Stephen V. Faraone, PhDThere has been much interest in omega-3 Polyunsaturated fatty acids (PUFAs) as treatments for ADHD. Humans are unable to synthesize omega-3 PUFA alpha-linolenic acid (ALA) and the omega-6 PUFA linoleic acid (LA), and must therefore obtain these through food, which is why they are known as essential fatty acids. Because cells in the brain need omega-3 PUFAs, they have been studied as a treatment for ADHD by many researchers. In fact, several meta-analyses are available.

A 2014 meta-analysis by Elizabeth Hawkey and Joel Nigg combined nine studies involving 586 participants. It found mean blood levels of omega-3 PUFAs in persons with ADHD to be lower than in controls. The standardized mean difference (SMD) effect size was medium (SMD = .42, 95% CI = .26-.59), with less than a one in one thousand probability of such a result being obtained by chance alone. Adjusting for publication bias reduced the effect size slightly to .36 with a 95% CI of .21-.51, in the small-to-medium range. The authors then examined whether omega-3 supplementation could help alleviate ADHD symptoms. Combining 16 studies with 1,408 participants, they found improvements, but this time with a small effect size (SMD = .26, 95% CI = .15-.37), again with less than a one in a thousand probability of such a result being observed by chance. Adjusting for publication bias reduced the effect size to .16 with a 95% CI of .03-.28. For comparison, the SMD for stimulants is about 0.9.

Another meta-analysis conducted in the same year by Basant Puri and Julian Martins combined 18 PUFA supplementation studies involving 1,640 participants. They also found a small effect size for reduced ADHD symptoms (SMD = .19, 95% CI = .09-.30, p<.001). Adjusting for publication bias further reduced the effect size to a paltry and statistically insignificant level (SMD = .12, 95% CI = -.01-.25). It should be noted that while 16 of the studies involved omega-3 supplementation, two involved only omega-6 supplementation. Yet the results for the latter did not differ noticeably from the former. When the authors limited the analysis to the 11 studies specifically including both the omega-6 GLA and the omega-3 EPA, the effect size for reducing inattention symptoms was a bit higher (SMD = .31, 95% CI = .16-.46, p<.0001). But the results were not significantly different than those for the studies without the GLA+ALA combination (.012; 95% CI: .161-.137; p=.875). Publication bias was not addressed, and the hunt for a highly specific subset with positive results may have produced a false positive finding. The authors conceded, “Weaknesses of this study include the following: although the pooled effect was statistically significant, only two studies showed a significant effect by themselves; the funnel plot showed evidence of publication bias; there was evidence of reporting bias; few studies were formally registered; study methodological quality was variable; and the placebo used across studies varied.”

A 2016 meta-analysis by Laura Lachance et al. tried looking for differences in the ratio of omega-6 to omega-3 PUFAs, and more specifically, AA to EPA, in the blood of persons with ADHD versus normally developing persons. Pooling five studies with 485 participants, it found the omega-6 to omega-3 ratio to be significantly higher in persons with ADHD, and pooling three studies with 279 participants, it likewise found the AA to EPA ratio significantly higher.

A 2017 meta-analysis by Jane Pei-Chen Chang et al. reexamined comparative levels of omega-3 PUFAs in ADHD patients versus normally developing controls. Combining six studies with 396 participants, ADHD patients had lower levels in blood and mouth tissue, with a medium effect size (SMD = .38) that was not statistically significant (p=.14). Omega-6 levels were indistinguishable (SMD = .03) in the two groups. AA (SMD = .18, p=.33) and EPA (SMD = .25, p=.17) levels were slightly lower, but once again statistically not significant. DHA levels were lower as well, this time with a medium effect size (SMD = .56), but at the outer margin of significance (p=.05). Only by dropping one study were the authors able to claim significance for EPA, AA, and omega-3 differences.

Chang et al. also performed a meta-analysis of supplementation studies. Combining seven studies with 534 participants, they found a small to medium reduction in ADHD symptoms with omega-3 supplementation (SMD = .38, 95% CI = .2-.56, p<.0001). Corrections for publication bias were not reported. The authors also reported large reductions in both omission errors (SMD = 1.09, 95% CI = .43-.1.75, p<.001) and commission errors (SMD = 2.14, 95% CI = 1.24-3.03, p<.00001) on a neuropsychological test of attention. But the former involved only 3 studies with 214 participants, and the latter only two studies with 85 participants.

