Autism spectrum disorder (ASD) is a lifelong condition that can severely impair social skills and autonomy, and whose prevalence in recent years has increased dramatically, now occurring in 1% to 2% of children.1 The etiology is presumably multifactorial, resulting from the interaction of both genetic and environmental factors.2 Behavioral interventions seem to lead to better outcomes,3 although in some cases pharmacotherapy (eg, with atypical antipsychotics, in particular risperidone and aripiprazole) can be associated with a more comprehensive treatment for reducing problematic behaviors.4 Because conventional medicine has not been able to provide a complete cure, it is not surprising that parents of children with ASD often resort to alternative treatments.
Complementary and alternative medicine (CAM) includes theories and techniques of diagnosis, treatment, and prevention based on traditional medicine, either used together with conventional medicine (complementary) or instead of it (alternative).5 During the past few decades there has been a broad adoption of CAM by families searching for a treatment for children with ASD.6 It has been estimated that the use of CAM in children with ASD ranges from 52% to 95% compared with about 30% of children in the general population.5 According to the conclusions of a review by Whitehouse5 in 2013, melatonin could be recommended as a treatment for sleep disorders in children with ASD, although there is not enough evidence regarding the effects of modified diets (eg, gluten-free, casein-free), hyperbaric oxygen therapy, immunotherapy (immunoglobulins), vitamins (vitamin B6 + magnesium), and supplementation of fatty acids. Methodologically rigorous studies are necessary to give families and clinicians an evidence-based guide concerning complementary and alternative practices for people with ASD.5 Also of interest is the possible role of probiotics in the treatment of ASD, as suggested by several authors.7,8 According to Rosenfeld,9 definitive evidence that this therapy improves behavior in patients with ASD is lacking.
In this article, we address more specifically the topic of omega-3 polyunsaturated fatty acid (PUFA), which is one of the most widely used CAM treatments in children with ASD,5 to evaluate the possible beneficial effects on problems such as social interaction deficit, stereotypies, and hyperactivity. To accomplish this we reviewed the relevant literature highlighted by searches of PubMed from 1949 to present; then, we critically discuss the findings from the literature, proposing a series of questions to be answered in the future to clarify the possible role of omega-3 in the treatment of ASD.
Structure, Food Sources, and Functions of PUFA
Omega-3 PUFAs are a category of essential fatty acids characterized by the position of the first double bond that, starting the count from the terminal carbon (the so-called “omega” carbon), occupies the third position: hence the term omega-3; Figure 1 shows one example of omega-3, alpha-linolenic acid. The main omega-3 food sources include fish, seafood, cereal-based products, vegetable oils, meat, and eggs.10Figure 2 shows linoleic acid, an example of omega-6, which is characterized by the first double bond occupying the sixth position. The main omega-6 food sources include vegetable oils, meat, and cereal-based products.10
Alpha-linolenic acid, an example of omega-3.
Linoleic acid, an example of omega-6.
Three main functions of PUFA have been reported11: (1) Omega-6 and omega-3 are fundamental components of the phospholipids, the major constituents of cell membranes.12 The presence of omega-3 in the cell membrane increases its fluidity; this can be a key to explain the neurologic effects of omega-3.13 (2) Omega-6 and omega-3 act as endogenous ligands for the peroxisome proliferator-activated receptors (PPAR).14 PPARs are nuclear receptors that function as transcription factors regulating gene expression in metabolic processes related to cellular differentiation and development.15 PPARs are widely expressed in all regions of the brain, particularly in areas responsible for learning and memory, such as the hippocampus.16 (3) PUFAs are precursors of a variety of molecules such as prostaglandins and interleukins involved in inflammatory processes.12 In this context, PUFAs have divergent functions: omega-6 is a proinflammatory precursor, whereas omega-3 is an anti-inflammatory precursor.17
PUFA and Etiopathogenesis of ASD
In 2014, van Elst et al.11 developed a fascinating hypothesis concerning the link between PUFA and ASD. The significant increase in prevalence of ASD in these past few decades seems to go in parallel with changes in the dietary composition of fatty acids, namely the replacement of cholesterol with omega-6 in many food products, which led to a marked increase in the ratio of omega-6 to omega-3. Dietary changes in the ratio of omega-6 to omega-3, and specifically the lack of omega-3, may induce, particularly during the earliest stages of life, modifications of myelination, neurogenesis, and synaptogenesis; synthesis and turnover of neurotransmitters; brain connectivity; expression of PPAR (see above); inflammatory responses; cognitive functioning; and behavior; all of which are directly related to ASD.11
The blood level of omega-3 in patients with ASD did not give unequivocal results. In 2001, Vancassel et al.18 reported a deficit of omega-3 in the plasma of children with ASD compared to controls with intellectual disability. In 2006, Bu et al.19 failed to replicate this result comparing the fatty acid composition of red blood cell membranes between 40 children with ASD and 40 controls (20 normal and 20 with non-ASD developmental disabilities). In 2013 Ghezzo et al.20 found an increased omega-6 to omega-3 ratio in the erythrocyte membrane in children with ASD compared to healthy controls. In 2015, Mostafa et al.21 reported that PUFA plasma levels were significantly lower in 80 children with autism age 4 to 12 years than in 80 matched healthy children. The omega-6 to omega-3 ratio was significantly higher in patients with autism than in controls. In 2015, Brigandi et al.22 compared the fatty acid composition of red blood cell membranes between 121 patients with autism and 110 controls without autism or developmental delay who were age 3 to 17 years. Total PUFA percentage was lower in subjects with autism than in controls; the levels of arachidonic acid (omega-6) and docosahexaenoic acid (DHA) (omega-3) were particularly low.22
The reason for the variability of these results is not clear, but it suggests the possibility that there are abnormal levels of omega-3 in at least one subgroup of children with ASD.23 Despite these controversial data, various researchers have tried to study the effects of omega-3 supplementation in patients with ASD.
