Drawing Attention to Omega-3 Supplements in Attention Deficit Hyperactivity Disorder (ADHD) by Rochelle Fernandes, MSc, ND (Cand), PhD (Cand)

Abstract

Attention deficit hyperactive disorder (ADHD) is a common challenge among children, adolescents, and adults. Parents, especially, remain cautious in utilizing medications as a first line therapy for their young children who have been diagnosed with ADHD, hence creating an expanding need for natural therapeutics. Omega-3 polyunsaturated fatty acids (PUFAs) have been effective at alleviating symptoms in various diagnoses (neurological, cardiovascular, endocrine and more) due to their anti-inflammatory nature. Omega-3 PUFAs would be a good option for children with ADHD due to their moderate efficacy and lower level of side effects. This article comments on studies that address this efficacy by focusing on which subtype of ADHD patients would benefit the most, as well as the best dosage, duration, age range, and symptom profile that show clinical benefits. This article also comments on mechanisms of action that are relevant and that underlie the logic of utilizing omega-3 PUFAs in a clinical setting. Overall, based on a review of a collection of studies in ADHD, omega-3 PUFAs are promising natural therapeutic agents alone or in combination with conventional medications in children age six to 15, at a dose >500mg EPA/DHA and in those with the hyperactive/impulsive subtype of ADHD.

Introduction

Attention deficit hyperactive disorder (ADHD) can be a challenging diagnosis for children and a worrisome one for their parents. It has been noted that 6.1 million children in the United States of America between the ages of two and 17 are thought to have ever been diagnosed (CDC 2020). Parents are often careful in pursuing conventional medications for children, especially younger ones. Therefore, the pressing need for natural interventions in this niche has been growing immensely over recent decades for young children and those who wish to pursue natural means before seeking medication.

ADHD can often be diagnosed in childhood, as early as three years of age. The primary features of ADHD include inattention and hyperactive-impulsive behavior. The symptoms can be mild, moderate or severe. If unresolved, these can make their way into adult life. ADHD is more prevalent in males than in females. Moreover, the expression of the array of behaviours can be different in boys and girls. There are three types of ADHD: a) inattentive, b) hyperactive/impulsive, and c) mixed (Mayo Clinic 2019). Most common treatments include psychostimulant drugs and behaviour therapy. Among the drugs, there are three main types that are available in either short or longer acting forms. The first is the Amphetamine class.  This includes but is not limited to dextroamphetamine (Dexedrine), dextroamphetamine-amphetamine (Adderall XR) and lisdexamfetamine (Vyvanse). The second is the Methylphenidate class. This includes but is not limited to methylphenidate (Concerta, Ritalin) (Mayo Clinic 2019). The third class is slower acting and is classified as being in the antidepressant category, such as bupropion (Wellbutrin).  Key side effects of concern are cardiovascular in nature and include elevated blood pressure and increased pulse rate. Additional side effects of further behaviour alterations can occur, such as hallucinations, psychoses, and manic expression. These worrisome side effects and pharmaceutical hesitancy create an immense need for efficacious alternatives to conventional medication or a need to improve the outcomes of conventional therapies.

There have been several natural therapeutic options that have been examined for mental health diagnoses such as ADHD. One promising natural option has been omega-3 PUFAs. Deficiencies in omega-3 PUFAs have been found, more specifically DHA, in children diagnosed with ADHD (Hawkey and Nigg 2014, Stevens et al 1995). This concept is extended clinically as well. Lower levels of EPA and DHA were found in the blood of those with symptoms of ADHD (Colter et al 2008, Crippa et al 2018). These and other studies have been monumental in creating an interest in the use of omega-3 supplements alone or with medication for ADHD.

Background

Prior to appreciating the clinical usefulness of omega-3 PUFAs in the neurological system and more specifically to ADHD, the structure, function, and mechanisms of action of these crucial players should be revisited. Omega-3 fatty acids are PUFAs; there is a double bond at the third carbon atom from the end of the carbon chain. PUFAs are a part of the phospholipid structure of the cell membrane. They also create eicosanoids that participate in cell signalling for processes in neurological, cardiovascular, pulmonary, and immune systems. There are three types of omega-3 fatty acids that are clinically relevant to this article: α-linolenic acid (ALA) (found in plant oils), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) (found in fish oils).

