Introduction

Complementary and alternative medical (CAM) therapies are commonly used by patients with autistic spectrum disorders (ASDs). In four recent surveys, the prevalence of CAM use was 32, 52, 74, and 95% (Hanson et al. 2007; Harrington et al. 2006; Levy et al. 2003; Wong and Smith 2006). The variability in the reported prevalence is likely related to the substantial differences in survey designs and the populations studied, but it is clear that CAM use is common.

Omega-3 fatty acids are among the most commonly used CAM therapies, and have been reported to be currently used by 28.7% of children with ASDs (Green et al. 2006). Omega-3 fatty acids are polyunsaturated fatty acids and three main types are found in the human diet: ALA (alpha-linolenic acid), DHA (docosahexaenoic acid), and EPA (eicosapentaenoic acid). DHA and EPA are found in seafood, while ALA is found in nut and plant oils. Interestingly, fish do not produce EPA and DHA, but the oils are synthesized by single-cell marine organisms that are eaten by fish (Harris 2004). While the human body can synthesize both DHA and EPA from ALA, it can not synthesize any of these three types of fatty acids “from scratch.” Thus, these substances are typically considered essential human nutrients and are often called “essential fatty acids” (Freeman et al. 2006). DHA and EPA are used by the body to produce a variety of different compounds, including cyclooxygenases and lipoxygenases, which have many different physiological actions (Harris 2004).

While the potential mechanism of action of omega-3 fatty acids for improving symptoms of ASD is unknown, neural tissue contains high concentrations of DHA, and studies suggest that this fatty acid is essential to the growth and functional development of the human brain (Freeman et al. 2006). Omega-3 fatty acids are also known to exert an anti-inflammatory effect (Kris-Etherton et al. 2002). Three prior studies have reported low levels of omega-3 fatty acids in children with ASD compared to controls (Bell et al. 2004; Meguid et al. 2008; Vancassel et al. 2001), while a fourth found no difference (Bu et al. 2006). Fatty acid deficiencies have also been reported in individuals with other psychiatric disorders, including schizophrenia and attention deficit hyperactivity disorder. A recent systematic review found statistically significant benefits from omega-3 fatty acids for the treatment of depression, although there was considerable heterogeneity in the results and marked variation in the methodology of included studies (Freeman et al. 2006).

Because omega-3 fatty acids are commonly used by children with ASDs and there is some limited evidence regarding a possible physiological basis for beneficial effects, we conducted a systematic review to identify and evaluate all prior clinical studies that reported treatment effects of omega-3 fatty acids in children with ASDs.

Methods

Protocol

All study procedures were defined a priori in a study protocol that specified the search strategy, the inclusion and exclusion criteria, the quality rating system, and the method of analysis.

Search

We searched MEDLINE, EMBASE, and the Cochrane Collaboration Clinical Trials Registry from 1966 to September 2008 to identify relevant studies in all languages. The search strategy used the following terms: (autism OR autistic) AND (unsaturated fatty acid OR unsaturated fatty acids OR omega 3 OR omega3). We reviewed the reference lists of all identified studies and contacted experts to identify additional studies.

Study Selection

We set broad inclusion criteria to include not only randomized controlled trials but also any other study design that (1) enrolled human subjects of any age who had ASDs, (2) treated patients with omega-3 fatty acids with any dose and duration, and (3) reported at least one outcome measure (including clinical or parental observation) that addresses the core symptoms of ASDs (social difficulties, communication problems, and repetitive or restrictive behaviors) or any associated symptom (such as sleep disturbance, gastrointestinal problems, or anxiety). We excluded studies that combined omega-3 fatty acids with other interventions. The primary reason for setting broad inclusion criteria was to evaluate not only the randomized controlled trials, but also other study designs that may be commonly presented to families and care providers as the rationale to begin treatment with omega-3 fatty acids. Our goal was to evaluate all studies in an unbiased manner to summarize the current scientific evidence for families and clinicians who are making treatment decisions.

Quality Assessment and Data Abstraction

For each study, two authors independently abstracted data regarding study eligibility, study quality, treatment, and ASD-related outcomes. For randomized controlled trials, study quality was assessed using the Jadad scale (Jadad et al. 1996). For designs other than randomized controlled trials, we provided a written description of the design and the potential limitations, but did not provide a quantitative quality score, as there is no widely accepted tool for other designs.

