Neuropsychiatr Dis Treat. 2016; 12: 1869–1882.

Published online 2016 Jul 26. doi: 10.2147/NDT.S68652

PMCID: PMC4968854

PMID: 27555775

Critical appraisal of omega-3 fatty acids in attention-deficit/hyperactivity disorder treatment

Anja Königs and Amanda J Kiliaan

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Abstract

Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder. The classical treatment of ADHD where stimulant medication is used has revealed severe side effects and intolerance. Consequently, the demand to search for alternative treatments has increased rapidly. When comparing levels of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) in ADHD patients with those in age-matching controls, lower levels are found in ADHD patients’ blood. ω-3 PUFAs are essential nutrients and necessary for proper brain function and development. Additionally, there are strong indications that ω-3 PUFA supplements could have beneficial effects on ADHD. However, the results of ω-3 PUFA supplementation studies show high variability. Therefore, we reviewed recent studies published between 2000 and 2015 to identify effective treatment combinations, the quality of design, and the safety and tolerability of ω-3-containing food supplements. We searched the databases MEDLINE, PubMed, and Web of Science with keywords such as “ADHD” and “ω-3/6 PUFA” and identified 25 studies that met the inclusion and exclusion criteria. The results of these ω-3 PUFA studies are contradictory but, overall, show evidence for the successful treatment of ADHD symptoms. The tolerability of the given supplements was high, and only mild side effects were reported. In conclusion, there is evidence that a ω-3 PUFA treatment has a positive effect on ADHD. It should be added that treatment could be more effective in patients with mild forms of ADHD. Moreover, the dosage of stimulant medication could be reduced when used in combination with ω-3 PUFA supplements. Further studies are necessary to investigate underlying mechanisms that can lead to a reduction of ADHD symptoms due to ω-3 PUFA treatments and also determine the optimal concentrations of ω-3 PUFAs, whether used as a single treatment or in combination with other medication.

 

Keywords: ADHD, ω-3 fatty acids, treatment, DHA, EPA

Introduction to the emerging use of omega-3 in attention-deficit/hyperactivity disorder

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder, which has its onset in childhood but can also persist until adulthood.1 The overall pooled prevalence of ADHD in the world is 7.2% but differs between sex and age.2–4 In general, the prevalence of ADHD is higher in males than in females and is most common in school-aged children. On the basis of criteria stated in the Diagnostic and Statistical Manual of Mental Disorders (DSM), ADHD patients can be divided into three groups: mainly inattentive, mainly hyperactive/impulsive, or a combination of both.1 The diagnosis is based on a number of age-dependent symptoms of inattention and/or hyperactivity/impulsivity that should occur for a period of at least 6 months. These symptoms often lead to severe problems in social behavior as well as in peer relationships. For ADHD patients, social life in a family environment and at school/work is therefore difficult. Furthermore, ADHD is often accompanied by learning difficulties and mood and behavior disorders.5 Problems in social life are the main reason for ADHD treatment.

One of the most commonly used treatments for ADHD is the stimulant drug called methylphenidate. Due to side effects and unknown long-term effects, however, there are concerns about the use of methylphenidate.6 These concerns are the main reason for families to postpone methylphenidate treatment for months to years after a confirmed diagnosis of ADHD by a physician. The most important reason for families to start using methylphenidate as a treatment for ADHD is the ultimate urge to solve problems at school, work, and home. This kind of stimulant medication is only treating symptoms, however, and not the cause. This means that the drug is only effective for a couple of hours after intake (half-life time of intermediate-release methylphenidate is 2–4 hours) but will not change the situation over the long term.7Studies have shown that stimulant drugs provoke mild side effects in most patients but also cause severe side effects, such as decreased appetite, insomnia, and headaches.8,9 These general concerns and side effects of the stimulant treatment clearly accentuate the need to search for alternative and less harmful treatments for ADHD. The best known alternative treatment is supplementation with omega-3 polyunsaturated fatty acids (ω-3 PUFAs).

It is interesting to use ω-3 PUFAs as a treatment for ADHD since ADHD patients, in general, show a lack of ω-3 PUFAs.10–13 To understand the function of ω-3 PUFAs, the family of ω-6 PUFAs also need to be considered. The pre-cursors of both ω-3 and ω-6 families are essential nutrients, which means that they cannot be produced by the body itself and should be obtained via dietary intake. In addition to the reliance on the intake of essential PUFAs, the processing of the precursors is inefficient in humans.14 During the Paleolithic period, the diet provided sufficient ω-3 PUFAs due to the high intake of fish. The ratio of ω-3 to ω-6 PUFAs was therefore high. In the western diet, the ratio is low due to an increase in ω-6 PUFAs and decrease in ω-3 PUFAs.15–17 Furthermore, ADHD is multifactorial and depends on genetic background on the one hand, and, for a large part on environmental factors on the other hand. Reduced ω-3 PUFAs levels in ADHD could be an interesting additional environmental factor because these deficiencies clearly have the greatest impact during the development of the central nervous system. This is also the time of onset of ADHD. This leads to the question of whether a food supplement containing ω-3 PUFAs can serve as an alternative treatment for ADHD, taking into consideration that there are fewer side effects, a higher efficiency, and fewer concerns about the impact on health. The purpose of this article is to critically review recent literature on ω-3 PUFAs treatment for ADHD, to determine 1) effective treatment combinations, 2) the quality of design of the clinical trials, and 3) the safety and tolerability of the food supplements.