Omega-3 fatty acids are broken apart into smaller fatty acid units. Therefore, products are vital to downstream processes, such as the construction/disruption of lipid rafts, promotion of optimal signalling mechanisms, formation of changes in gene expression, and regulation of lipid/peptide mediators (Calder 2013). An important concept to note is the following: unlike plants, humans/animals do not have the delta-15 desaturase enzyme that enables the construction of ALA. Humans are able to metabolize it via processes of desaturation and elongation. ALA forms stearidonic acid via delta 6 desaturase and then stearidonic acid is worked on to create EPA (Calder 2013). It is important to note that the conversion of α-linolenic acid to EPA is in competition with the conversion of linoleic acid to arachidonic acid (AA), thus swaying the outcomes of inflammatory versus anti-inflammatory actions.

EPA and DHA acid are key players in cellular function and help with actions such as the reduction of platelet function and plasma fibrinogen. The anti-inflammatory effects of Omega-3 PUFAs are the reason they are used in clinical application. Higher levels of EPA or DHA have been shown to decrease levels of prostaglandin E2 (PGE2) and 4 series leukotrienes (LT). The anti-inflammatory effects are mainly a result of the fact that omega-3s and in turn EPA/DHA produce a different set of eicosanoids than AA, which then alters leukotriene synthesis. EPA, for instance, contends with AA for desaturation enzymes (Calder 2013). The anti-inflammatory aspect is due to the formation of 3 series prostaglandins (PGs) and 5 series thromboxanes (TXs), respectively.

EPA and DHA also demonstrate anti-inflammatory effects by producing molecules known as resolvins and protectins via cyclooxygenase and lipoxygenase molecular pathways. These molecules prevent transendothelial migration of neutrophils. They also prevent the formation of tumour necrosis factor (TNF) and interleukin (IL)-1β (Calder 2010). Omega-3 fatty acids also contribute to anti-inflammatory states by reducing adhesion molecule expression on leukocytes and on endothelial cells, which in turn reduces intercellular adhesive interactions. Omega-3 PUFAs are considered to be ligands for peroxisome proliferator activated receptor (PPAR) gamma that regulates nuclear factor (NF)κB activation and hence inflammatory gene expression (Calder 2010).

The analysis of mechanisms of action involved in the relationship between ADHD and omega 3s and other PUFAs have to do with neuroprotective effects mainly involving changes in the synaptic membranes (Mischoulon and Freeman 2013). Detailed mechanisms related to protection of neuromembranes include but are not limited to cell signalling within the brain, maintenance and regulation of monoamines, and receptor alterations related to signal transduction pathways (Assisi et al 2006, de la Presa and Innis 1999, Hallahan and Garland 2005, Ross et al 2007). Additional findings of omega-3 PUFAs involved a role in alterations in the function of the dopamine transporter/dopamine production and dopamine/serotonin levels at the synapse (Foster et al 2008). The regulation of neurotransmitters and the sustenance of an anti-inflammatory state are the main mechanisms at play for omega-3 PUFAs and their neurological success.

Promising Evidence for the Use of Omega-3 PUFAs in ADHD

The clinical application of omega-3 PUFAs in ADHD is immense and worth examining. Chang et al (2018) provided a systematic review and meta-analysis to delve into this and have shown that children with ADHD had lower red blood cell levels of EPA and DHA, as well as that supplementation with omega-3 PUFAs in those with ADHD provided a significant clinical improvement in cognitive performance. Symptom assessment also echoed this improvement; a dose of EPA greater than 500mg/d improved symptoms in individuals with the hyperactivity/impulsivity subtype of ADHD.

