Can essential fatty acid supplementation play a role in the treatment of Attention-Deficit Hyperactivity Disorder?

For submission 22nd April 2006

Dissertation, 3rd Year ION
Contents
Abstract 3 1.0 Introduction 4 1.1 Prevalence 4 1.2 Diagnosis 4 DSM-IV Checklist for Diagnosing ADHD 6 Figure 1. DSM-IV Checklist for Diagnosing ADHD 6 1.3 Associated Conditions 7 1.4 Prognosis 7 1.5 Aetiology 7 1.5.1 Genetics 8 1.5.2 Environmental Influences 8 1.5.3 Essential Fatty Acids 8 1.5.4 Food Sensitivities 9 1.5.5 Heavy Metal Toxicity 9 1.5.6 Nutrient deficiencies 9 1.5.7 Pregnancy/birth trauma 10 1.5.8 Hypoglycaemia 10 1.5.9 Digestive 10 1.5.10 Thyroid 11 1.6 Clinical Management 11 1.7 Understanding the Role of Essential Fatty Acids 12 1.7.1 What are Essential Fatty Acids? 12 Figure 2. Major Food Sources of Essential Fatty Acids 12 Figure 3. Omega-3 and Omega-6 metabolic pathways 13 1.7.2 Essential Fatty Acids and Brain Function 13 1.7.3 Physical Signs of Fatty Acid Deficiency 14 2.0 Literature Review 15 2.1 DHA Supplementation 15 2.2 Combined DHA, EPA, GLA Supplementation 18 2.3 Combined EPA, DHA, ALA Supplementation 19 2.4 ALA Supplementation 22 2.5 Summary of studies reviewed 23 Figure 4. Summary of Studies Reviewed 23 3.0 Discussion 24 3.1 Future Research 27 4.0 Conclusion 28 5.0 Nutritional Strategy 29 5.1 Benchmarking 29 5.2 Dietary Strategy 29 5.3 Lifestyle Strategy 29 5.4 General Supplement programme 30 6.0 Acknowledgements 31 7.0 References and Bibliography 32 7.1 Primary References 32 7.2 Secondary References 34 7.3 Bibliography 35 8.0 Appendix 36 8.1 Glossary 36

Abstract

Attention-Deficit Hyperactivity Disorder (ADHD) is a diagnostic label used to describe individuals, who display a wide range of behavioural symptoms broadly defined as inattention, hyperactivity and impulsiveness. These symptoms emerge in childhood and often persist into adulthood.

Nutritional management of ADHD is receiving greater focus as parent groups, consumer advocacy organisations and progressive health professionals call for alternatives to methylphenidate (Ritalin) and the many other potent stimulants used to treat ADHD. Nutritional factors such as food sensitivities, nutrient deficiencies, hypoglycaemia and essential fatty acids (EFA’s) are now increasingly the subject of research.

The link between essential fatty acids (EFA’s) and ADHD was first hypothesized in 1981 and there is now considerable clinical and experimental evidence to support the idea that deficiencies or imbalances of EFA’s may contribute to ADHD symptoms.

Recent supplementation studies are reviewed and conclude that EFA supplementation can be of benefit to ADHD sufferers but further research is required to establish the optimal dosage, formulation and duration of treatment. A nutritional strategy should incorporate supplementation of EFA’s as part of a wider treatment protocol.

1.0 Introduction
Attention Deficit Hyperactivity Disorder (ADHD) is a diagnostic label used to describe individuals, who display a wide range of behavioural symptoms broadly defined as inattention, hyperactivity and impulsiveness. These symptoms emerge in childhood and often persist into adulthood.

ADHD is not a new phenomenon, first being labelled over 100 years ago as “Morbid Defect of Moral Control”. Over subsequent years it has taken a number of aliases including “Post-encephalitic Behaviour Disorders”, “Minimal Brain Dysfunction” and “Hyperkinetic Reaction”. It was not until 1980 that the condition was termed “Attention Deficit Disorder” but later redefined to Attention Deficit Hyperactivity Disorder.
1.1 Prevalence
The condition is relatively common but the exact percentage is not known and estimates vary widely from 2% to 17% depending on diagnostic definitions and geography (Zametkin & Ernst 1999, Kidd 2000). School age boys with the disorder are thought to outnumber girls by ratio’s of anywhere from 2:1 to 4:1 (Le Fever GB et al 1999, SIGN 2001).

The increased prescribing of stimulant drugs for ADHD reflects the increased frequency of diagnosis of the condition, almost doubling between 1998 and 2004 (NICE 2006). This may suggest an increase in recognition and diagnosis of the condition but could also be an indication of an increased incidence.
1.2 Diagnosis
No objective test exists to confirm the diagnosis of ADHD, which remains a clinical diagnosis. There are two main sets of diagnostic criteria in current use. The first and more commonly used, particularly in North America, is taken from the American Psychiatric Association’s “The Diagnostic and Statistical Manual of Mental Disorders fourth edition, 1994 (DSM-IV)” shown in Figure 1. In simple terms, ADHD can be characterized by two distinct sets of symptoms—inattention and hyperactivity. ADHD is further divided into three specific diagnostic forms, each based on a specific clinical presentation that seeks to better describe a child's behaviours. These forms are ADHD-Primarily Inattentive Type (sometimes called just ADD, attention deficit disorder), ADHD-Primarily Hyperactive/Impulsive Type, and ADHD-Combined Type (both inattentive and hyperactive).

The second set of diagnostic criteria is the World Health Organisation’s International Classification of Mental and Behavioural Disorders 10th revision (ICD-10), which has stricter requirements for pervasiveness across situations than DSM-IV. ICD-10 has been more often used in Europe where the diagnosis is known as Hyperkinetic Syndrome although the use of DSM-IV is becoming more common. These diagnostic criteria differences can account for the marked differences in incidence figures for ADHD.

Diagnosis is based on a highly detailed clinical history from information provided by parents, teachers and also the afflicted individual. Objective assessment tools such as Conners’ Teacher and Parent Rating Scales are also used. In future, MRI may be used as brain structure and imaging studies have found differences between ADHD patients and non-ADHD individuals (Zametkin et al 1998).

