Clinical trials of fatty acid treatment in ADHD, dyslexia, dyspraxia and the autistic spectrum

Abstract

Considerable clinical and experimental evidence now supports the idea that deficiencies or imbalances in certain highly unsaturated fatty acids may contribute to a range of common developmental disorders including ADHD, dyslexia, dyspraxia and autistic spectrum disorders (ASD). Definitive evidence of a causal contribution, however, can only come from intervention studies in the form of randomised, double-blind, placebo-controlled trials. Published studies of this kind are still fairly few in number, and mainly involve the diagnostic categories of ADHD and dyslexia, although other trials involving individuals with dyspraxia or ASD are in progress. The main findings to date from such studies are reviewed and evaluated here with the primary aim of guiding future research, although given that fatty acid supplementation for these conditions is already being adopted in many quarters, it is hoped that some of the information provided may also help to inform clinical practice.

Introduction

Omega-3 and omega-6 fatty acids are absolutely essential for normal brain development and function, but cannot be synthesised de novo in humans and must therefore be provided by dietary sources. The highly unsaturated fatty acids (HUFA) that are particularly important to the brain include arachidonic acid (AA) and di-homo-gamma-linolenic acid (DGLA) from the omega-6 series and eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) from the omega-3 series. If these are not provided directly by the diet, they must be manufactured via processes of desaturation and elongation from the simpler essential fatty acids: linoleic acid (LA) in the case of omega-6 or alpha-linolenic acid (ALA) in the case of omega-3.

Increasing evidence suggests that some common developmental disorders of childhood including ADHD, dyslexia, dyspraxia and autistic spectrum disorders (ASD) may involve functional deficiencies or imbalances in these fatty acids [1]. Thus physical signs of fatty acid deficiency are unusually common in individuals with ADHD, dyslexia or ASD when compared with matched controls [2], [3], [4], [5]; blood biochemical studies have shown depletion—particularly of the omega-3 HUFA—in red cell membranes and/or plasma in children with ADHD or hyperactivity [2], [3], [6] or ASD [5], [7]; and other evidence suggests abnormalities of cerebral membrane lipid turnover [8] and elevated cytosolic PLA2 enzymes in red cell membranes [9] in adults with dyslexia.

These observations have naturally led to the idea that treatment with fatty acids might be of benefit in these conditions. In the many years since a possible link between ADHD and fatty acid deficiency was first proposed by the UK Hyperactive Childrens’ support group [10], plentiful anecdotal evidence has suggested that some individuals with this diagnosis can benefit from fatty acid supplementation. The same is true for dyslexia and dyspraxia, in which open studies have suggested possible benefits [11], [12], and also in the autistic spectrum, for which the first published evidence of fatty acid anomalies is more recent [13].

The proper evaluation of potential treatment effects, however, requires careful and systematic investigation; and randomised, double-blind placebo-controlled trials have long been regarded as the ‘gold standard’ in this respect. Unfortunately, randomised controlled trials (RCTs) also have their limitations [14]. They are most suited to evaluating single treatments for physical medical conditions involving clear diagnostic criteria and homogeneous study populations. They are much less suited to multi-dimensional, behaviourally defined conditions such as ADHD, dyslexia, dyspraxia or the autistic spectrum, where the causes are almost inevitably complex and multi-factorial, and even the rigorous use of formal diagnostic criteria will usually identify a very heterogeneous population. Given this variability, it seems a priori unlikely that fatty acid abnormalities would be a pre-dominant cause of the behavioural and learning difficulties that define these conditions in more than a subset of cases. Nonetheless, the serious consequences of these common behavioural and learning disorders, together with the relative lack of proven interventions that are both safe and effective, make this issue an important one that clearly merits formal investigation.

The few properly controlled trials of fatty acid treatment published to date have involved individuals with a primary diagnosis of either ADHD (or similar difficulties) or dyslexia. Unfortunately, these have mainly been small, researcher-led studies and have involved different methods of identifying study populations, different study designs and different outcome measures, while the compositions and dosages of fatty acid treatments (and placebos) used have also varied between them. This obviously makes either direct comparisons between studies, or a clear synthesis of their collective findings, somewhat difficult. Furthermore, few trials have included biochemical measures of fatty acid status, either in the selection of subjects, to monitor treatment compliance, to assess the physical effects of treatment on fatty acid status, or to investigate how this may relate to baseline characteristics or outcome measures; and this also limits the interpretation of current findings.

Here, the controlled trials to date will therefore simply be summarised by condition, and their main findings outlined and evaluated as far as possible in the light of current knowledge. The primary aim of this review is to guide future research in these areas, but it is hoped that some of the information provided may also be useful to clinicians and others interested in its potential practical applications.