Positive results were shown in a study that provided omega-3 PUFAs to children age six to 12 for 12 weeks, where higher concentrations of EPA/DHA were found in red blood cells (RBC) and correlated significantly with improvements in working memory. There was no effect seen in parent and teacher rated behaviour (Widenhorn-Müller et al 2014). A double-blind, randomized, placebo-controlled trial (DBRPCT) found that boys aged eight to 14 who were given 650mg EPA/DHA for 16 weeks had improved parent rated attention and symptoms of ADHD, however had no effect on cognitive control or functional MRI outcomes of brain activity (Bos et al 2015). Kidd (2007) also discussed a neuroprotective effect of EPA/DHA; for instance, a DBRCT that administered phosphatidylserine compounds with EPA/DHA showed improved symptoms of ADHD.

Conversely, several studies have shown no differences between omega-3 PUFA treatment groups versus placebo in those with ADHD. One example is a study that had a crossover design where children took EPA, DHA or linoleic acid and the study measured attention, cognition, literacy, and utilized the Conner’s Parent Rating Scale (CPRS) (Milte et al 2015). Another review that assessed RCTs had looked at studies with omega-3 PUFAs in children and adolescents as measured by CPRS and showed no statistically significant changes between placebo and treatment groups (Abdullah et al 2019). One RCT administered Omega-3 and -6, methylphenidate (MPH), or both for one year to 90 individuals with ADHD, who were assessed via the ADHD Rating Scale and Clinical Global Impressions-Severity (CGI-S) scale. The findings showed that a combination of omega-3 and -6 with MPH had similar findings to the group with MPH alone (Barragán et al 2017). These studies with findings of no improvements in the treatment group are equally valuable, as they lead us to examine underlying reasons behind the lack of aimed result and strive to improve future efficacy, as will be further addressed in the discussion.

Overall, it seems that despite the group of aforementioned studies, there is compelling evidence to support the therapeutic use of omega-3 PUFAs in improving outcomes of ADHD. A randomized control trial with supplementation of 500mg per day of EPA and 2.7mg per day of DHA reduced inattentiveness but not hyperactivity (Gustafsson et al 2010). Other similar evidence was found in a study where restlessness and impulsive symptoms (parental rated input) improved in the treatment group when compared to placebo (Manor et al 2012). Another study with parent rated input demonstrated a reduced set of symptoms of hyperactivity, inattentiveness, and impulsive behaviour in the treatment group (Sinn et al 2008). One study used measurement outcomes of parental and teacher rated conduct/attention levels; the treatment group (480mg EPA, 80mg DHA, 40mg AA, and 96mg GLA) showed a significant reduction in symptoms when compared to placebo (Stevens et al 1995). One review showed that 13 of the 16 RCTs reviewed demonstrated improvement in a wide variety of symptoms including hyperactivity/impulsiveness, inattentiveness, working memory, and visual queued learning. Furthermore, a subset of these studies had a dosage of 9:3:1 of EPA/DHA/GLA that showed success alone or in combination with conventional medication (Derbyshire 2017).

Discussion

A large array of studies has supported the use of omega-3 PUFAs in ADHD; these effects depend on age, dosage regimen, length of treatment, and method of outcome measurement. Yet overall, there is still consistency that treatment groups with omega-3 PUFAs have improved clinical outcomes and that also reflect improved physiological findings (e.g. blood markers).

Although some studies have shown no difference between treatment (omega-3 PUFAs) and placebo groups in ADHD, there are several explanations and things to consider. Perhaps these findings could lead us to consider if this may be related to the half-life and metabolism of these molecules. One study showed that the half-life values of ALA is one hour, EPA is 39-67 hours and DHA is 30 hours (Braeckman et al 2014, Nguyen et al 2014). It may be possible that clinical usefulness might involve administration at the immediate onset of symptoms and for a shorter duration, rather than with long-term use, to maximize the half life.