DSM-IV Checklist for Diagnosing ADHDThe Diagnostic and Statistical Manual of Mental Disorders IV, published by the American Psychiatric Association, describes three patterns of behaviour that indicate ADHD. These are: not paying attention, being overactive and acting without thinking. A child can have symptoms of all three signs. However, to be diagnosed with ADHD a child must have: * Six or more symptoms of not paying attention (inattention) AND * Six or more symptoms of being overactive (hyperactivity) and acting before thinking (impulsivity). Signs of inattention include: * Often pay no attention to detail and make careless mistakes in schoolwork or other activities * Can't concentrate on one game or task for long * Often seem not to listen when spoken to * Often don't follow instructions, and fail to finish schoolwork and tasks around the house * Often have difficulty organising tasks and activities * Often avoid tasks that need a lot of concentration * Often lose things * Are easily distracted * Are often forgetful. Signs of hyperactivity include: * Often fidget or squirm when sitting down * Keep getting up * Often run about or climb instead of sitting still * Often have difficulty playing quietly * Are on the go all the time, and act as if driven by a motor * Talk too much. Signs of impulsivity include: * Often blurt out answers before a question is finished * Often have difficulty waiting their turn * Often interrupt others. Because everyone displays signs of these behaviours at times, the DSM contains specific guidelines for determining when they indicate ADHD. Doctors also look for the following: * Your child must have been behaving like this for at least six months. * Some of the symptoms must have been present before your child reached the age of 7 years old. * Above all, your child's behaviour must be causing problems in at least two places (for example, at home and at school). Before diagnosing ADHD your doctor will also check that your child's symptoms are not caused by another condition such as bipolar disorder, anxiety disorder or personality disorder. (Adapted from American Pyschiatric Association 1994 The Diagnostic and Statistical Manual of Mental Disorders fourth edition, (DSM-IV) |

Figure 1. DSM-IV Checklist for Diagnosing ADHD

1.3 Associated Conditions
ADHD appears to be associated with a wide variety of other conditions and this is considered the norm rather than the exception (NICE 2006). Common associations include Oppositional Defiant Disorder (ODD), Conduct Disorder (CD), learning disorders, epilepsy, tic disorders, Tourette’s syndrome, depression and anxiety. In addition, children with ADHD are frequently seen to have a clinical overlap with dyslexia and/or dyspraxia (Richardson 2002). Some children will have several of these difficulties making it difficult to assess their relative contributions to the child’s ADHD patterns.
1.4 Prognosis
The rate of ADHD falls with age but more than 70% of hyperactive children may continue to meet the criteria for ADHD in adolescence, and up to 65% of adolescents may continue to meet criteria for ADHD in adulthood (Biederman 1996). Although ADHD manifests differently in adults than in children, its symptoms and impairments create similar challenges for patients and their families as they cope with daily living (Eyestone et al 1994).
1.5 Aetiology
There has been much speculation about the underlying causes of ADHD but it is generally acknowledged to be multifaceted involving both biological and environmental factors. The dysfunction of ADHD is thought to be due to an imbalance in the brain’s neurotransmitter chemicals, noradrenaline and dopamine. This imbalance is mostly found in those parts of the brain responsible for self-monitoring and behaviour. The reasons for this dysfunction are still under intense debate but the following areas are the subjects of research.
1.5.1 Genetics
There is now little doubt that ADHD is a hereditary condition. Numerous studies have demonstrated that ADHD is highly heritable and more recent studies are now beginning to examine which particular genes might be implicated in ADHD. Cook et al (1995) reported an association with a single dopamine transporter gene and other candidate genes have also been investigated including the serotonin transporter gene (Manor et al 2001).
1.5.2 Environmental Influences
Intervention studies have demonstrated improvements in ADHD symptoms when parents have been taught alternative parenting skills (Sonuga-Barke et al 2001, Bor et al 2002 cited by Daley 2005). However Fisher (1998) has suggested that the genetic predisposition to ADHD might fuel a negative family atmosphere that exacerbates latent ADHD in the child.
1.5.3 Essential Fatty Acids
Colquhoun & Bunday first hypothesized the link between essential fatty acids and ADHD in 1981 but clinical support was not obtained until 1987 when a study by Mitchell et al confirmed low blood plasma levels of certain long-chain polyunsaturated fatty acids (LCPFA) in children with hyperactivity. A review by Richardson et al (2004) suggests that essential fatty acids play a role in ADHD for a number of reasons; males are more vulnerable to long-chain fatty acid deficiencies and this probably explains why ADHD is more prevalent in males; the presence of chronic health problems, in particular atopic conditions, are more common in children suffering from ADHD and in these conditions there is a problem in conversion from EFA’s to long-chain polyunsaturated fatty acids (LCPUFA). EFA deficiency is known to contribute to general health problems such as proneness to infections and digestive disorders and children with ADHD are reported to suffer from these symptoms more often than children without ADHD.
1.5.4 Food Sensitivities
Ben Feingold in 1975 first proposed the link between food additives, specifically synthetic food colours and flavours and naturally occurring salicylates being responsible for hyperactive behaviour in children. Feingold developed a diet requiring children to eliminate all artificial colours, flavours and foods containing salicylates. He reported that as many as 50% of hyperactive children who carefully followed the regimen responded favourably to the diet. Although the validity of Feingold’s study has since been criticised, subsequent studies have also shown positive results for a small sub-group of children with behavioural disturbances (Schnoll, 2003).
1.5.5 Heavy Metal Toxicity
Toxic metals are ubiquitous in the modern environment and these environmental pollutants have been linked to abnormalities in behaviour, perception, cognition and motor ability. Numerous studies have shown that children exposed to lead, arsenic, aluminium, mercury or cadmium either acutely or chronically, are often left with neurological difficulties such as attentional deficits, emotional liability and behavioural reactivity (Kidd, 2000).
1.5.6 Nutrient deficiencies
In a study by Dr Bernard Rimland in California, 1591 hyperactive children treated with drugs were compared to 191 hyperactive children given nutritional supplements. The nutritional approach was found to be 18 times more effective at reducing hyperactivity.