Clinical Recommendation

In order to provide a concise clinical recommendation about whether the use of omega-3 fatty acids is indicated based on a review of current scientific evidence, we chose to follow the methods of the US Preventive Services Task Force (USPSTF), which provides letter grades evaluating the certainty and magnitude of the benefit of an intervention (letters A–D and “I” for insufficient information; Sawaya et al. 2007). In general, letter grades of A or B indicate that the treatment should be provided to eligible patients, treatments with a letter grade of C should not be offered routinely, and D-grade treatments should not be provided. Treatments with insufficient evidence are rated as “I,” and no recommendation is made regarding clinical use (Sawaya et al. 2007).Two authors (SB and KB) independently followed the methodology of this rating framework to determine the clinical recommendation.

Results

The database searches, reviews of bibliographies, and contact with experts yielded 143 potentially relevant articles. Six articles satisfied all inclusion and no exclusion criteria and are included in this systematic review. Reasons for exclusion of other articles are shown in Fig. 1.

Fig. 1
figure 1

Reason for exclusion of studies

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The characteristics of the six included studies are shown in Table 1.

Table 1 Characteristics of studies of omega-3 fatty acids in autistic spectrum disorder
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Only one study was a randomized controlled trial (Amminger et al. 2007). This study enrolled 13 children with autism (based on DSM-IV criteria and the ADI-R) and randomly assigned them to the daily use of 1.5 gms of omega-3 fatty acids or an identical placebo for 6 weeks. The outcome measure was the Aberrant Behavior Checklist. The difference in the change in each of the subscales between groups is shown in Table 2.

Table 2 Results of the one randomized controlled trial of omega-3 fatty acids (Amminger et al. 2007)
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Each subscale showed a greater improvement in the omega-3 group compared to the placebo group, but none of these changes reached statistical significance. The largest changes were in the hyperactivity and stereotypy subscales. The study was methodologically sound, and received a four out of five point rating on the Jadad score (the score was reduced by one point because the method of randomization was not described).

Four studies were uncontrolled, open-label studies that enrolled children or young adults with autism or Asperger’s. Politi et al. 2008 conducted an open-label study of 19 young adults (mean age 29) with severe autism, moderate to profound mental retardation, and severe maladaptive behaviors. All subjects were given 0.93 gms of omega-3 fatty acids (DHA + EPA) and a vitamin supplement containing 5 mg of vitamin E daily for 6 weeks. The frequency and severity of problematic behaviors was assessed using an instrument (the Rossago Behavioral Checklist) for 6 weeks before, during, and after treatment (18 week total study period). The authors found no improvement in the mean severity score of problematic behaviors between the pre-treatment and treatment periods. Interestingly, there appeared to be an improvement in both the frequency and severity of symptoms in the post-treatment period, though it is not clear if this was due to beneficial effects of omega-3 fatty acids or other factors (as there was no control group).

Meguid et al. 2008 treated 30 children with autism from a National Research Center in Egypt for 3 months with a combination of omega-3 (240 mg DHA + 52 mg EPA daily) and omega-6 fatty acids (68 mg) and Vitamin E. They reported that 20 of 30 children improved on the Childhood Autism Rating Scale, but they did not report the mean change in the overall group of 30 children.

Patrick et al. enrolled 22 children who were all treated in an open-label manner with one daily capsule containing 247 mg per day of omega-3 fatty acids for 90 days (Patrick and Salik 2005). The authors reported that there was a statistically significant increase from day 0 to 90 in each of the subscales of the assessment of basic language and learning skills. However, no raw data were presented.

Bell et al. 2004 included a very brief description of an open-label study where nine children with autism or Asperger’s were given one of two different omega-3 supplements of varying dose for at least 6 months. No structured outcomes were assessed, but parents reported improvements in general health and a variety of outcome measures (Table 2).

The sixth study was a case report involving an 11 year-old child who had been diagnosed with autism at age 2.5 and was having problems with high levels of anxiety and agitation associated with compulsive rituals (Johnson and Hollander 2003). Fish oils were initiated and advanced to 3 g/day (540 mg EPA). The parents and the clinician reported complete elimination of anxiety and agitation after 1 week, and the improvement was stable over 8 months of follow-up.