The Effects of Omega-3 in Patients with ASD Based on Data in Literature
In 2003, working under the assumption of a possible favorable effect of omega-3 in depression and bipolar disorder as well as schizophrenia, and considering that in autism there are often associated symptoms such as depression, affective instability with sudden fluctuations in mood and “psychotic” symptoms, Johnson and Hollander24 assessed the effectiveness of omega-3 supplementation as adjunctive therapy for autism. They reported the case of an 11-year-old boy with autism, presenting with extremely high levels of anxiety and agitation. A dramatic clinical improvement was observed after supplementation with omega-3 fatty acids from fish oil was started, gradually increasing to 540 mg/day of eicosapentaenoic acid. This had a positive effect on the overall quality of life of the boy. The clinical improvement persisted after 8 months of follow up.24
In the following years, several studies were performed to assess the effects of omega-3 in ASD. In 2011, James et al.25 reviewed the effects of omega-3 on the main features of ASD and on the associated symptoms. They reviewed all the randomized controlled trials studying omega-3 supplementation versus placebo in people with ASD. The authors conducted out a meta-analysis of the studies selected for three primary outcomes (social interaction, communication, stereotypies) and one secondary outcome (hyperactivity). Six trials were excluded because they were nonrandomized, there was not a control group, or the control group had not received a placebo.25 Two trials were included, for a total of 37 children with ASD (and intellectual disability) randomized to groups that received omega-3 or placebo.26,27 Overall, there was no evidence that omega-3 had effects on social interaction, communication, stereotypies, or hyperactivity. James et al.25 concluded that there is a need for well-conducted randomized controlled trials on large series of patients, evaluating both high- and low-functioning people with ASD and with a longer follow-up period.
In 2014, Bent et al.28 reported an Internet-based, randomized, controlled trial of omega-3 for hyperactivity in autism. The primary outcome measures were changes in hyperactivity assessed by parents and teachers based on the Aberrant Behavior Checklist. Fifty-seven children age 5 to 8 years were included, and they were randomly assigned to treatment with omega-3 (1.3 g/day) or placebo for 6 weeks. In the children treated with omega-3, a greater reduction in hyperactivity was found compared to the placebo group, but the difference was not significant. The authors concluded that a wider sample is necessary to definitively establish the efficacy of omega-3.28
In 2014, Voigt et al.29 described a trial involving 48 children with ASD, age 3 to 10 years, randomized in a double-blind manner to receive 200 mg/day of DHA (omega-3, n = 24 cases) or a placebo (n = 24 cases) for 6 months. The DHA group did not show any improvement in autism core symptoms versus the placebo group according to the Clinical Global Impressions-Improvement scale completed by the parents and the investigator. According to the Behavior Assessment Scale for Children, parents (and not teachers) gave a higher average rating of social skills for the placebo group versus the DHA group (P < .05), whereas teachers (and not parents) gave a higher average rating of functional communication for the DHA group versus the placebo group (P < .05). The authors concluded that DHA supplementation does not improve autism core symptoms, but the results may have been limited by an insufficient sample size.29
In 2015, Ooi et al.30 reported a 12-week open trial designed to evaluate the efficacy and safety of omega-3 in ASDs. They included 41 children age 7 to 18 years with ASD. Significant improvements were found in all the subscales of the Social Responsiveness Scale (P < 0.01) and in the subscales concerning the social and attention problems of the Child Behavior Checklist (P < 0.05). A significant correlation between blood levels of fatty acids and the variations of the main symptoms of the ASD was found. The baseline blood levels of fatty acids were predictive of response to treatment. The authors concluded that the results give some preliminary support to the use of omega-3 in ASD. In the future, randomized controlled trials with measurements of fatty acids in the blood of a larger series with a longer follow-up are justified.30
In 2015, Mankad et al.23 reported a randomized controlled trial of omega-3 (1.5 g/day) versus placebo for 6 months in children age 2 to 5 years with ASD. The primary outcome measures were severity of autistic symptoms (Pervasive Developmental Disorders Behavioral Inventory) and externalizing behaviors (Behavior Assessment System for Children). Secondary outcome measures were global improvement (Clinical Global Impression-Improvement), adaptive functioning (Vineland Adaptive Behavior Scale), language (Preschool Language Scale), and safety. Possible correlations between changes in cytokine profiles and response to treatment were investigated. Thirty-eight participants randomized in a 1:1 ratio were included. No significant differences were found between the groups regarding the severity of autistic symptoms. A significant increase in externalizing behaviors in the treatment group compared to the placebo group was detected (P < .05). No significant differences with respect to adaptive functioning and language were found. Changes of cytokines in the course of the study were not significantly correlated with treatment response. The authors concluded that the study is not in favor of the use of high doses of omega-3 in children with ASD.23