An epidemiological study by Dr Neil Ward identified hyperactive children had statistically lower zinc and iron levels than control children for blood serum, urine and hair. Zinc deficiency has been linked to gastrointestinal changes and damage, which may then result in malabsorption of other nutrients including EFA’s. Numerous further studies have also implicated deficiencies in Magnesium, Iron, B-vitamins, in particular Vitamin B6 and serotonin (Bellanti 1999).
1.5.7 Pregnancy/birth trauma
Several studies indicate that pregnancy and delivery complications raise the risk for ADHD. Specific complications include eclampsia, poor maternal health including poor diet, smoking and consumption of alcohol, maternal age, foetal post-maturity, long duration of labour, foetal distress and antepartum haemorrhage. These complications can frequently lead to hypoxia affecting the basal ganglia of the foetus and it is the basal ganglia, which is commonly implicated in ADHD (Biederman 2005).
1.5.8 Hypoglycaemia
According to Langseth and Dowd (cited in Prinz & Riddle 1986), sugar consumption may cause or aggravate hyperactivity. They hypothesized that hypoglycaemia is associated with increased levels of epinephrine, which in turn can stimulate the symptoms of nervousness or restlessness in susceptible individuals. Similar findings have been found in subsequent studies although in general the results do not support the contention that sugar consumption ‘causes’ hyperactivity, rather that excess sugar may exacerbate symptoms in a certain sub-group of sufferers.
1.5.9 Digestive
Dr Natasha Campbell-McBride MD in her book, Gut and Psychology Syndrome, groups ADHD sufferers with other behavioural disorders such as dyslexia, dyspraxia, autistic spectrum disorder and schizophrenia. Based on studying recent research combined with her clinical experience she cites that digestive abnormalities are the common underlying disorder, manifesting themselves in different combinations of symptoms in different children. These abnormalities include dysbiosis and candida albicans, thought to be caused by over-use of antibiotics and anti-inflammatories, poor nutrition and vaccinations during childhood. Several research studies confirm these findings.
1.5.10 Thyroid
Thyroid hormones help regulate neurotransmitter systems in the brain and several studies have linked thyroid hypo-function during early childhood to diminished mental function. Brucker-Davis (1998) postulated that abnormal thyroid responsiveness, perhaps provoked perinatally by environmental pollutants, might predispose individuals to ADHD. In a major review of thyrotoxicity from chemicals, Brucker-Davis listed 77 chemicals proven to damage mammalian thyroid. These included polychlorinated biphenyls (PCB’s), dioxins, phenols amongst others – all synthetic chemicals released into the environment as pesticides, herbicides and other environmental pollutants.
1.6 Clinical Management
The conventional management of ADHD involves a multi-modal approach including individual and family education, counselling, behavioural therapy and medication. Usual medication is stimulant based, acting on the central nervous system with a dopamine-agonistic effect. The single most common intervention for the symptomatic management of ADHD is Methylphenidate (Ritalin), which has been used for over 40 years.

There is overwhelming evidence from randomised controlled trials that Methylphenidate is effective in the treatment of ADHD symptoms (NICE 2006) however the side effects can include reduced appetite and resulting weight loss, growth retardation, rebound leading to exaggerated behavioural symptoms, headache, jitters, gastrointestinal upset, sleep difficulty, irritability, depression, anxiety, blood glucose changes, increased blood pressure, psychosis or paranoia as well as tics and stereotyped (repetitive) movements.
Parent groups, consumer advocacy organisations and progressive health professionals are now calling for alternatives to methylphenidate (Ritalin) and the many other potent stimulants used to treat ADHD.
1.7 Understanding the Role of Essential Fatty Acids
1.7.1 What are Essential Fatty Acids?
Essential fatty acids are polyunsaturated fats that are essential for health but cannot be made in the body and therefore must be obtained in the diet (See Figure 2 for major dietary sources). Major Food Sources of Essential Fatty Acids | Omega-6-Fatty Acids | Omega-3-Fatty Acids | Linoleic Acid | Gamma-Linolenic Acid | Alpha-Linolenic Acid | Eicosapentaenoic Docosahexaenoic | Corn oil Safflower oil Sesame oil Sunflower oil Cotton seed oil Soybean oil Peanut oil Grape seed oil | Evening primrose Borage oil Blackcurrant oil VegetablesLegumes | Linseed oil Canola oil Walnut oil Soybean oil VegetablesLegumesWatercressSeaweeds | Oily fish: Sardines Salmon Tuna Mackerel HerringsWhite fish Shell fish | These foods also contain other types of fatty acids in varying amounts |

Figure 2. Major Food Sources of Essential Fatty Acids

The two truly essential fatty acids are linoleic acid (LA) and alpha-linolenic acid (ALA). LA and ALA are both metabolically transformed into long-chain polyunsaturated fatty acids (LCPUFAs, sometimes also known as Polyunsaturated Fatty Acids – PUFA’s) in the liver with the aid of many cofactors, including insulin, zinc and several vitamins.
These long-chain fatty acids include the omega-6 fatty acids of dihomo-y-linolenic acid (DGLA; 20:3n-6) and arachidonic acid (AA; 20:4n-6), both metabolised from linoleic acid, and the omega-3 fatty acids of eicosapentaenoic acid (EPA; 20:5n-3) and docosahexaenoic acid (DHA; 22:6n-3), both metabolised from ALA. These derivatives of LA and ALA contain at least 20 carbon atoms making up the backbone chain and are therefore also known as Highly Unsaturated Fatty Acids (HUFA’s). Figure 3 below shows the synthesis process. The numbers (in omega-3 and omega-6) refer to the points on the molecules where the first double-bonds are located. Omega-3 Fatty Acids | Enzymes Involved | Omega-6 Fatty Acids | Alpha-Linolenic (ALA) | 18:3 | | Linoleic Acid (LA) | 18:2 | ↓ | | Delta-6 Desaturase | ↓ | | Octadecatetraenoic | 18:4 | | Gamma-linolenic (GLA) | 18:3 | ↓ | | Elongase | ↓ | | Eicosatetraeonic | 20:4 | | Dihomogamma-linolenic (DGLA) | 20:3 | ↓ | | Delta-5 Desaturase | ↓ | | Eicosapentanoic (EPA) | 20:5 | | Arachadonic Acid (AA) | 20:4 | ↓ | | Elongase | ↓ | | Docasapentanoic | 22:5 | | Adrenic | 22:4 | ↓ | | Elongase, Delta-6 Desaturase, Beta-oxidation | ↓ | | Docasahexaenoic (DHA) | 22:6 | | Docosapentaenoic (DPA) | 22:5 |