Only the randomized controlled trial reported the details of the method of ascertaining adverse medication effects (UKU Side Effect Rating Scale) (Amminger et al. 2007). In this study, one child withdrew due to gastrointestinal complaints and lack of perceived benefit. The authors noted that a mild adverse event of fever was reported in the omega-3 group (but the number of patients reporting this was not shown). In one uncontrolled study, 2/22 children withdrew due to reports of increased physical activity, but no other adverse effects were noted (Patrick and Salik 2005). In another uncontrolled study, a “few parents” reported “increased hyperactivity and behavioral problems” (Bell et al. 2004). Two uncontrolled studies (Meguid et al. 2008; Politi et al. 2008) and the case report (Johnson and Hollander 2003) did not discuss whether adverse events were assessed.

Based on the evidence summarized above, two independent raters agreed that the evidence for efficacy of omega-3 fatty acids for the treatment of autism should be rated as “I,” indicating that there is insufficient evidence to determine if it is effective.

Discussion

Despite the high prevalence of use of omega-3 fatty acids among children with ASD’s, there is very limited scientific evidence evaluating the safety and efficacy of the supplement in this population. We conducted an extensive literature search in all languages and found only one randomized controlled trial. The randomized controlled trial reported a small, non-significant trend towards benefit in the hyperactivity and stereotypy subscales of the Aberrant Behavior Checklist. While this pilot study was methodologically sound, it was limited by a small sample size and short duration, and it did not examine outcomes other than aberrant behavior. Also, because the omega-3 group had higher (or “worse”) scores for hyperactivity and stereotypy at baseline than the placebo group, the observed benefits may have been due to regression to the mean, with the more severe initial measurements (in the omega-3 group) improving more through natural variation than the less severe initial scores (in the placebo group; Gilbert 2008).

The four uncontrolled studies (Bell et al. 2004; Meguid et al. 2008; Patrick and Salik 2005; Politi et al. 2008) and the one case report (Johnson and Hollander 2003) provide interesting, hypothesis-generating information and raise the possibility that omega-3 fatty acids may have some benefits. However, these studies are significantly limited by the lack of a control group, and are therefore not able to determine if the reported improvements are due to omega-3 fatty acids or to the natural variation in symptoms of ASD that may be due to many other factors. Similarly, the lack of blinding makes all of the uncontrolled studies susceptible to reporting bias. Given the limitations of current studies on omega-3 fatty acids for ASD, families should be educated to properly weigh the evidence when considering treatment decisions. A plain-language summary of this article is provided in Appendix 1. A plain-language summary of the key issues related to interpreting scientific evidence in studies of CAM in ASD is provided in Appendix 2.

Prior studies examining the prevalence of omega-3 fatty acid deficiencies in children with ASD have found inconsistent results. One case-control study found that children with classic autism or Asperger’s had a 10% lower level of total omega-3 fatty acids compared to controls (Bell et al. 2004), and a second case-control study found a 20% lower level of omega-3 fatty acids (Vancassel et al. 2001). A third case-control study found no difference in omega-3 fatty acids levels when comparing 40 children with autism to 20 children with other developmental disabilities or 20 typically developing children (Bu et al. 2006). The reasons for these inconsistent findings are unclear, but may relate to differences in the selection of control populations or differences in laboratory methods of measuring fatty acids. If omega-3 fatty acids have beneficial effects, it is possible that these effects may be limited to a subset of children with ASD. Future studies should consider measuring omega-3 fatty acid levels over the course of a clinical trial to determine if any beneficial effects are limited to children with initial deficiencies or specific fatty acid profiles.

In summary, this systematic review identified one randomized controlled trial, four uncontrolled studies, and one case report examining the efficacy of omega-3 fatty acids for the treatment of ASD. Overall, there is insufficient scientific evidence to determine if omega-3 fatty acids are beneficial for symptoms of ASD (Evidence Rating = “I” or Insufficient). Although there is very limited evidence regarding the efficacy of this therapy, future studies are indicated based on the high prevalence of use, the favorable initial safety profile and low cost, and the lack of studies with sufficient size to identify clinically important benefits. Since the one randomized controlled trial found the largest trend suggesting a possible benefit for improving hyperactivity, future studies should target this symptom area as the primary outcome measure. Measurement of free fatty acid levels during the course of future studies has the potential to identify subsets of patients who might benefit from this therapy. Future studies would also benefit from larger sample sizes with sufficient power to detect clinically important benefits, a longer duration to examine the time-course of treatment effects, a careful assessment of side effects and safety, and a determination of the adequacy of blinding. These recommendations are consistent with the widely accepted guidelines for the conduct and reporting of clinical trials (CONSORT Statement; Altman et al. 2001).