So far, randomized clinical trials as a whole have not produced encouraging results for the effects of omega-3 supplementation in children with ASD. Therefore, at least for now, evidence-based medicine seems to reject this kind of treatment. However, based on anecdotal experiences and on nonrandomized trials, we cannot exclude that there might be a subset of people with ASD who do respond to this type of approach. The presence of this subgroup of responders, in fact, might go unnoticed if the effects of omega-3 are evaluated only in the entirety of a sample. Currently, randomized clinical trials are almost universally regarded as the most reliable system for evaluating the effectiveness of a drug; but no matter how well conducted they are not foolproof, due to methodologic problems that are, at least in part, unavoidable.31,32 Therefore, we should not consider the results of the randomized clinical trials as final and unquestionable judgments.
On the other hand, due to the heterogeneity of phenotypes and etiologies of ASD, it is really unlikely that a certain treatment has the same effects in all patients; conversely, it is presumable that individual features of patients with ASD may influence the treatment effects.33 An important step would be to determine if patients with ASD that seem to be “responders” to omega-3 really exist and, if so, the reasons for this phenomenon and the possible clinical features that distinguish them from other people with ASD. These statements are also valid for other types of complementary and alternative treatments.
Some questions specific to the topic of treating ASD with omega-3 also need to be addressed. First, what is the amount of omega-3 administered orally that actually reaches the bloodstream?34 In addition, what is the amount of omega-3 that really reaches the brain through the blood-brain barrier? Furthermore, what are the specific brain areas that really need omega-3? Is supplementation with high doses of omega-3 really without toxic effects, as is commonly believed?
On the other hand, it should also be considered that after a certain age the possible damage caused by the hypothetical lack of omega-3 at the neuronal level could no longer effectively be reversible with omega-3 supplementation or with another approach. Finally, if a relative or absolute deficit of omega-3 was demonstrated in these children, its primary cause should still be identified, meaning that basic research studies at the molecular level would be needed. Alternatively, we cannot exclude that these hypothetical alterations of omega-3 may be an epiphenomenon caused by an unbalanced diet (possibly caused by food selectivity typical of people with autism).
Any studies in the future that will consider the effects of omega-3 supplementation in people with ASD should try to address at least some of these questions.
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- Tordjman S, Somogyi E, Coulon N, et al. Gene × Environment interactions in autism spectrum disorders: role of epigenetic mechanisms. Front Psychiatry. 2014;5:53. doi:10.3389/fpsyt.2014.00053 [CrossRef]
- Weitlauf AS, McPheeters ML, Peters B, et al. Therapies for children with autism spectrum disorder: behavioral interventions update. Rockville, MD: Agency for Healthcare Research and Quality (US); 2014. http://www.ncbi.nlm.nih.gov/books/NBK241444/. Accessed February 1, 2016.
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- Whitehouse AJ. Complementary and alternative medicine for autism spectrum disorders: rationale, safety and efficacy. J Paediatr Child Health. 2013;49:E438–442. doi:10.1111/jpc.12242 [CrossRef]
- Akins RS, Angkustsiri K, Hansen RL. Complementary and alternative medicine in autism: an evidence-based approach to negotiating safe and efficacious interventions with families. Neurotherapeutics. 2010;7:307–319. doi:10.1016/j.nurt.2010.05.002 [CrossRef]
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- Meyer BJ, Mann NJ, Lewis JL, et al. Dietary intakes and food sources of omega-6 and omega-3 polyunsaturated fatty acids. Lipids. 2003;38:391–398. doi:10.1007/s11745-003-1074-0 [CrossRef]
- van Elst K, Bruining H, Birtoli B, et al. Food for thought: dietary changes in essential fatty acid ratios and the increase in autism spectrum disorders. Neurosci Biobehav Rev. 2014;45:369–378. doi:10.1016/j.neubiorev.2014.07.004 [CrossRef]
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- Green JT, Orr SK, Bazinet RP. The emerging role of group VI calcium-independent phospholipase A2 in releasing docosahexaenoic acid from brain phospholipids. J Lipid Res. 2008;49:939–944. doi:10.1194/jlr.R700017-JLR200 [CrossRef]
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