Figure 3. Omega-3 and Omega-6 metabolic pathways
(Adapted from Richardson, A.J. Fatty Acids in Dyslexia, Dyspraxia and ADHD).

1.7.2 Essential Fatty Acids and Brain Function
Omega-3 and omega-6 essential fatty acids are vital for the normal structure and function of the nervous system. They are important components of phospholipids and cholesterol esters, which are vital to cell membrane structures in the brain. A deficiency of essential fatty acids in the cellular membrane makes it difficult for the cell membrane to perform its normal function.
Phospholipids comprise approximately 25% of the dry weight of the human brain. Together, AA and DHA account for roughly half of total brain phospholipids, which are essential for fluidity of nerve cell membranes and affect the functional capacity of neurotransmitter receptors. EPA and DGLA play more minor structural roles but are still crucial for normal brain function.
The fatty acid components of neuron membrane phospholipids are central to the integrity of cell-signalling systems and electrical activity in brain cells. EFA’s also control the synthesis of chemicals such as eicosanoids and cytokines, which are thought to have a direct effect on mood and behavior.
However, various dietary, lifestyle and disease factors (e.g., oxidative damage, viral infection and hormonal changes) can interfere with the synthesis process. Thus, many individuals may be deficient in the long-chain fatty acids (DGLA, GLA, AA, EPA and DHA), despite an availability of the EFA precursors in their diet. Individuals will also differ in their ability to convert EFA’s and this is the suggestion in ADHD as well as other behavioural disorders (Richardson, Fatty Acids in Dyslexia, Dyspraxia and ADHD. Can Nutrition Help? 2002)
1.7.3 Physical Signs of Fatty Acid Deficiency
Various physical signs are associated with deficiencies in essential fatty acids. These include: * excessive thirst * frequent urination * rough, dry or scaly skin * dry or dull hair * dandruff * soft brittle nails * raised bumps on the skin.

Many other features also appear to be associated with deficiencies or imbalances including: * allergic or atopic tendencies (eczema, asthma, hayfever) * visual disturbances * attention and concentration problems * sleep disturbances * mood swings * anxiety.
Although these signs and symptoms can be associated with other causes, studies suggest they can frequently be linked with a deficiency or imbalance in essential fatty acids. Many of these symptoms are frequently reported in children with ADHD compared with normal children (Richardson and Puri, The Potential Role of Fatty Acids in ADHD).
2.0 Literature Review
Research into the effects of EFA’s on ADHD has accelerated in recent years, however many of these studies have been small, researcher-led studies using different study designs, different outcome measures and varying methods of identifying study populations as well as various compositions and dosages of essential fatty acids. This makes direct comparisons between studies difficult but the following are a selection of studies that demonstrate the primary areas of current supplement-based research.
2.1 DHA Supplementation
Voigt et al (2001) was a study into the affects of DHA supplementation on ADHD symptoms. Sixty three children aged 6 to 12 years with ADHD and all receiving effective maintenance therapy with stimulant medication, were assigned randomly in a double-blind fashion, to receive DHA supplementation of 345mg per day or a placebo. Unlike other similar studies, children were selected using strict exclusion criteria, ruling out any comorbidity and ensuring the children were ‘pure’ ADHD. Studies by Kadesjo et al (2001) suggest this may have excluded up to 90% of ADHD sufferers and ultimately may have impacted on results of the study by narrowing the study population too much.

Outcome measures included plasma phospholipids fatty acid patterns, scores on laboratory measures of inattention and impulsivity (Test of Variables of Attentions, Children’s Colour Trails Test) and parental behavioural rating scales. Patients were being treated successfully with stimulant medication and so stopping medication for the duration of the trial was considered inappropriate. However prior to the DHA supplementation, medication was stopped for 24 hours before the laboratory measures were taken so that the stimulant was eliminated from the body and didn’t affect these measures. Follow up laboratory assessments were continued in the same manner. However parent behavioural rating scales based on observations were conducted while the child was taking both supplementation and medication and this may have affected outcomes.

After four months although the DHA supplemented group had a 2.6-fold higher plasma phospholipid DHA content, there was no statistically significant improvement in any of the behavioural measures. In fact, although no group differences reached statistical significance levels, the effects of treatment appeared to be worse for DHA than placebo on almost every outcome measure.

The researchers concluded that DHA supplementation at 345mg per day does not decrease symptoms of ADHD but that further research should be considered to evaluate supplementation with arachidonic acid (AA) in combination with DHA over a longer period of time.

Although this outcome may on the face of it appear disappointing, it was an important negative finding as it was consistent with other evidence that EPA rather than DHA is likely to be the more important omega-3 fatty acid for the treatment of disturbances in attention, cognition and mood. The idea that DHA alone is ineffective in treating ADHD has been reinforced by the results of a more recent study.

