July 16, 2021
There has been much interest in omega-3 Polyunsaturated fatty acids (PUFAs) as treatments for ADHD. Humans are unable to synthesize the 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. Several meta-analyses are available.
A 2014 meta-analysis by Elizabeth Haw key and Joel Niggcombined 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 BasantPuri and Julian Martins combined 18 PUFA supplementation studies involving1,640 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 while16 of the studies involved omega-3 supplementation, two involved only omega-6supplementation. 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-6GLAand 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 from 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 with485 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 2012meta-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, 324participants, 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.
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, MelissaJ 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: AMeta-Analysis," Journal of the Canadian Academy of Child and AdolescentPsychiatry (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., "NonpharmacologicalInterventions for ADHD: Systematic Review and Meta-Analyses of RandomizedControlled Trials of Dietary and Psychological Treatments," American Journal of Psychiatry (2013),170:275-289.
A meta-analysis of short-term, placebo-controlled, randomized clinical trials (Cortese et al. 2018), looking at both efficacy and safety, supported prescribing stimulants – methylphenidate use in children and adolescents and amphetamine use in adults – as first-choice medications.
However, these were short-term studies, and they focused on relieving ADHD symptoms. What about longer-term outcomes, especially looking more broadly at functional impairment and overall quality of life?
Sweden has a single-payer health insurance system that encompasses virtually every resident and is linked to national registers that enable researchers to conduct nationwide population studies.
A joint Finnish-Swedish research team used Sweden’s registers to study outcomes for all individuals of working age, 16 to 65 years old, living in Sweden who had received a diagnosis of ADHD from 2006 through 2021. The resulting study cohort encompassed 221,714 persons with ADHD.
The team adjusted for the following confounding variables: Genetics, baseline severity of symptoms, baseline comorbidities, temporal order of treatments (which medication was used as first, second, third, and so forth, including also nonuse of ADHD medications), time since cohort entry, and time-varying use of psychotropic drugs, including antidepressants, anxiolytics, hypnotics, mood stabilizers (carbamazepine, valproic acid, and lamotrigine), lithium, antipsychotics, and drugs for addictive disorders.
With these adjustments, they discovered that amphetamine treatment was associated with a roughly 25% reduction in psychiatric hospitalization relative to unmedicated ADHD. Lisdexamphetamine was associated with a roughly 20% reduction, dexamphetamine with a 12% reduction, and methylphenidate with a 7% reduction. All four medications are stimulants.
None of the non-stimulant medications – atomoxetine, guanfacine, clonidine – had any significant effect on psychiatric hospitalization. Nor did modafinil a drug that is not FDA approved for ADHD but is sometimes used when other drugs fail.
Amphetamine was also associated with the greatest reduction in suicide attempts or deaths, with a roughly 40% decline relative to unmedicated ADHD. Dexamphetamine was associated with a roughly 30% decline and lisdexamphetamine with a roughly 25% decline. The stimulant methylphenidate was only associated with an 8% reduction, and modafinil had no significant effect.
Surprisingly, non-stimulant medications were associated with significant increases in suicide attempts or deaths: 20% for atomoxetine, 65% for guanfacine, and almost double for clonidine.
Amphetamine and lisdexamphetamine also reduced the risk of nonpsychiatric hospitalization by more than a third compared to unmedicated ADHD. Dexamphetamine was associated with a risk reduction of more than 25%, methylphenidate with 20% lesser risk.
The non-stimulant atomoxetine was associated with a roughly 15% reduction in risk of nonpsychiatric hospitalization. But neither guanfacine nor clonidine had any significant effect.
Turning to work disability, atomoxetine was the only ADHD medication associated with a reduction – a roughly 10% improvement. All other medications had no significant effect.
The team concluded, “In this cohort study of adolescents and adults with ADHD, the use of medications for ADHD, especially lisdexamphetamine and other stimulants, was associated with decreased risk of psychiatric hospitalizations, suicidal behavior, and nonpsychiatric hospitalizations during periods when they were used compared with periods when ADHD medication was not used. Non-stimulant atomoxetine use was associated with decreased risk of work disability.”
Noting that “Oxidative stress disrupts the structure and function of neurons in the prefrontal lobe of the brain,” and “Structural and functional impairments in the prefrontal cortex have been shown to be highly correlated with behavioral and emotional problems of ADHD,” a Chinese team at Dalian University set out to systematically evaluate the safety and efficacy of antioxidant therapy in children and adolescents with ADHD.
The team’s systematic search of the peer-reviewed medical literature identified a total of 48 randomized controlled trials (RCTs) or prospective studies involving 12 antioxidant agents (resveratrol, pycnogenol, omega-3, omega-6, quercetin, phosphatidylserine, almond, vitamin D, zinc, folic acid, ginkgo biloba, Acetyl-L-carnitine) that met criteria for inclusion:
Treatment efficacy was measured through ADHD symptom scores using Conners’ parent rating scale (CPRS), Conners’ teacher rating scale (CTRS), ADHD rating scale-parent (ADHD RS-Parent), and ADHD rating scale-teacher (ADHD RS-Teacher), as well as secondary outcome indicators such as the Clinical Global Impressions scale (CGI) and Continuous Performance Test (CPT), relative to controls.
None of the antioxidant therapies were significantly better than placebo.
One limitation is that no effort was made to assess publication bias.
These results indicate that antioxidants should not be used for treating ADHD.
A 2021 consensus statement by an international group of scientists and clinicians (Bauer et al.) recommended that pregnant individuals “forego [acetaminophen] unless its use is medically indicated,” due to the potential risk of developmental disorders such as autism and attention-deficit/hyperactivity disorder (ADHD).
A mostly Swedish research team, collaborating with a U.S. researcher, nevertheless noted that previous studies have been limited by:
Sweden has a single-payer health insurance system that includes virtually its entire population, and national registers that enable tracking the health history of mothers and their children, including their children’s siblings.
The team used the Swedish registers to identify the roughly two-and-a-half million children born in Sweden from mid-1995 through 2019. They were also able to identify all siblings to be able to control for otherwise unmeasured familial and genetic confounding.
Almost 186,000 of these children were exposed to acetaminophen during pregnancy.
After adjusting for available known confounders, including (but not limited to) child sex and birthdate, mother’s age and medical history, use of any other painkillers, use of any psychoactive medications, country of birth, residential region, smoking status, highest household education, and disposable income, children exposed to acetaminophen during pregnancy were 7% more likely to be diagnosed with ADHD subsequently than those who were not exposed.
However, roughly the same results were found for other painkillers, including aspirin, non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs), opioids, and antimigraine medication. High doses of acetaminophen did not produce any stronger association with subsequent ADHD than low dosage.
Moreover, when confining results to siblings – 8,526 children who were exposed versus 87,679 who were unexposed – the association between acetaminophen use during pregnancy and subsequent offspring ADHD vanished altogether (and, again, at every dose level). The associations similarly vanished with every other painkiller medication.
The Swedish team concluded, “Acetaminophen use during pregnancy was not associated with children’s risk of autism, ADHD, or intellectual disability in sibling control analyses. This suggests that associations observed in models without sibling control may have been attributable to confounding.”
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