Rationale for ω-3 in ADHD

To clarify the hypothesis that supplements containing ω-3 PUFAs could be used as an effective ADHD treatment, the role of ω-3 PUFAs in the healthy brain in comparison with the brain of an ADHD patient needs to be discussed. When precursors of ω-3 and ω-6 long-chain PUFAs (LCPUFAs) enter the body, they enter the same enzyme pathway. The precursor α-linolenic acid (ALA) belongs to the group of ω-3 PUFAs and can be found in flax and in small amounts in soybeans, canola oil, and green leafy vegetables. The precursor can be converted into docosahexaenoic acid (DHA), which forms an important part in the production of phospholipids in neuronal membranes in the brain. DHA is responsible for fluidity and permeability of the neuronal membrane. High concentrations are found particularly in synapses, which makes DHA necessary for the function of neurons. An important intermediate is an eicosapentaenoic acid (EPA), which is responsible for the production of eicosanoids. These eicosanoids can function as anti-inflammation signaling molecules.18 High concentrations of DHA and EPA are found in fish and fish oil.

Eicosanoids are also responsible for the regulation of the interaction of the ω-3 and ω-6 PUFA pathways. In addition to eicosanoids, the ratio between ω-3 and ω-6 PUFAs is also responsible for the regulation of both pathways. A high intake of ω-6 PUFAs may inhibit the production of ω-3 PUFAs from its precursor and benefits processing of ω-6 PUFAs. The ω-6 PUFAs precursor is linoleic acid (LA) and is transformed into arachidonic acid (AA) as an important intermediate. In addition to EPA, AA produces anti-inflammatory eicosanoids, which can also be found in reasonable amounts in neuronal membranes.18 The final product is docosapentaenoic acid (DPA), which has inflammatory effects.18

Several arguments why ω-3 PUFAs may serve as good candidates for the treatment of ADHD can be found in the literature. These arguments are based on the biochemical and physiological functions of ω-3 PUFAs. First, membranes of neurons contain high amounts of ω-3 and ω-6 PUFAs, especially DHA and AA, for proper neuronal function. The amount of ω-3 and ω-6 PUFAs affects the fluidity of the membrane, which could affect neurotransmission, permeability, as well as the structure and function of membrane-bound proteins. In blood and plasma of ADHD patients, the level of ω-3 PUFAs is lower than in age-matching controls. These lower levels can be found in children, adolescent, and adults.10–13 Postmortem measurements of the cortex showed that DHA concentration in a healthy brain increases until the age of 18 years.19 Furthermore, ω-3 PUFAs have an important function in brain development.20–23 This could explain why ω-3 PUFA deficiency during development has a wide impact on the function and development of the brain.

The second argument concerns the ratio of ω-3/ω-6 PUFAs in blood and plasma cells, which is lower in patients with ADHD. The relatively higher amount of ω-6 PUFAs may increase neuroinflammation. Since ADHD patients and controls consume similar amounts of ω-3 and ω-6 PUFAs, it is likely to presume that there are other causes for this change in ratio.10,13 One possible cause could be that processing of PUFAs is less effective in patients with ADHD.13 Common signs of essential fatty acid deficiency in ADHD patients are skin rashes and increased thirst.10 It is presumed that these symptoms are due to a deficiency in ω-6 PUFAs.24 In any case, it should be added that there is no competition between ω-3 and ω-6 PUFAs during uptake but only at the processing level.25 This offers the opportunity to increase the amount of ω-3 PUFAs through higher dietary intake.

Search methodology

The following databases were searched between January 2000 and March 2016: MEDLINE, PubMed, and Web of Science. For this search, keywords such as Attention Deficit Hyperactivity Disorder (ADHD), ω-3 and ω-6 (long-chain) poly, unsaturated fatty acids (LCPUFAs), DHA, EPA, γ-linolenic acid (GLA), ALA, and fish oil were used. Other relevant information was also searched in references to reviews, studies, and meta-analyses. Inclusion criteria for trials were 1) a treatment with ω-3 PUFAs or in combination with ω-6 PUFAs, 2) a study design of open-labeled studies excluding a placebo group or double-blind studies including a placebo group, and 3) a diagnosis or suspicion of ADHD. Studies, where ADHD was accompanied by the presence of comorbidity, were also included. As an additional treatment, antioxidants such as vitamin E and carriers such as phospholipids, which improve the availability of PUFAs for the body, were included as well. Trials related to other deficiencies in combination with ω-3 PUFA deficiency such as zinc are excluded. Titles and abstracts of identified articles were controlled for inclusion and exclusion criteria. A flow diagram of the study selection is provided in Figure 1.

Flow diagram of study selection.

Results

In several studies, it has been indicated that supplementation of ω-3 PUFAs has a beneficial effect on ADHD symptoms.26–30 However, the results of these studies show high variability and inconsistency about its effect on ADHD. In this review, only studies that were published between 2000 and 2015 are included. First, general information about all selected trials is provided followed by a separate discussion on the results of each trial. These studies are divided into open-labeled trials without the presence of a placebo group (Table 1) and double-blind trials with the presence of a placebo group (Table 2).