This more recent study investigating DHA supplementation was conducted by Hirayama et al 2004 but using a higher dose over a shorter time period than Voigt et al. The study was conducted in Japan, and was a placebo-controlled double blind study with 40 ADHD children of 6-12 years where the DHA group of 20 took active foods containing fish oil for 2 months, whereas the control group took indistinguishable control foods without fish oil but with olive oil. Unlike Voigt where all participants received stimulant medication, in this study, of the placebo group, 4 were receiving stimulant medication and 2 were receiving medication in the DHA group. Outcomes were measured on 7 different criteria including DSM-IV symptoms, aggression, visual perception, visual and auditory short-term memory, development of visual-motor integration, continuous performance and impatience. The results showed no significant differences between the two groups for 5 of the tests but interestingly significant improvements in two of the tests were found in the control group, which was not anticipated. The researchers concluded that DHA supplementation did not improve ADHD related symptoms but that further investigation into fatty acids should be made with careful attention paid to which fatty acids are used.

This study appeared to be a carefully designed but the limitations were that the study group was quite small and the placebo used was not inert.
2.2 Combined DHA, EPA, GLA Supplementation
Stevens et al (2003) was a pilot study evaluating the affects of supplementation with PUFA on blood FA composition and behaviour in children with ADHD-like symptoms also reporting thirst and skin problems (signs of EFA deficiency). The study group selected differed with other studies in that in order to be eligible, children had to show clinical signs consistent with fatty acid deficiency based on a simple checklist including such symptoms as excessive thirst and dry skin. Children had no formal psychiatric diagnoses of ADHD although all participants were under the care of a clinician for ADHD based on parental report. This selection process was used with the aim of reducing heterogeneity and to provide a valid test of the fatty acid hypothesis. Fifty children aged 6 to 13 years were randomised to receive a PUFA supplement consisting of 60mg DHA, 10mg EPA, 5mg AA, 12mg GLA and 3mg Vitamin E as a preservative, or a placebo of olive oil. Both groups received 8 capsules daily for a period of 4 months. A total of 18 patients in the PUFA group and 15 in the placebo group were included in the outcome analysis.

At the end of the intervention period, both parents and teachers completed the Conners’ Abbreviated Symptom Questionnaire and the Disruptive Behaviour Disorders Rating Scale, which were the primary outcome measures. Physical symptoms were also compared. The physical symptoms of thirst and dry skin on which children had been selected actually improved in both treatment groups with no significant advantage for active treatment over placebo.

With respect to behavioural outcome measures, parental measures showed a significant improvement for both the PUFA and the placebo groups but there was no clear benefit from PUFA supplementation over the placebo. Group differences were significant only for parent-rated behaviour problems and teacher-rated attentional difficulties. Some biochemical changes in the placebo group were similar to those induced by active treatment suggesting that fatty acid changes may have contributed to the behavioural improvements seen in these children. The researchers concluded that the olive oil placebo appeared to produce some similar biochemical changes to those found with the active supplement and therefore further research is warranted.

This study is one of many over the last 30 years that Laura Stevens et al have conducted at Purdue University into biochemical factors affecting ADHD. The study seems robust in design although an inert placebo may be a better choice in future studies.
2.3 Combined EPA, DHA, ALA Supplementation
Richardson and Puri, (2002) designed a pilot study to assess the effects of highly unsaturated fatty acid (HUFA) supplementation in the form of fish oil and evening primrose oil (providing mainly omega-3 but some omega-6 HUFA) on behavioural and learning disorders in children with specific learning difficulties (mainly dyslexia) in which ADHD related symptoms were the major focus. Given the high comorbidity between dyslexia and ADHD and previous research implicating fatty acid deficiencies in both conditions, it was thought the benefits from treatment might be particularly evident in a group of children showing features of both conditions. The study included 41 children from Northern Ireland with an age range of 8-12 years. The children’s general ability was average but their reading age was almost 3 years behind chronological age. The children were randomised for 21 to receive HUFA supplementation and 19 to receive an olive oil placebo over a 12 week period. At 12 weeks there was a one-way crossover, placebo to active so that both groups received the HUFA supplementation for a further 12 weeks. The HUFA supplementation consisted of 186mg EPA, 480mg DHA, 96mg GLA, 60iu Vitamin E, 864mg LA, 42mg AA and 8mg thyme oil. Conners’ Parent Rating Scale was used to assess a range of behavioural and learning outcomes associated with ADHD. No child in this study had been formally assessed for ADHD by a psychiatrist and case histories and clinical impressions suggested that not more than a few would have met full diagnostic criteria for DSM-IV ADHD.

After 12 weeks results showed significant improvements in 7 out of 14 scales for the active group, compared with no improvements for the placebo group. At the end of 24 weeks the crossover group showed significant improvements in 9 out of 14 measures, in stark contrast to their earlier lack of improvement at 12 weeks on the placebo. The conclusions drawn by the researchers were that HUFA supplementation appears to reduce ADHD-symptoms in children with specific learning difficulties. They also recommended that given the safety and tolerability of the treatment that the results strongly supported further investigations. Study numbers on this pilot study were small so statistical power is limited however the treatment effects obtained were quite substantial and the researchers concluded that this indicated further investigations were warranted.

Similar results were achieved in the Oxford-Durham study, which received extensive publicity in the media even before the final results of the study were published because the results were considered to be so dramatic. The Guardian reported the following:
‘The data shows a significant improvement in concentration and behaviour. Symptoms of the sort associated with attention deficit and hyperactivity disorder (ADHD) were reduced by an order of magnitude usually achieved with stimulants such as Ritalin. Parents reported that other health problems, such as eczema and asthma, also improved, although no specific data on these other conditions has been published in the study.’
This study was a randomised, double-blind and placebo-controlled study of 117 children aged between 5 and 12 years old, with developmental coordination disorder (DCD or dyspraxia). Although no child had a formal diagnosis of ADHD, 31% of the children had baseline scores within the usual clinical range for a DSM-IV diagnosis.

Patients were randomised to receive placebo, or a capsule containing 558 mg EPA, 174 mg DHA, and 60mg GLA given as 2 capsules three times a day for 3 months. Patients allocated to placebo were then switched to active treatment for 3 months while patients already allocated to active treatment remained on that treatment for a further 3 months.

DCD diagnoses were confirmed with age-standardised measure (full-scale IQ>70) and motor skills below the 15th percentile with objective testing) and case histories from parents and teachers to verify that children’s impairments interfered with academic achievement and activities of daily living.