Also in 2017, Pelsser et al. published a systematic review that identified only two meta-analyses of double-blind, placebo-controlled trials of PUFA supplementation. One of those, a 2012 meta-analysis by Gillies et al., found no statistically significant declines in either parent-rated ADHD symptoms (five trials, 413 participants, SMD = -.17, 95% CI = -.38-.03) or teacher-rated ADHD symptoms (four trials, 324 participants, SMD = .05, 95% CI = -.18-.27). The other, a 2013 meta-analysis by Sonuga-Barke et al., found only a slight and barely statistically significant reduction in symptoms (11 trials, 827 participants, SMD = .16, 95% CI = .01-.31). Pelsser et al. concluded, “Considering the small average ESs [effect sizes] PUFA supplementation is unlikely to provide a tangible contribution to ADHD treatment.”

Putting all of this together, there are indications that individuals with ADHD may have lower levels of omega-3 PUFAs, and that omega-3 supplementation may slightly reduce symptoms of ADHD, but the evidence remains inconclusive, with at best small effect sizes. It is possible, but not yet demonstrated, that omega-3 PUFAs might produce good outcomes in a small subset of patients.

REFERENCES
Jane Pei-Chen Chang, Kuan-Pin Su, Valeria Mondelli, and Carmine M Pariante, “Omega-3 Polyunsaturated Fatty Acids in Youths with Attention Deficit Hyperactivity Disorder: a Systematic Review and Meta-Analysis of Clinical Trials and Biological Studies,” Neuropsychopharmacology (2017), 43(3): 534–545.

Donna Gillies, John KH Sinn, Sagar S Lad, Matthew J Leach, Melissa J Ross, “Polyunsaturated fatty acids (PUFA) for attention deficit hyperactivity disorder (ADHD) in children and adolescents,” Cochrane Database of Systematic Reviews (2012), DOI:10.1002/14651858.CD007986.pub2.

Elizabeth Hawkey and Joel T. Negg, “Omega−3 fatty acid and ADHD: Blood level analysis and meta-analytic extension of supplementation trials,” Clinical Psychology Review (2014), 34(6), 496-505.

Laura LaChance, Kwame McKenzie, Valerie H. Taylor, and Simone N. Vigod, “Omega-6 to Omega-3 Fatty Acid Ratio in Patients with ADHD: A Meta-Analysis,” Journal of the Canadian Academy of Child and Adolescent Psychiatry (2016), 25(2), 87-96.

Lidy M. Pelsser, Klaas Frankena, Jan Toorman, Rob Rodrigues Pereira, “Diet and ADHD, Reviewing the Evidence: A Systematic Review of Meta-Analyses of Double-Blind Placebo-Controlled Trials Evaluating the Efficacy of Diet Interventions on the Behavior of Children with ADHD,” PLOS ONE (January 25, 2017), 1-25.

Basant K. Puri and Julian G. Martins, “Which polyunsaturated fatty acids are active in children with attention-deficit hyperactivity disorder receiving PUFA supplementation? A fatty acid validated meta-regression analysis of randomized controlled trials,” Prostaglandins, Leukotrienes and Essential Fatty Acids (2014), 90, 179-189.

Edmund J.S. Sonuga-Barke et al., “Nonpharmacological Interventions for ADHD: Systematic Review and Meta-Analyses of Randomized Controlled Trials of Dietary and Psychological Treatments,” American Journal of Psychiatry (2013), 170:275-289.

Stephen V. Faraone, PhD

About Stephen V. Faraone, PhD

Dr. Faraone is the Principal ADHD Expert for ADHD in Adults. He is Distinguished Professor of Psychiatry, SUNY Upstate Medical University, and is a member of the Board of APSARD, the American Professional Society of ADHD and Related Disorders. He is the Principal Investigator for ADHD in Adults.com and serves on the Advisory Board.