disabilities would have less benefit from PUFA supplementation in improving ADHD symptoms (because they are secondary to reading difficulties or less severe than in a ADHD clinical population).

Cumulative evidence suggests that there is currently CEBM level-1 evidence demonstrating the efficacy of omega-3 fatty acids for the treatment of ADHD. Current evidence would recommend supplementation with a dose of 1-2g daily with a substantial content of EPA within the omega-3 formulation. However, evidence supporting supplementation much less clear when examining ADHD symptoms in children with other primary disorders (such as dyslexia, developmental coordination disorder and with reading impairments). Table 1 summarizes the results of randomized, placebo-controlled trials of nutritional supplements in ADHD.