The primary outcome measures were the changes observed at 3 months in age standardised tests of motor function, reading and spelling achievement (using Wechsler Objective Reading dimensions) and Teacher-rated ADHD related symptoms (Conners’ Teacher rating scales). Researchers reported that after 3 months of treatment there was no effect on motor skills but significant improvements in reading, spelling and behaviour for active treatment versus placebo. After a one-way treatment crossover from placebo to active, similar changes were seen in the placebo crossover group, whereas children continuing with the active treatment maintained or improved their progress. It was concluded that these results might be more widely generalizable for ADHD sufferers.

Although these two studies both involved an 80:20 ratio of fish oil to evening primrose oil (EPO), the fish oil used in the Oxford-Durham trial had an unusually high ratio of EPA to DHA, while that used in the earlier trial was the reverse. Both of these studies seemed to be of robust design and could provide a good basis for further research in these areas.
2.4 ALA Supplementation
In a pilot study, Joshi et al 2005 moved away from the use of fish oils in previous studies by using flax oil combined with Vitamin C. The study evaluated the effect of ALA-rich nutritional supplementation in the form of flax oil and antioxidant emulsion on blood fatty acid composition and behaviour in children with ADHD. ALA is a precursor to EPA and DHA. A trained clinical psychologist using DSM-IV criteria diagnosed thirty children with ADHD. The children were administered flax oil supplementation equivalent to 200mg ALA along with 25mg Vitamin C twice a day for 3 months. No other mode of treatment was given to the children during the trial and there was no placebo group included.

Prior to the study, children were assessed based on DSM-IV. The Stanford Binet test was used to find mental age and intelligent quotient and Parent Rating Scales were used to validate pre and post supplementation scores. Outcomes were measured against pre and post psychopathology tests as well as parallel changes in the RBC membrane EPUFA and plasma peroxides. The study found significant improvements in all ADHD symptoms measured as well as significantly higher levels of EPA and DHA in RBC membranes.

The limitation with this study was the lack of a placebo group as well as the small number of participants. It seemed overly simplified in comparison to other studies reviewed but as the researchers concluded, the results provided a good basis for further studies with a placebo-controlled clinical trial on a larger number of patients over a longer period of time. Additionally, LiTaka Pharmaceuticals provided Flax oil emulsion and raises the question of whether this provision created any bias in the results.

2.5 Summary of studies reviewed

Author | n | Population | Supplement | Outcome | Voigt et al2001Double-blind parallel treatment with | 54DHA (n=27)Placebo (n=27) | ADHDContinued with medication | 345mg DHA | * Plasma phospholipid DHA content in supplemented group 2.6 fold higher than placebo group * No significant improvement in ADHD symptoms | Hirayama et al2004Double blind Parallel treatment with placebo of olive oil | 40DHA (n=20)Placebo (n=20) | ADHD6 on medication | 3600mg DHA per week in food700mg EPA per week in food | * Visual short-term memory improved in control group over the DHA group * Continuous performance improved in the control group over the DHA group | Stevens et al2003Pilot studyDouble Blind parallel treatment with Olive oil | 48PUFA (n=18)Placebo (n=15) | ADHD | 480mg DHA80mg EPA40mg AA96mg GLA24mg Vit E | * Substantial increase in EPA, DHA plasma concentrations * Improvement for both groups in hyperactivity, attention and defiant behaviour | Richardson and Puri, 2002Pilot studyDouble Blind parallel treatment with Olive Oil | 41HUFA (n=22)Placebo (n=19) | ADHD + Specific Learning Difficulties | 186mg EPA480mg DHA96mg ALA60iu Vit E42mg AA | * Improvements for global Conners score and the subscales anxious/shy and cognitive problems | Richardson and MontgomeryCrossover trial | 117HUFA (n=60)Placebo (n=57) | DCD | 80% Fish Oil20% Evening Primrose558mg EPA174mg DHA60mg ALA9.6mg Vit E | * Improvements for reading, spelling and behaviour * No improvement motor skills | Joshi et al2005Pilot studyNo placebo | 30 | ADHD | 400mg ALA50mg Vit C | * Significant improvement in ADHD symptoms * Significant improvement in plasma levels of EPA and DHA |

Figure 4. Summary of Studies Reviewed

3.0 Discussion
The diagnosis and management of children with ADHD remains a challenge. The studies all conclude that further investigation is necessary, even those that produced negative results. The importance of these negative results is that they appear to have eliminated DHA as being the primary factor for improvements in symptoms of ADHD seen in previous EFA research. This will allow a more focused approach in future studies, particularly given the success of the EPA, AA and GLA studies reviewed.

Although the studies reviewed appeared fairly robust and the majority carried out by researchers with considerable experience, the following matters should be considered to ensure the efficacy of future research.

In all but one study, no baseline serum EFA levels were taken and therefore the studies were not able to exclude participants with adequate EFA levels – this could skew the results negatively as those with adequate EFA levels may not necessarily see any improvements with supplementation. For future trials, it would be useful to investigate biochemical measures of fatty acids in relation to specific disorders. It would also be useful to establish the nutritional status of each child using hair mineral analysis, urine analysis and blood serum analysis both prior to and at the end of each trial to add clinical supporting evidence to behavioural assessment evidence. This may also aid identification of subgroups of children that will benefit from EFA supplementation and help to understand the aetiology ADHD in each participant.

Ongoing compliance of supplemental trials may be a problem. In the Oxford-Durham study, children were expected to take 2 capsules three times daily and their teachers administered the supplements during school time. Stevens et all administered 8 capsules daily for a period of 4 months. Outside of a clinical trial setting, taking this number of supplements daily would not necessarily be very practical or achievable and this needs to be taken into consideration when providing treatment protocols.

The studies don’t identify whether supplementation can be used in combination with stimulants to improve symptoms or whether there may be any interactions, whether positive or negative. In Voigt et al, medication was continued during supplementation and although no significant improvements were seen in ADHD symptoms, it would have been more difficult to assess the extent of any impact that supplementation may have had.