Another thing to note in maximizing efficacy would be the ratios of EPA to DHA in the dosage administration in ADHD. Some studies used a nearly 1:1 ratio, while others used DHA alone. DHA tends to exist in high concentrations in the retina and brain and plays a large role in pre and postnatal brain development, whereas EPA is more important in regulating mood/behaviour. This is important when considering clinical usage of either one. Adjusting the regimen to incorporate higher ratios of DHA versus EPA or vice versa might be promising, depending on the ADHD subtype. Interestingly, the notion of levels of EPA/DHA versus AA are important in the context of cell exposure, accumulation and membrane fatty acid structure, as this will determine how those cells function from the standpoint of measuring cell inflammation. Additionally, it begs the question of whether an improved molecular profile of EPA/DHA influenced anti-inflammatory metabolites would translate clinically to improved symptoms. From the evidence provided above, the answer confirms it mostly will. However, it should be noted that most studies did not do any baseline EPA/DHA blood/RBC measurements to compare to post treatment levels.

Consideration should also be given to what would be deemed a therapeutic dose. Calder reports that a minimum dose of 2g/d of omega-3 PUFAs appears to produce a significant anti-inflammatory effect (difficult to achieve through diet or normal over the counter supplements) (Calder 2010, Calder 2013). Moreover, it would be harder to get children to consume these higher levels of omega-3 PUFAs.

Another interesting notion is that most of the studies were performed in school-age children. Perhaps an effect may have been omitted that could have been observed in the younger age groups, given that ADHD can be diagnosed as early as three years of age. Another interesting perspective is to question whether certain severity subsets of ADHD benefit more from therapy with omega-3 PUFAs than others. For instance, one study showed that EPA/DHA given for three months to children aged six to 15 with ADHD did not benefit the treatment group as there was no measured benefit in symptom improvement in those with mild ADHD (Cornu et al 2018). Perhaps there could have been better efficacy in those with moderate or severe ADHD, either through measured symptoms or molecular markers. Another aspect to efficacy is the gender factor. A study noted that boys (12.9%) are more likely to have ever been diagnosed with ADHD than girls (5.6%) (CDC 2020). Girls may demonstrate a more muted symptom profile and manifest these symptoms differently, hence revealing an underlying bias.

It was also noticed that symptoms as measured by parent scores in studies were improved in the PUFA treated group, whereas this effect was less seen with teacher measured scores. Teachers assess children during the day in class and use different criteria to assess attentiveness, whereas parents might take a wholistic approach in assessing the child for a broader list of activities in the home. This may have impacted the findings in a lack of effect noted with teachers in the treatment group when compared to an effectiveness of PUFA in ADHD as reported by parents.

Conclusion

There is a strong body of evidence that supports the use of omega-3 PUFAs in ADHD. Patterns indicate that most studies in those with ADHD showed either a) a specific, deficient profile of cellular/molecular/bio markers, b) improvement in these same marker levels of PUFAs post supplementation (e.g. RBCs), and/or c) reduced symptoms in the treatment group. Overall, this was more specifically demonstrated by >500mg EPA/DHA, in the six to 15-year age group, for greater than three months duration, and with improvements mostly found in the hyperactive/impulsive subtypes and those with more severe ADHD, as measured by parent rated symptom assessment.

While some studies showed no improvement in treatment groups that were administered omega-3 PUFAs for ADHD, the dose, ratio of EPA/DHA, duration of treatment, age range, and type of measurement outcome would need to be further examined to assess whether there was truly no benefit.

For combination treatments (conventional therapy and omega-3 PUFAs), no additional benefit was seen with the combination compared to either therapy alone. However, a systematic review by Bloch and Qawasmi suggests that omega-3 PUFAs, although less effective than psychostimulant medication, is still promising. Omega-3 therapy delivers reduced side effects compared to medication and still demonstrates moderate success in ADHD symptom relief. Therefore, omega-3 PUFAs can be used alongside conventional medication or alone (in those who are reluctant to use medication) (Bloch and Qawasimi 2011). Omega-3 supplementation is a safe intervention with solid evidence supporting a role in ADHD management, either to be attempted as a monotherapy, or alongside conventional treatments.

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