The choice of placebo should be considered carefully in clinical trials of essential fatty acids. Placebo effects were seen in both Voigt and Hirayama and possibly Stevens where olive oil was used. The use of olive oil as a placebo is not ideal as it is a rich source of oleic acid, which when synthesized has a number of actions on neurotransmitter and receptor sites and therefore may impact any control group results.

In Hirayama et al, supplementation was taken in the form of food containing DHA and EPA. Consideration needs to be given to the accuracy of measurement of composition of DHA and EPA derived from the food and also whether these food agents had any confusing effect on outcomes.

There were variations in the diagnostic criteria used for selection into each trial. Voigt et al selected ‘pure’ ADHD children while other studies used a variety of other selection criteria including children with comorbidities. Added to this are the different diagnostic criteria of DSM-IV and ICD-10. Although the studies reviewed all used DSM-IV, future trials may need to consider greater consistency in selection of participants to ensure repeatability.

It is known that ADHD symptoms and clinical features differ in different ages and this may affect the outcome and response of trials, particularly if outcome measures are taken at different times of the day and across a wide range of age groups.

A further limitation concerns the validity and reliability of the measures of behavioural outcomes. The Conners’ scale used in many studies does not assess certain behaviours such as irritability and sleep disturbances. To overcome this problem, Rowe and Rowe developed a 30-item behavioural rating checklist that was devised from an examination of the clinical histories of 50 suspected reactors. For consistency and repeatability, this type of checklist may be more valid.

The sample size of the studies reviewed was small as the majority were pilot studies. This could impact the statistical significance of outcomes. Although pilot studies are necessary to determine whether a full-scale trial is warranted, the results of such trials are not sufficiently powerful to support firm conclusions.

Consideration needs to be given to whether ethnicity might impact on results as it is known that varying diets according to ethnicity can impact on blood plasma levels of EFA’s. The studies reviewed included populations from Japan, India, UK and USA.

Children’s behaviour varies according to their environment and the reliability of parents as observers and raters of their children’s behaviour may be questionable. It is difficult to conceal trial design from parents and therefore eliminate any parental expectations and subsequently affect a parent’s subjectiveness. Additionally, the timing of observations of behaviour (both duration and time of day) may impact outcome.

None of the studies established or recommended suitable dosages and optimum formulations nor established levels of toxicity or the long-term effects of supplement use. For example, adverse side effects of fish oils include decreased glucose tolerance, diarrhoea, abdominal pain, bloating, nausea, flatulence, fatigue, prolonged bleeding, skin irritation and in large doses, oxidative damage. Clarity on this is important if clinicians are to recommend EFA’s as part of a treatment approach.

Does the funding source affect the interpretation of any study? In the studies reviewed, Joshi et al appeared to be the only study benefiting from a commercial interest by receiving the EFA supplementation from LiTaka Pharmaceuticals. In the other trials there appeared to be no commercial interest that may result in any skew but care needs to be taken to ensure results remain impartial.
3.1 Future Research
Based on the above, future research should consider the following to aid validity and repeatability: * A consistent definition of ADHD * Evaluation of parental bias * Consistency of symptom ratings and outcome measures * Separate results for different age groups * Individual data published as well as group data * Length of trials needs to be greater than 3 months * Minimise placebo effect by using inert placebo * Establish the nutritional status of each child using hair mineral analysis, urine analysis and blood serum analysis both prior to and at the end of each trial * Long-term efficacy of EFA’s

4.0 Conclusion
The aetiology of ADHD is far from coherent and diagnosis is based on a collection of symptom clusters. It seems evident that ADHD does not stem from a single cause. The many variations in behaviours, learning disabilities, impulsiveness and the presence of co-morbid and associated conditions are indicative of biochemical individuality and therefore individual chemical imbalances. This may be as a result of anything from nutritional shortages to exposure to allergens to parental influence and genetics or combinations of any of these factors. To understand the underlying causes of a child suffering from ADHD much detective work must be done to ascertain a suitable treatment protocol.
Research provides clear evidence to support the role of fatty acid supplementation in the management of ADHD but at present, research has not identified the optimal formulation or dosage of EFA’s nor the long-term efficacy of EFA supplementation. However the research does make clear that it is EPA and not DHA that is more effective in reducing the problems with attention, perception and memory that are associated with ADHD so supplements with a high ratio of EPA to DHA are likely to be most effective. GLA should also be supplemented to aid in the reduction of dry skin problems and allergies often associated with ADHD. Finally, the exact mechanism behind the supplements’ effect is still not fully understood but success is most likely in those where there is some evidence of EFA deficiency.

5.0 Nutritional Strategy

5.1 Benchmarking
To provide some form of benchmark and improve motivation for compliance, a checklist of behaviours should be drawn up together with each child’s’ particular problems. This should include all signs and symptoms, sleep disturbances, atopic tendencies and behaviours. Each should be rated on a scale of 0-10 with 0 being no symptoms and 10 being extreme symptoms. This benchmarking sheet should be reassessed prior to each visit and used for monitoring progress.
5.2 Dietary Strategy * Include a diet high in essential fatty acids, both omega-3 and omega-6. This should include 3 portions of oily fish each week, nuts and seeds and cold pressed oils such as flax oil and olive oil. * Balance blood sugar * Remove or reduce as far as possible sugar and refined carbohydrates * Eat little and often with good quality protein at each meal * Reduce exposure to environmental toxins by eating organic foods * Minimise or avoid saturated fats * Minimise or avoid processed and pre-packaged foods
5.3 Lifestyle Strategy * Exercise at least 20-30 minutes each day and fresh air each day * Aim for at least 20 minutes exposure to sunlight each day (avoid the middle of the day, particularly during summer, to avoid sunburn)
5.4 General Supplement programme
A general supplement protocol should ensure the following micronutrients are included. Thought should be given to minimising the number of supplements needed to ensure compliance. Exact dosages have not been provided, as further research is required to establish optimal levels.

* EPA, DHA, GLA * Multi-vitamin and mineral * B-complex * Magnesium * Zinc * Vitamin C * Chromium * Digestive enzymes * Probiotics

6.0 Acknowledgements

My thanks go to ION for their kind support in sourcing material as well as the staff at the British Library. Also to my husband James for providing valuable babysitting services allowing me the time to research and write up my findings. Thanks also to Maria Gendelmann who provided me with the inspiration to research into this fascinating topic.

7.0 References and Bibliography

7.1 Primary References

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Cook, E. H., Stein, M. A, Krasowski, M. D., Cox, N. J., Olkon, D. M., Kieffer, J.E. & Leventhal, B. L. 1995. Association of attention-deficit disorder and the dopamine transporter gene. Am J Hum Genet. 56(4):993-8.

Daley, Dr D. 2006, Attention deficit hyperactivity disorder: a review of the essential facts, Child: Care, Health & Development, 32,2,193-204 Blackwell Publishing Ltd.
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Richardson A.J. Puri, B.K. 2000, The potential role of fatty acids in attention-deficit hyperactive disorder, Prostaglandins Leukot Essent Fatty Acids. 63(1/2):79-87

Richardson, A., Montgomery, P., 2005. The Oxford-Durham Study: A Randomized, Controlled Trial of Dietary Supplementation With Fatty Acids in Children With Developmental Coordination Disorder, Pediatrics 115; 5 466-475

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7.2 Secondary References

Bor, W., Sanders, M. R. & Markid-Dadds, C. 2002. The effects of the Triple P-Positive Parenting Program on preschool children with co-occurring disruptive behaviour and attentional/hyperactive difficulties. Journal of Child Psychology and Psychiatry, 30, 571-578

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7.3 Bibliography

Holford, P. & Colson, D., 2006. Optimum Nutrition for your Child’s Mind, Piatkus, London.

Erasmus, U. 1993. Fats that Heal, Fats that Kill Fourteenth Printing, Alive Books, Burnaby, Canada

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8.0 Appendix

8.1 Glossary Alpha-linolenic acid (LNA,ALA)an 18 –carbon fatty acid with 3 double bonds, positioned between w carbons 3 and 4, 6 and 7, and 9 and 10.
Arachidonic acid (AA) a 20-carbon, 4 times unsaturated fatty acid made from the essential linoleic acid by enzymes in the body, and also found in animal products(meat, eggs, and dairy).It is the parent compound from which series 2 prostaglandins are made.
Autistic spectrum - A psychiatric disorder of childhood characterized by marked deficits in communication and social interaction, preoccupation with fantasy, language impairment, and abnormal behavior, such as repetitive acts and excessive attachment to certain objects. It is usually associated with intellectual impairment
Basal ganglia - the large masses of gray matter at the base of the brain which, if damaged, would impair motor abilities
Conduct Disorder (CD) – A repetitive and persistent pattern of behaviour in which the basic rights of others or major age-appropriate societal norms or rules are violated, as manifested by the presence of three (or more) of the following criteria in the past 12 months, with at least one criterion present in the past 6 months
Cytokine-any of several non-antibody proteins that are released by a cell population on contact with a specific antigen and act as intercellular mediators, as in the generation of an immune response.
Delta-6-desaturase-the enzyme that converts w6 linoleic acid (LA) to gamma linolenic acid(GLA), and the w3 alpha-linolenic acid (LNA) to stearidonic acid(SDA).
Desaturation-the enzymatic process by which 2 hydrogen atoms are removed from neighbouring carbon atoms in a fatty acid chain and at the same time, an additional bond is created between these 2 atoms.
Docosahexaenoic acid (DHA)- a 22-carbon fatty acid with 6 double bonds in its chain. It can be manufactured in healthy human tissue from the essential alpha-linolenic acid (18:3w3).
Dopamine - A monoamine neurotransmitter formed in the brain and essential to the normal functioning of the central nervous system
Double bond- a linking of adjacent atoms in the carbon chain by sharing 2 pairs of electrons between the carbons instead of the usual 1 shared pair of a single bond.
Double blind-a testing procedure, designed to eliminate biased results, in which the identity of those receiving a test treatment is concealed from both administrators and subjects until after the study is completed.
Dyslexia - Dyslexia is an inherited condition that makes it extremely difficult to read, write, and spell in your native language—despite at least average intelligence.
Dyspraxia - impairment of the ability to perform coordinated movements
Eicosanoid - Any of a group of substances that are derived from arachidonic acid, including leukotrienes, prostaglandins, and thromboxanes.
Eicosapentaenoic acid (EPA) a 20- carbon fatty acid with 5 double bonds in its chain. It is the parent substance from which the body makes series 3 prostaglandins.
Leukotriene-physiological active substance that function as mediators of inflammation and as participants in allergic responses.
Linoleic acid (LA)-an 18-carbon fatty acid with 2 double bonds, positioned between w carbon atoms 6 and 7, and 9 and 10.
Neurotransmitter- any of the various chemical substances, such as serotonin that transmit nerve impulses across a synapse.

Omega- symbolized by w, it refers to the methyl end of a fatty acid.
Oppositional Defiant Disorder (ODD) - pattern of negativistic, hostile, and defiant behavior lasting at least 6 months, during which four (or more) of the following are present
Phospholipid - any of the various phosphorous containing lipids that are composed mainly of fatty acids, a phosphate group, and a simple organic molecule.
Placebo- a substance containing no medication and prescribed or given to reinforce a patients expectation to get well.
2. An inactive substance or preparation used as a control in an experiment or test to determine the effectiveness of another drug or substance.
Prostaglandin-any of a group of hormone like substances produced in various tissues that are derived from amino acids and mediate a range of physiological functions, such as metabolism and nerve transmission.
Serotonin - An organic compound, formed from tryptophan and found in animal and human tissue, especially the brain, blood serum, and gastric mucous membranes, and active as a neurotransmitter and in vasoconstriction, stimulation of the smooth muscles, and regulation of cyclic body processes